May 5, 2025<a href="https://parade.com/news/khloe-kardashian-announces-exciting-career-update">Khloe Kardashian</a> took to her Instagram Story on May 4 to show off the scar and indent left on her right cheek after she had a tumor removed back in 2022
The 40-year-old reality star shared the stark difference in her scar from when she first got the surgery and the after photos
where it left a slight indent on her cheek and wrote &quot;Isn&apos;t this crazy&quot; on the overlay text
Kardashian added that she was &quot;grateful that I was able to remove the skin cancer from my face&quot; and thanked her doctor and cosmetic team to help reduce the scar and indentation
The post comes after Kardashian opened up about her need for facial fillers after she had the tumor removed. On October 2024, <a href="https://www.eonline.com/news/1408576/khloe-kardashian-shares-before-and-after-photos-of-facial-injections-after-removing-tumor" rel="nofollow noopener" onclick="return phoenixTrackClickEvent(this, event);" target="_blank">E! News</a> reported that she opened up about the experience on Snapchat and included before and after photos to show off the difference
and the tumor my incredible doctor removed
I ended up with an indentation in the side of my face,&#x201D; Kardashian wrote
&quot;I waited 9 months after surgery to get the indentation filled.&#x201D;
She also addressed why she took so long to address the issue and added that &#x201C;We had to make sure medically everything was safe and my doctor gave me the go ahead.&#x201D;
&#x1F3AC;<a href="https://parade.com/newsletters/daily?utm_source=article&amp;utm_medium=top">SIGN UP for Parade&apos;s Daily newsletter to get the latest pop culture news &amp; celebrity interviews delivered right to your inbox</a>&#x1F3AC;
Kardashian previously opened up about her cancer journey on Instagram back in 2023 and wrote that &quot;I never imagined that this tiny spec would turn into skin cancer
And I can&apos;t fathom what could have possibly happened had I not gone to the doctor to get it looked at.&#x201D; 
She also documented the whole process during season 3 of <a href="https://parade.com/1003866/stefanieparker/kylie-jenner-kim-kardashian-family-net-worth/">The Kardashians </a>and shared her doctor ended up removing more of her cheek than previously anticipated
She also encouraged her fans to be vigilant about their health and especially &#x201C;consistent&#x201D; with their skin cancer check-ups
so I have this scar that created this kind of lump there,” the 46-year-old said of her pregnancy with her now 8-year-old son Joshua
“It looks like a little hot dog bun on my lower belly that will be there forever now.”
saying she never expected to be left with a C-section scar because “nobody told me that would happen.”
“Everybody acted like the cesarean scar would be nothing
I will never look like I did pre-pregnancy.”
While her postpartum scar is something she had to get used to
the actress made it clear that it’s something she’s grateful for
and she frequently reality checks herself to remember that her scar is a reminder of everything she’s experienced thus far
“I had to sort of smack myself and be like
“I think you have those days where you beat yourself up and think
I wish I looked like I did when I was 25.’ But then there’s the reality check of
you’re not 25 and I wouldn’t want to go back to 25 for all the tea in China
I am very grateful for the existence I’ve had thus far
because you’re basically telling the world about your personal perimenopausal journey
‘Do I want everyone to be aware of what my body is doing?’ But then I just felt like
“I know I’m not the only one this happens to and I know that the more we sort of act embarrassed
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Highway 20 is open again following a deadly crash in Island Park Thursday evening
At least seven people, including six foreign nationals, <a href="https://www.eastidahonews.com/2025/05/7-people-dead-following-fiery-crash-in-island-park/">died in the wreck</a> that happened around 7:15 p.m
Here are photos taken by Tony Blakeslee in the East Idaho News Chopper Friday morning showing the aftermath of the incident
<a href="https://www.eastidahonews.com/2025/05/foreign-nationals-killed-in-fiery-island-park-crash-witness-recounts-the-tragedy/">RELATED | Foreign nationals killed in fiery Island Park crash, witness recounts the tragedy</a>
<a href='https://www.eastidahonews.com/submit-a-correction/?headline=GALLERY | Photos from East Idaho News Chopper show massive burn scar, aftermath of fiery crash&url=https://www.eastidahonews.com/2025/05/gallery-photos-from-the-east-idaho-news-chopper-show-aftermath-of-fiery-crash/' target='_blank'>SUBMIT A CORRECTION</a>
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The term “popcorn lung” dates back to the early 2000s when several workers at a microwave popcorn factory <a href="https://pubmed.ncbi.nlm.nih.gov/15332401/">developed lung problems</a> after inhaling a chemical called diacetyl – the same ingredient used to give popcorn its rich
Diacetyl, or 2,3-butanedione, is a flavouring agent that <a href="https://pubmed.ncbi.nlm.nih.gov/27025954/">becomes a toxic inhalant</a> when aerosolised
It causes inflammation and scarring in the bronchioles (the smallest branches of the lungs)
making it increasingly difficult for air to move through
Diacetyl is officially banned in e-cigarettes in the EU and UK, but not in the US and other jurisdictions. And illegal vapes that may not comply with regulations <a href="https://www.bbc.co.uk/news/articles/cnv5e6rjq2zo">are common</a>
Popcorn lung can also be triggered by inhaling other toxic chemicals, including volatile carbonyls like formaldehyde and acetaldehyde – both of which <a href="https://www.ncbi.nlm.nih.gov/books/NBK507184/">have also been detected</a> in e-cigarette vapours
The scariest part? There’s no cure for popcorn lung. Once the lungs are damaged, treatment is limited to managing symptoms. This can include bronchodilators, steroids, and in extreme cases, <a href="https://my.clevelandclinic.org/health/diseases/22590-popcorn-lung-bronchiolitis-obliterans">lung transplantation</a>
prevention – not treatment – is the best and only defence
candy-like flavours come with a chemical cost
E-liquids may contain nicotine, but they also include <a href="https://www.nature.com/articles/s41598-019-39550-2">a chemical cocktail</a> designed to appeal to users
Many of these flavouring agents are approved for use in food
Here’s why that matters: when chemicals are eaten, they go through the digestive system and are processed by the liver before entering the bloodstream. That journey reduces their potential harm. But when <a href="https://doi.org/10.1038/s41598-024-59619-x">chemicals are inhaled</a>
they bypass this filtration system entirely
They go straight into the lungs – and from there
reaching vital organs like the heart and brain within seconds
That’s what made the original popcorn factory cases so tragic. Eating butter-flavoured popcorn? <a href="https://www.cdc.gov/niosh/flavoring-related-lung-disease/about/index.html">Totally fine</a>
With vaping, the situation is even murkier. Diacetyl is not found in all vapes, but its substitutes – acetoin and 2,3-pentanedione – <a href="https://doi.org/10.1038/s41598-024-59619-x">may be just as harmful</a>
<a href="https://doi.org/10.1136/tobaccocontrol-2019-055447">Experts estimate</a> there are over 180 different flavouring agents used in e-cigarette products today
many of these chemicals break down into new compounds – some of which have never been tested for inhalation safety
Even if diacetyl isn’t the sole culprit, cumulative exposure to <a href="https://theconversation.com/whats-in-vapes-toxins-heavy-metals-maybe-radioactive-polonium-210462">multiple chemicals</a> and their byproducts could increase the risk of popcorn lung and other respiratory conditions
it produces a highly toxic gas called ketene
<a href="https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-024-03428-6">More recent studies</a> are raising alarm bells about vaping’s impact on young people’s respiratory health. <a href="https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-024-03428-6">A multi-national study</a> found that adolescents who vape report significantly more respiratory symptoms
and frequency of use were all linked to these symptoms
It’s clear that history is repeating itself
Just as workplace safety rules were overhauled to protect popcorn factory workers
we now need similar regulatory urgency for the vaping industry – especially when it comes to protecting the next generation
Popcorn and vaping might seem worlds apart
but they’re connected by a common thread: exposure to inhaled chemicals that were never meant for the lungs
The danger lies not in what these chemicals are when eaten
but in what they become when heated and inhaled
If we apply the lessons from industrial safety to today’s vaping habits – particularly among young people – we could avoid repeating the same mistakes
and educational campaigns can help minimise the risks
stories like that of the American teen serve as powerful reminders that vaping
despite its fruity flavours and sleek designs
what seems harmless can leave damage that lasts a lifetime
Details of where e-cigarettes containing diacetyl are available and how the two have been scientifically linked have been added to this article
hooded travelling group known as the Seraphites or "Scars."
Now, I'm not going to tell you everything about this group &mdash; if you've played the games, you'll know what happens with them in <a href="https://mashable.com/article/last-of-us-part-2-review" target="_blank" data-ga-click="1" data-ga-label="$text" data-ga-item="text-link" data-ga-module="content_body">The Last of Us Part II</a>
But here's what I can tell viewers of the HBO series about the Seraphites as it happens in Season 2 (with no spoilers beyond what happens in the latest episode on Max)
The first we see of the Seraphites beyond <a href="https://mashable.com/article/the-last-of-us-season-2-trailer-hidden-details" target="_blank" data-ga-click="1" data-ga-label="$text" data-ga-item="text-link" data-ga-module="content_body">the trailer</a> comes in Season 2
We meet a group of people on a forest trail to Seattle (the same road Ellie (Bella Ramsey) and Dina (Isabela Mercred) take later in the episode)
with each member clad in hooded garments branded with the same strange symbol
They're all also marked by the same self-inflicted facial scarring on either cheek (hence their nickname
It looks like these marks are given early in life for members of this group
They're mentioned in episode 4 as the "holy mortification" to join the faction
The Seraphites also prefer melee weapons like their signature hammer or stealth weapons like bows and arrows
and they communicate in a sophisticated whistling language
We don't know much about the Seraphites' spiritual beliefs at this point in the TV series
we know they follow a leader known as "The Prophet."
they're just people that see truths hidden from others and share their truth no matter what the cost," the Seraphite leader (Michael Abbott Jr.) explains to Constance in episode 3
In episode 4, during <a href="https://mashable.com/article/the-last-of-us-washington-liberation-front-abby-season-2-explainerhttps://mashable.com/article/the-last-of-us-washington-liberation-front-abby-season-2-explainer" target="_blank" data-ga-click="1" data-ga-label="$text" data-ga-item="text-link" data-ga-module="content_body">Washington Liberation Front (WLF)</a> leader Isaac Dixon's (Jeffrey Wright) brutal torture and interrogation of a Seraphite (Ryan Masson)
the captive calls Wolves "heretics" and repeats the phrase
the Seraphite in the woods also mentions that The Prophet has been dead for 10 years
and that he "wouldn't count on her to help" their situation
"You know there are even Scars who don&rsquo;t believe she&rsquo;s some magic fairy in the sky
Some of you actually understand she was just a person."
who is this Prophet and what do they preach
Judging by the Seraphite leader's reaction to "Wolves" over what his daughter calls "Demons" as a threat
we think they're more scared of the WLF than they are of Infected
with Ellie and Dina finding the entire group slain at the end of episode 4 &mdash; it's not clear who committed the massacre
both Isaac and his captive accuse the WLF and the Seraphites of "breaking the truce" (we don't know what that is yet)
and Isaac looks amused when he's told his side will lose
"So tell me how are we going to lose?&rdquo;
the rivalry seems territorial &mdash; but from the looks of the WLF's tanks
the odds seem somewhat against the Seraphites
But the Seraphite captive indicates that their ranks are building
"Every day a Wolf leaves you to take the holy mortification and become a Seraphite," they say
"And none of us leaves to become a Wolf." And remember
Ellie and Dina find a WLF man riddled with arrows in a Seattle building and later find a whole group of Wolves hanged and disembowelled
with a Seraphite symbol and message written in their blood on the wall reading "Feel her love." It's pretty gruesome and meant to be found as a terrifying message
referring to the Seraphites' spiritual leader
<a href="https://mashable.com/article/april-27-how-to-play-the-last-of-us" target="_blank" data-ga-click="1" data-ga-label="$text" data-ga-item="text-link" data-ga-module="content_body">Watching The Last of Us and want to play the games? Here's how</a>
Kiora Pharmaceuticals (NASDAQ: KPRX) presented promising preclinical data for KIO-104
The study demonstrated significant reduction in scar formation for treating proliferative vitreoretinopathy (PVR)
the leading complication following retinal detachment surgery
Key findings from the rabbit model study showed: The high dose group (10 μg/eye) completely prevented scar formation in all subjects
The low dose group (1 μg/eye) showed reduced scar formation with only 9 retinal scars in 2 of 6 rabbits
The control group developed 20 retinal scars in 4 of 6 animals
KIO-104 is currently in Phase 2 clinical trials for macular edema treatment in patients with diabetic retinopathy and posterior non-infectious uveitis
Kiora Pharmaceuticals (NASDAQ: KPRX) ha presentato dati preclinici promettenti per KIO-104
Lo studio ha evidenziato una significativa riduzione della formazione di cicatrici nel trattamento della vitreo-retinopatia proliferativa (PVR)
la principale complicanza dopo un intervento di distacco della retina
I risultati chiave dello studio sul modello con conigli hanno mostrato: Il gruppo ad alta dose (10 μg/occhio) ha completamente prevenuto la formazione di cicatrici in tutti i soggetti
Il gruppo a bassa dose (1 μg/occhio) ha mostrato una riduzione della formazione di cicatrici
con solo 9 cicatrici retiniche in 2 su 6 conigli
con una lunghezza media delle cicatrici di 43 ± 16 μm
Il gruppo di controllo ha sviluppato 20 cicatrici retiniche in 4 su 6 animali
con lunghezza media delle cicatrici di 110 ± 28 μm
KIO-104 è in fase 2 di sperimentazione clinica per il trattamento dell’edema maculare in pazienti con retinopatia diabetica e uveite posteriore non infettiva
Kiora Pharmaceuticals (NASDAQ: KPRX) presentó datos preclínicos prometedores para KIO-104
El estudio demostró una reducción significativa en la formación de cicatrices para el tratamiento de la vitreorretinopatía proliferativa (PVR)
la principal complicación tras la cirugía de desprendimiento de retina
Los hallazgos clave del estudio en modelo de conejo mostraron: El grupo de alta dosis (10 μg/ ojo) previno completamente la formación de cicatrices en todos los sujetos
El grupo de baja dosis (1 μg/ ojo) mostró una reducción en la formación de cicatrices
con solo 9 cicatrices retinianas en 2 de 6 conejos
con una longitud media de cicatriz de 43 ± 16 μm
El grupo control desarrolló 20 cicatrices retinianas en 4 de 6 animales
con una longitud media de cicatriz de 110 ± 28 μm
KIO-104 se encuentra actualmente en ensayos clínicos de fase 2 para el tratamiento del edema macular en pacientes con retinopatía diabética y uveítis posterior no infecciosa
Kiora Pharmaceuticals (NASDAQ: KPRX)는 ARVO 2025에서 새로운 DHODH 억제제인 KIO-104의 유망한 전임상 데이터를 발표했습니다
이 연구는 망막박리 수술 후 주요 합병증인 증식성 유리체망막병증(PVR)의 흉터 형성을 현저히 줄이는 효과를 입증했습니다
토끼 모델 연구의 주요 결과는 다음과 같습니다: 고용량 그룹(10 μg/눈)은 모든 피험자에서 흉터 형성을 완전히 차단했습니다
저용량 그룹(1 μg/눈)은 6마리 중 2마리에서 9개의 망막 흉터가 나타나 흉터 형성이 감소했으며
KIO-104은 현재 당뇨병성 망막병증과 후부 비감염성 포도막염 환자의 황반부종 치료를 위한 2상 임상시험 중에 있습니다
Kiora Pharmaceuticals (NASDAQ : KPRX) a présenté des données précliniques prometteuses pour KIO-104
L'étude a démontré une réduction significative de la formation de cicatrices dans le traitement de la rétinopathie vitréo-proliférative (PVR)
la principale complication après une chirurgie du décollement de la rétine
Les résultats clés de l'étude sur modèle lapin ont montré : Le groupe haute dose (10 μg/œil) a complètement empêché la formation de cicatrices chez tous les sujets
Le groupe basse dose (1 μg/œil) a montré une réduction de la formation de cicatrices avec seulement 9 cicatrices rétiniennes chez 2 des 6 lapins
avec une longueur moyenne des cicatrices de 43 ± 16 μm
Le groupe contrôle a développé 20 cicatrices rétiniennes chez 4 des 6 animaux
avec une longueur moyenne des cicatrices de 110 ± 28 μm
KIO-104 est actuellement en essais cliniques de phase 2 pour le traitement de l'œdème maculaire chez les patients atteints de rétinopathie diabétique et d'uvéite postérieure non infectieuse
Kiora Pharmaceuticals (NASDAQ: KPRX) präsentierte vielversprechende präklinische Daten zu KIO-104
Die Studie zeigte eine signifikante Reduktion der Narbenbildung bei der Behandlung der proliferativen vitreoretinopathie (PVR)
der häufigsten Komplikation nach einer Netzhautablationsoperation
Die wichtigsten Ergebnisse der Kaninchenstudie waren: Die Hochdosisgruppe (10 μg/Auge) verhinderte die Narbenbildung bei allen Versuchstieren vollständig
Die Niedrigdosisgruppe (1 μg/Auge) zeigte eine reduzierte Narbenbildung mit nur 9 Netzhautnarben bei 2 von 6 Kaninchen
mit einer durchschnittlichen Narbenlänge von 43 ± 16 μm
Die Kontrollgruppe entwickelte 20 Netzhautnarben bei 4 von 6 Tieren
mit einer durchschnittlichen Narbenlänge von 110 ± 28 μm
KIO-104 befindet sich derzeit in klinischen Phase-2-Studien zur Behandlung von Makulaödem bei Patienten mit diabetischer Retinopathie und posteriorer nicht-infektiöser Uveitis
Kiora's preclinical PVR data shows promise
but represents early-stage research with significant development hurdles ahead
Kiora Pharmaceuticals has presented encouraging preclinical data for KIO-104 in treating proliferative vitreoretinopathy (PVR)
an unmet medical need with no FDA-approved treatments
The in vivo rabbit model demonstrated dose-dependent efficacy
with the high dose (10 μg/eye) completely preventing scar formation in all test subjects - a critical endpoint for this condition
This data expands the potential applications for KIO-104
which is already in Phase 2 clinical trials for macular edema
Multiple potential indications improve the compound's commercial prospects if development succeeds
KIO-104's mechanism as a DHODH inhibitor that suppresses T cell replication provides scientific rationale for its effectiveness in inflammatory eye conditions
investors should recognize this represents very early-stage research
The translational gap between animal models and human efficacy is substantial - preclinical success doesn't guarantee clinical results
No timeline was provided for potential clinical development in PVR
suggesting commercial applications remain distant
The dose-dependent response (complete prevention at high dose
partial at low dose) strengthens confidence in the mechanism
expanding indications for lead compounds is strategically sound
potentially maximizing return on R&D investment if successful
KIO-104's complete prevention of scarring in PVR model addresses significant unmet need
Proliferative vitreoretinopathy represents a serious complication following retinal detachment surgeries
The condition develops when inflammatory processes trigger uncontrolled cellular proliferation
creating fibrous membranes that contract and re-detach the retina
Each subsequent surgery carries diminishing success rates
making PVR a dreaded complication among retinal specialists
The complete prevention of scar formation in the high-dose group is particularly noteworthy
Current management of PVR is purely surgical
requiring complex vitreoretinal procedures often with silicone oil tamponade
A pharmacological approach that could prevent PVR would dramatically improve surgical outcomes
KIO-104's mechanism targeting DHODH (dihydroorotate dehydrogenase) is scientifically sound
it selectively affects rapidly proliferating cells driving the scarring process
The statistically significant reduction in scar length (43±16 μm vs
110±28 μm in controls) and decreased inflammatory cell infiltration suggest both anti-fibrotic and anti-inflammatory effects
doesn't fully recapitulate human disease complexity
The transition from subretinal injection in controlled experimental settings to clinical application faces multiple challenges
intravitreal injections carry risks including endophthalmitis and retinal detachment - ironically the very condition this treatment aims to prevent complications from
Encinitas, California--(Newsfile Corp. - May 5, 2025) - <a rel="nofollow noopener" href="https://api.newsfilecorp.com/redirect/4QjmwhPkWE">Kiora Pharmaceuticals, Inc.</a> (NASDAQ: KPRX)
("Kiora" or the "Company") today announced the results from a preclinical study demonstrating KIO-104 significantly reduced scar formation in an established in vivo model of proliferative vitreoretinopathy (PVR)
The findings further support KIO-104 as a promising therapeutic candidate for inflammatory and proliferative diseases of the retina that lead to vision threatening scarring
effectively prevents proliferative vitreoretinopathy in a rabbit model," was presented by Romana Seda-Zehetner
Preclinical Development at the 2025 Association for Research in Vision and Ophthalmology (ARVO) meeting
"PVR is the leading complication following retinal detachment surgery," said Eric J
"This condition is driven by uncontrolled cellular proliferation
This results in scarring which may lead to repeated retinal detachments as well as progressive and permanent loss of vision
Given the reduction in scar formation and scar size observed in this study and the fact that there are no approved drugs for this condition
further development of KIO-104 in PVR is warranted."
The study evaluated the efficacy of intravitreal delivery at multiple dose levels of KIO-104
in the prevention of PVR-related scar formation
The study used an established retinal detachment model in rabbits that mimics the structural and functional disruption observed in human retinal detachment including glial reactivity
By disrupting an essential molecular pathway for rapidly dividing cells
de novo biosynthesis of pyrimidine nucleotides
KIO-104 significantly reduced scar formation in a dose-dependent manner
Retinal detachments were induced in Dutch Belted rabbits (n=6 per group) by subretinal injection of ~500 &#181;L of 0.25% hyaluronic acid into the right eye
inferior to the optic disc/medullary ray followed by a retinotomy to deliver the test article KIO-104 near the detachment site
animals received an intravitreal injection (50 &#181;L) of either vehicle (group 1) or KIO-104 at 1 &#181;g/eye (low dose
Eyes were collected on day 8 post-induction for histology
and 10 slides per eye taken at regular intervals were evaluated
Tissue sections were stained for vimentin and Isolectin I-B4
Slides were imaged on a widefield fluorescence microscope equipped with plan apochromatic objectives
The outcome measures included (1) the number of glial scars per group (qualitative assessment)
and (3) total count of cells testing positive for I-B4 (macrophages and microglia) per eye
These endpoints were selected to evaluate the extent of fibrosis and inflammation
KIO-104 is a small molecule DHODH inhibitor that works by suppressing T cell replication and function
Suppressing T cell numbers and activity could provide a novel approach to reducing or eliminating the underlying proliferative and inflammatory environment that often leads to scar formation
KIO-104 is being evaluated in a Phase 2 clinical trial in patients with macular edema
an inflammation driven condition secondary to several conditions including diabetic retinopathy and posterior non-infectious uveitis
Kiora Pharmaceuticals is a clinical-stage biotechnology company developing advanced therapies for retinal disease
We target critical pathways underlying retinal diseases using innovative small molecules to slow
KIO-301 is being developed for the treatment of retinitis pigmentosa
It is a molecular photoswitch that has the potential to restore vision in patients with inherited and/or age-related retinal degeneration
KIO-104 is being developed for the treatment of retinal inflammation
and small-molecule inhibitor of dihydroorotate dehydrogenase (DHODH)
In addition to news releases and SEC filings, we expect to post information on our website, <a rel="nofollow noopener" href="https://api.newsfilecorp.com/redirect/jpwgyhLArX">www.kiorapharma.com</a>
and social media accounts that could be relevant to investors
We encourage investors to follow us on X and LinkedIn as well as to visit our website and/or subscribe to email alerts
Some of the statements in this press release are "forward-looking" and are made pursuant to the safe harbor provision of the Private Securities Litigation Reform Act of 1995
These "forward-looking" statements include statements relating to
Kiora's ability to execute on development and commercialization efforts and other regulatory or marketing approval efforts pertaining to Kiora's development-stage products
with such approvals or success may not be obtained or achieved on a timely basis or at all
the sufficiency of existing cash and short-term investments on hand to fund operations for specific periods
the ability to timely complete planned initiatives for 2025
including Phase 2 clinical development of KIO-301 and KIO-104
the completion of enrollment and the timing of topline results from the ABACUS-2 Phase 2 trial
the potential for KIO-301 to be the first treatment options for patients with inherited degenerative diseases like RP
the potential for KIO-104 to reduce inflammation
the timing of topline results from the Phase 2 KLARITY trial of KIO-104
the potential for KIO-104 to apply to other retinal inflammatory diseases
and expected trends for research and development and general and administrative spending in 2025
These statements involve risks and uncertainties that may cause results to differ materially from the statements set forth in this press release
the ability to conduct clinical trials on a timely basis
market and other conditions and certain risk factors described under the heading "Risk Factors" contained in Kiora's Annual Report on Form 10-K filed with the SEC on March 25
2025 or described in Kiora's other public filings
Kiora's results may also be affected by factors of which Kiora is not currently aware
The forward-looking statements in this press release speak only as of the date of this press release
Kiora expressly disclaims any obligation or undertaking to release publicly any updates or revisions to such statements to reflect any change in its expectations with regard thereto or any changes in the events
or circumstances on which any such statement is based
Investors<a rel="nofollow noopener" href="mailto:Investors@kiorapharma.com">Investors@kiorapharma.com</a>
To view the source version of this press release, please visit <a rel="nofollow noopener" href="https://api.newsfilecorp.com/redirect/v17Mvuj5Dk">https://www.newsfilecorp.com/release/250663</a>
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UConn researchers come closer to understanding the implications of scars
While scar formation has been extensively studied
less is understood about the impact of a new scar in the tissue microenvironment
<a href="https://facultydirectory.uchc.edu/profile?profileId=Kshitiz-.">Kshitiz</a>, associate professor of biomedical engineering in the UConn School of Dental Medicine, took a closer look at this scar tissue phenomenon in <a href="https://www.nature.com/articles/s41467-024-52351-0">Nature Communications</a>
accompanied by postdoctoral student Wenqian Du
Kshitiz studied the rare yet life-threatening maternal fetal condition placenta accreta
which occurs when the placenta grows too deeply into the uterine wall
placenta accreta cases are also increasing
The connection between uterine scarring and placenta accreta seems significant
leading the research team to further question how scarring can trigger invasive properties
is that the scar is like an “empty road” and the placenta forms and moves into the scar
Kshitiz is skeptical of this standing theory
“We questioned it because it does not make any sense,&#8221; Kshitiz says
&#8220;If it’s an &#8217;empty road,&#8217; why doesn’t the mother’s womb cells take the empty road
What we found is that it is not an empty road—the scar is full of collagen.”
transforms the endometrium of the mother into an inflammatory state
the researchers created a synthetic scar matrix that mimicked placenta accreta
They uncovered that in the case of placenta accreta
causing calcium to infiltrate the endometrium and cause inflammation
specific molecules start aggressively recruiting placental cells towards themselves in a very invasive manner
The researchers now have a better understanding about the implications of scarring
unlocking the possibility for more studies about scar tissue in the future
“As one of the first major studies on the basic biology of placenta accreta
this discovery opened a whole new area where we can start asking questions about the implications of scars,” says Kshitiz
“By looking at placenta accreta we can learn about the invasive processes caused by scar tissue.”
Last year, Kshitiz was <a href="https://today.uconn.edu/2024/09/researchers-receive-2-5-million-in-nih-funding-to-address-placenta-accreta/">awarded $2.5 million</a> in R01 funding from the Eunice Shriver National Institute of Child Health and Human Development (NICHD) to address the mechanisms driving placenta accreta spectrum
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<a href="/">HOME</a>  <a href="/article/">ARTICLES</a>  	Myanmar’s Earthquake Threatens a Lasting Economic Scar
City residents try to cope with the effects of the 7.7 earthquake as seen on 8 April 2025
(Photo by Magdalena Chodownik / ANADOLU / Anadolu via AFP)
<a href="https://fulcrum.sg/contributors/jared-bissinger/">Jared Bissinger</a>
The recent earthquake in central Myanmar threatens to deepen the country’s economic malaise
These figures likely understate the earthquake’s true impact as casualties and damage outside areas controlled by the State Administration Council (SAC) are underreported due to restrictions
The urgent humanitarian situation following the earthquake presents challenges which will likely persist despite responses from several countries
the earthquake threatens to compound Myanmar’s economic malaise
Unless the SAC rethinks its economic approach
the earthquake aftermath may lead to increased poverty and inflation
and decreased exports and productive capacity,&nbsp;with effects lasting years
The extensive damage and destruction of infrastructure
affect areas under SAC control and under non-state authorities
A historical bridge connecting Sagaing and Mandalay was destroyed and another damaged
limiting traffic to small trucks and blocking access to the river port near Mandalay
This damage leads to disruptions that affect not just earthquake relief, but also important supply chains, especially agriculture. Myanmar’s dry zone is the leading growing area for <a href="https://lift-fund.org/en/myanmar-dry-zone-development-programme-scoping-report-annex-2-seeds-crops-and-livestock-development" target="_blank" rel="noreferrer noopener">pulses, oilseeds, and cereals</a> (such as sesame
Disruptions in logistics that reduce farmers’ access to inputs or raise those prices could affect planting (and harvest)
potentially hurting farmers’ incomes in an already poor
Destruction and loss of life in the capital, Naypyidaw, may cause delays and disruptions to services. Government buildings and staff accommodation were <a href="https://myanmar-now.org/en/news/civil-servants-left-homeless-as-myanmars-capital-reels-from-impact-of-massive-quake/" target="_blank" rel="noreferrer noopener">reportedly hard-hit</a>
with numerous civil servants injured or killed
This could delay services such as food safety certifications for the export of agricultural goods
The SAC’s centralised economic control may exacerbate effects
especially if it affects functions such as trade licensing
and the withdrawal of some international insurers
The direct effects of the earthquake are significant beyond the tragic loss of life
The economic impact of the destruction to property
up just 9 per cent to 9.4 trillion kyats last year from 8.6 trillion kyats in 2021
which has tripled prices over the same time
This revenue position will likely decline further in earthquake-affected areas
The SAC faces similar challenges in borrowing money. Since the coup, most borrowing has been domestic, mainly from the regime’s Central Bank. Myanmar’s banks, businesses, and people are unlikely to buy bonds to support rebuilding for many reasons. For example, <a href="https://www.cbm.gov.mm/sites/default/files/upload2022/QFS_Bulletin_2024_Vol_II.pdf" target="_blank" rel="noreferrer noopener">interest rates</a> are hovering between 7.5 per cent and 8 per cent
which is running at 30-35 per cent (in essence
the SAC has few domestic options to fund rebuilding
though this will stoke inflation and risk exacerbating challenges
International assistance will likely be insufficient for the scale of the problem. International assistance, still incoming, is limited, especially compared to the <a href="https://commission.europa.eu/strategy-and-policy/priorities-2019-2024/stronger-europe-world/donors-conference-turkiye-and-syria_en" target="_blank" rel="noreferrer noopener">7 billion euros mobilised</a> for the 2023 Turkey-Syria earthquake
International lending to the SAC may be subdued
since donors and international financial institutions that have not engaged with the regime since the coup would be reluctant to lend to the regime
There are fears that the SAC’s multiple exchange rate system will reduce the benefits of foreign assistance and help the regime
foreign assistance providers often lost about 10 per cent of their incoming funds due to this system
There are pressing concerns that aid is not reaching areas controlled by non-state authorities
Perhaps the most significant concern is that the SAC might misappropriate earthquake recovery funds for other uses
The bigger question is whether the SAC’s changes to the economic system discourage reinvestment
Myanmar’s economic system no longer rewards productive investment as it did five years ago
especially for marginal businesses that got by with paid-off capital but would be unviable with new capital costs
All these threaten to leave a lasting scar from the earthquake: a central Myanmar with diminished economic capacity and intractable
Jared Bissinger is a Visiting Fellow with the Myanmar Studies Programme at ISEAS – Yusof Ishak Institute
and the Research Lead at Catalyst Economics
Kyaw Yin Hlaing|Kyi Sin|Jared Bissinger|Su Mon Thazin Aung|Moe Thuzar
Copyright © 2025 ISEAS – Yusof Ishak Institute
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Chronic complete spinal cord injury (SCI) is difficult to treat because of scar formation and cavitary lesions
While human iPS cell-derived neural stem/progenitor cell (hNS/PC) therapy shows promise
its efficacy is limited without the structural support needed to address cavitary lesions
Our study investigated a combined approach involving surgical scar resection
decellularized extracellular matrix (dECM) hydrogel as a scaffold
To mitigate risks such as prion disease associated with spinal cord-derived dECM
This material was chosen for its biocompatibility and angiogenic potential
In vitro studies with dorsal root ganglia (DRG) confirmed its ability to support axonal growth
scar resection enhanced the local microenvironment by increasing neuroprotective microglia and macrophages
while reducing inhibitory factors that prevent axonal regeneration
The combination of scar resection and dECM hydrogel further promoted vascular endothelial cell migration
These changes improved the survival of transplanted hNS/PCs and facilitated host axon regeneration
and hNS/PC transplantation has been proven to be a more effective treatment strategy for chronic SCI
no functional recovery occurred and further research is needed to enhance functional outcomes
the management of chronic SCI remains a challenge due to several complex pathological changes that occur over time
and it is difficult to progress to clinical trials in the chronic phase
considering scar formation as a factor in the treatment of chronic complete SCI
alternative approaches need to be developed
providing a more favorable environment for cell transplantation
scar resection could be used as a method to enhance the efficacy of hNS/PC transplantation in chronic complete SCI
considering the possibility that similar effects observed in organs with complex structures could be achieved when applied as a scaffold for SCI
To address the challenges of scars and cavitary lesions in chronic complete SCI
this study aims to evaluate the therapeutic effects of scar resection combined with dECM hydrogel as a scaffold and hNS/PC transplantation
</a>Preparation and characterization of dECM hydrogels and effect of dECM hydrogel substrates on DRG neurite growth
(a) Diagram of the preparation process for kidney-derived dECM hydrogel
(b) SEM images of decellularized kidney hydrogel (8 mg/ml)
(c) Experimental design and images of DRG culture on dECM hydrogel
(d) Tuj1-positive DRG neurites visualized using fluorescently stained images on different hydrogels
(e) Quantification of the neurite length of DRG on collagen I (n = 3) and dECM hydrogel (8 mg/ml (n = 4) and 16 mg/ml (n = 3))
One-way ANOVA followed by the Tukey–Kramer test; N.S.
To further investigate its potential in a more complex and clinically relevant setting
we hypothesized that the decellularized kidney hydrogel can provide a conducive environment for the engraftment and migration of hNS/PCs within the injured spinal cord
</a>Therapeutic effects of dECM hydrogel injection and iPSC-NSPCs for chronic phase complete transected spinal cord
and iPSC-NSPC transplantation in the chronic phase
(b) Representative STEM121-stained sagittal spinal cord sections at 12 weeks post-transplantation
showing non-viable transplanted cells in the epicenter
(c) Immunohistochemical analysis of the magnified boxed area from (b)
illustrating the transplanted cells adhering to the cavity
</a>Therapeutic effects of scar resection: immunohistochemical staining and RNA-seq analysis 7 days post-scar resection in the chronic transected SCI model
(a) Experimental design and images of scar resection in the chronic transected SCI model
(b) Representative midsagittal sections stained for Iba1 and Arg1 in the control and scar resection groups (enlarged images on the right)
(c) Percentages of the neuroprotective microglia and macrophages (Iba1 and Arg1) in the midsagittal sections (n = 4 each)
(d) Heatmap of the axon inhibitor-associated and scar formation-related genes
(e) Enriched GO biological process terms increased in the scar resection group
These findings are consistent with our immunohistochemical data
suggesting that scar resection not only reduces the inhibitory factors but also enhances the immune responses that are conducive to neural repair
</a>Therapeutic effects of scar resection and dECM hydrogel (scaffold)
(a) Experimental design and images of scar resection and dECM hydrogel (scaffold) in the chronic transected SCI model
(b) Heatmap of the angiogenesis-associated genes in the scar resection and scar resection + scaffold groups
(c) Examination of neovascularization at the epicenter using immunohistochemical staining for CD31
(d) Quantification of the CD31+ area in the 1000-μm-wide regions at the epicenter (n = 4 each)
</a>Therapeutic effects of iPSC-NSPC transplantation after scar resection and scaffold
(a) Experimental design and images of iPSC-NSPC transplantation after scar resection and scaffold in the chronic phase
(b) Representative immunohistochemical HNA staining of the midsagittal sections
(c) Quantification of the grafted cell volume in the transplantation and transplantation + scaffold groups (n = 9 each)
e) Representative images of the neural cells differentiated from the graft cells (HNA+)
showing co-staining with ELAVL3/4 (neurons)
</a>Combined therapy promoted the regeneration of neuronal fibers
(a) Examination of the host neurons around the lesion epicenter via immunohistochemical staining for rodent-specific NF-H
(b) Quantification of the NF-H + area: control group (n = 4)
(c) Immunohistochemical analysis of the magnified arrow area from (b)
Representative staining for Tuj and STEM121 in the midsagittal sections
The results of the present study indicate that although the combined therapy resulted in improved cell engraftment and host axon regeneration in the severe environment of chronic complete SCI
further improvements in research design are still needed
This study determined the feasibility of integrating scar resection
and hNS/PC transplantation in treating chronic complete SCI
Axonal growth was assessed in vitro to determine the optimal concentration of hydrogel
dECM hydrogel was used as a scaffold within the cavitary lesion
The presence of scar tissue prevented the successful engraftment of the transplanted cells at the injury epicenter
the surgical removal of these scars reduced the axonal growth inhibitors and promoted the neuroprotective microglia and macrophages
thereby creating an environment conducive to cell transplantation
The improvement in the spinal cord microenvironment
combined with the use of dECM hydrogel that supported angiogenesis
the transplanted cells at the lesion epicenter facilitated the host axonal regeneration
the combination of scar resection and hNS/PC transplantation is considered a promising treatment approach for chronic complete SCI
suggest that these hydrogels may offer a more practical and clinically feasible alternative for scaffold applications
performing scar resection may present a risk of invasiveness
especially in cases involving extensive scar removal
it is crucial to evaluate the extent of scarring using ultrasound or pharmacological agents and to limit the resection area to a minimum
a similar stimulation occurred in the present study
In cases of chronic complete SCI where no residual axons remain
encouraging clinical outcomes have been observed through the promotion of host axonal regeneration
Although the present study observed improvements in the cell engraftment rates and the host’s axonal extension
the recovery of motor function was not achieved
This outcome may be attributed to insufficient graft-derived axonal growth and cell migration at the lesion epicenter where the scaffold was implanted
which likely limited the formation of synapses between the host and graft
Considering that the lesion epicenter is deficient in trophic factors in the present cases of chronic complete SCI
future research should focus on the long-term release of neurotrophic factors or drugs from the scaffold
combining hNS/PC transplantation with scar resection and a decellularized scaffold may be a prospective treatment approach for chronic SCI
further research is needed to improve the functional outcomes
kidneys derived from minipigs (Oriental Yeast Co.
which were further washed in PBS and decellularized with 0.5% sodium dodecyl sulfate (SDS; Fujifilm Wako Pure Chemical Corp.) for 10 h
The decellularized kidney pieces were rinsed with PBS for 4 days at 4 ℃
The rinsing solution was changed four times a day to remove the residual detergent
The tissues were lyophilized and milled into a powder
the resulting powder was enzymatically digested in pepsin/HCl solution to prepare a decellularized kidney-derived collagen solution
This solution was further lyophilized and dissolved in water to prepare the hydrogel solutions at concentrations of 8 and 16 mg/ml
The solution was neutralized to pH 7.4 and subsequently used
Inc.) were prepared according to the manufacturer’s protocol
The DRGs with nerve roots were placed in Hank’s Balanced Salt Solution
After removing the nerve roots under a stereoscopic microscope
the DRGs were seeded onto 8-well plates pre-coated on the previous day with collagen I hydrogel or decellularized kidney hydrogel (8 or 16 mg/ml) (n = 3)
60–80 μl of each type of hydrogel was used: collagen I hydrogel
The chambers were then incubated at 37°C with 92% humidity and 5% CO2 for 15–30 min to ensure gelation
The DRGs were cultured for 5 days on each hydrogel in a Neurobasal medium (Gibco) supplemented with 100 ng/ml of nerve growth factor (NGF)
To perform the immunocytochemical analysis
the cells were fixed with 4% paraformaldehyde for 15 min and then rinsed three times with phosphate-buffered saline (PBS) for 5 min each
The cells were then permeabilized and blocked with 5% skim milk and incubated with a primary antibody for βIII-tubulin (mouse IgG2b
followed by incubation with the corresponding secondary antibodies: Fluor 488 (1:400; Abcam
The immunofluorescence images of the stained sections were obtained using a fluorescence microscope (Leica Microsystems 173 THUNDER Imager Live Cell
Experiments using hiPSCs were approved by the ethics committee of the Keio University School of Medicine (Approval Numbers: 20030092
Informed consent was acquired from the donor from whom the hiPSCs were derived
in accordance with the guidelines outlined in the Declaration of Helsinki
All procedures were conducted following the institutional guidelines
and adult (8-week-old) female athymic nude rats (F344/NJcl-rnu/rnu; weight
The rats were assigned randomly in groups of four per cage (24 × 42 × 24 cm)
The animals were kept under a controlled 12/12-h light/dark cycle with regulated temperature and humidity
and they had free access to food and water
Antibiotics (orbifloxacin; Sumitomo Dainippon Pharma Animal Health
Japan) were administered for 3 days after the surgeries
Urinary retention occurred after spinal cord transection injury
which required bladder expression for 1–2 weeks
Fluid supplementation was provided as needed for rats with poor food intake
All experimental procedures were authorized by the Experimental Animal Care Committee of Keio University
A2022-127) and conducted in compliance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health
the study adhered to the ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) to ensure transparency and reproducibility in the reporting of methods and results
the rats were anesthetized via the subcutaneous injection of 0.4 mg/kg medetomidine hydrochloride
and the dura mater was opened longitudinally
Complete spinal cord transection at this level was then performed using microscissors
A total of 90 rats were used for the in vivo experiments
The exclusion criteria were as follows: rats displaying a BBB score of ≥ 7 within 6 weeks after SCI
rats that developed soft tissue infections
The composition of each group was as described below: TP (+ hydrogel injection) without scar resection series (BBB score of ≥ 7 rats: n = 6
scar resection (BBB score of ≥ 7 rats: n = 3
TP + scaffold (BBB score of ≥ 7 rats: n = 3
the hNS/PCs (1 × 106 cells) were transplanted into the lesion epicenter (cell transplantation: TP group) with or without an 8 μl injection of dECM hydrogel (8 mg/ml)
The hNS/PCs were washed thrice with PBS and suspended in 2 μl of PBS
3.3 × 105 cells/2 μl or 2 μl of PBS were injected into three locations (the epicenter and areas 1 mm rostral and caudal to it) using a 27G metal needle and a microstereotaxic injection system (KDS310; Muromachi-Kikai Co.
the scar tissue (1 mm wide at the lesion epicenter) was resected 42 days after SCI using microscissors
Either 8 μl of PBS (scar resection group) or dECM hydrogel (8 mg/ml) was injected into the gap created by the scar resection (scar resection + scaffold group)
the rat was left undisturbed on a 37 °C warming incubator for about 20 min to confirm gelation
hNS/PCs (1 × 106 cells) were injected into three locations at the lesion epicenter one week after scar resection
the control group used a model without scar resection
exsanguinated transcardially with heparinized saline
The spinal cord tissues were dissected and postfixed in 4% PFA followed by sequential soaking in 10% and 30% sucrose solutions
the tissues were then embedded in a frozen section compound and sectioned at a thickness of 16 μm for the sagittal plane
The sections were then processed for histological analysis using the following primary antibodies: anti-HNA (MAB4383
The sections were then incubated with Alexa Fluor-conjugated secondary antibodies (1:400; Abcam
Picrosirius staining was performed using a staining kit (ScyTek Laboratories
The images were captured using a fluorescence microscope (Leica Microsystems 173 THUNDER Imager Live Cell (LAS X Version: 3.7.5.24914) and BZ-X710 (Keyence
Japan)) or confocal laser-scanning microscope (LSM 780; Carl Zeiss
All the image analyses were conducted using the ImageJ software (version 2.1.0/1.53c)
Behavioral analysis was conducted by two investigators who were blinded to the experimental groups
Three mm-long dissected spinal cord samples that were collected one week after scar resection (49 days after SCI) were used for the analysis
and the samples were pooled in the control (PBS
and scar resection + scaffold (scar resection + dECM hydrogel
The total RNA was extracted using the RNeasy Mini Kit (Qiagen) according to the manufacturer’s instructions
and the mRNA libraries were prepared following the TruSeq Stranded mRNA LT Sample Prep Kit (Illumina
United States) protocol and sequenced on the HiSeq 2500 System (Illumina) to obtain single-end reads
Raw reads were trimmed for quality and read length using Trimmomatic 0.38
Read mapping to the reference genome (rn6) was performed
and transcript counts were obtained using StringTie version 2.1.3b
The read count of each sample was normalized to fragments per kilobase of the transcript per million mapped reads (FPKM) and transcripts per kilobase million (TPM)
A differentially expressed gene (DEG) analysis was conducted on two comparison pairs as requested using DESeq2
The raw count data were normalized with DESeq2’s geometric mean-based size factors
and statistical analysis was carried out using the log2 fold change (FC) and Wald test for each pair
Significant results were identified based on a FC of ≥ 2 or ≤ 0.5 and a raw p value of &lt; 0.05 from the Wald test
GO enrichment analysis was performed using the gProfiler tool (g:GOSt: e111_eg58_p18_f463989d)
The genes with an adjusted p value below 0.05 were considered significant using the Bonferroni test
both graft and lesion volumes were measured in entire sagittal sections
The number of regenerating host neurons positive for rodent-specific NF-H at the injury epicenter was quantified in the sagittal sections (1000 μm-wide regions)
we analyzed all sagittal sections to ensure accurate volume measurements
Quantification of other tissues was performed using the midsagittal section
In cases where the total number of sections was even
or when quantification on the midsagittal section was not feasible
the adjacent section was used for analysis
All statistical analyses were conducted using SPSS Statistics (version 26.0.0.0; Japan IBM
The in vitro and in vivo immunohistochemistry (IHC) staining results of three and five groups were compared using the one-way ANOVA and Tukey–Kramer test
The in vivo immunohistochemistry (IHC) staining results of two groups were compared using the Mann–Whitney U tests
Statistical significance was set at a P value of &lt; 0.05 (as *P &lt; 0.05)
The datasets generated and/or analysed during the current study are available in the GEO repository
Phase I/II study of intrathecal administration of recombinant human hepatocyte growth factor in patients with acute spinal cord injury: A double-blind
randomized clinical trial of safety and efficacy
Intravenous infusion of auto serum-expanded autologous mesenchymal stem cells in spinal cord injury patients: 13 case series
Rho inhibitor VX-210 in acute traumatic subaxial cervical spinal cord injury: Design of the SPinal Cord Injury Rho INhibition InvestiGation (SPRING) Clinical Trial
phase I matched-comparison group trial of safety
and preliminary efficacy of riluzole in patients with traumatic spinal cord injury
First-in-human clinical trial of transplantation of iPSC-derived NS/PCs in subacute complete spinal cord injury: Study protocol
Regenerative medicine strategies for chronic complete spinal cord injury
Comparison of subacute and chronic scar tissues after complete spinal cord transection
Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions
Reducing pericyte-derived scarring promotes recovery after spinal cord injury
A pericyte origin of spinal cord scar tissue
CNS fibroblasts form a fibrotic scar in response to immune cell infiltration
Inflammation drives fibrotic scars in the CNS
Moving beyond the glial scar for spinal cord repair
Identification of a critical sulfation in chondroitin that inhibits axonal regeneration
Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury
The biology of regeneration failure and success after spinal cord injury
Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury
Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growth-associated protein-43-positive fibers after rat spinal cord injury
Human oligodendrogenic neural progenitor cells delivered with chondroitinase ABC facilitate functional repair of chronic spinal cord injury
Chronic spinal cord injury regeneration with combined therapy comprising neural stem/progenitor cell transplantation
Rehabilitative training enhances therapeutic effect of human-iPSC-derived neural stem/progenitor cells transplantation in chronic spinal cord injury
Combined treatment with chondroitinase ABC and treadmill rehabilitation for chronic severe spinal cord injury in adult rats
Transplantation of hUC-MSCs seeded collagen scaffolds reduces scar formation and promotes functional recovery in canines with chronic spinal cord injury
Microenvironmental modulation in tandem with human stem cell transplantation enhances functional recovery after chronic complete spinal cord injury
Anisotropic alginate hydrogels promote axonal growth across chronic spinal cord transections after scar removal
Chronic spinal cord injury repair by NT3-chitosan only occurs after clearance of the lesion scar
Differences in cytokine gene expression profile between acute and secondary injury in adult rat spinal cord
Resection of scar tissue in rats with spinal cord injury can promote the expression of βIII-tubulin in the injured area
Decellularized scaffold as a platform for novel regenerative therapy
An organ-derived extracellular matrix triggers in situ kidney regeneration in a preclinical model
Decellularization of nervous tissues and clinical application
Decellularized extracellular matrix in the treatment of spinal cord injury
Injectable extracellular matrix hydrogels as scaffolds for spinal cord injury repair
Decellularized brain matrix enhances macrophage polarization and functional improvements in rat spinal cord injury
Decellularization optimizes the inhibitory microenvironment of the optic nerve to support neurite growth
Decellularized peripheral nerve supports Schwann cell transplants and axon growth following spinal cord injury
Understanding the role of tissue-specific decellularized spinal cord matrix hydrogel for neural stem/progenitor cell microenvironment reconstruction and spinal cord injury
In vitro study of decellularized rat tissues for nerve regeneration
Injectable extracellular matrix hydrogels contribute to native cell infiltration in a rat partial nephrectomy model
Nerve growth factor improves functional recovery by inhibiting endoplasmic reticulum stress-induced neuronal apoptosis in rats with spinal cord injury
Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells
Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: Oncogenic transformation with epithelial-mesenchymal transition
Grafted human iPS cell-derived oligodendrocyte precursor cells contribute to robust remyelination of demyelinated axons after spinal cord injury
Type IIa RPTPs and glycans: Roles in axon regeneration and synaptogenesis
Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats
Astrocyte scar formation aids central nervous system axon regeneration
Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration
Holl, D. et al. Distinct origin and region-dependent contribution of stromal fibroblasts to fibrosis following traumatic injury in mice. Nat. Neurosci. <a href="https://doi.org/10.1038/s41593-024-01678-4" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41593-024-01678-4">https://doi.org/10.1038/s41593-024-01678-4</a> (2024)
Neurite outgrowth of dorsal root ganglia is delayed and arrested by aspirin
A robust culture system to generate neural progenitors with gliogenic competence from clinically relevant induced pluripotent stem cells for treatment of spinal cord injury
Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains
Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition
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We appreciate the assistance and instruction provided by Drs
all of whom are members of the Spinal Cord Research Team at the Department of Orthopedic Surgery and Physiology
We also thank the JSR-Keio University Medical and Chemical Innovation Center (JKiC) for providing the decellularized hydrogel
Harada for their assistance with the experiments and animal care
This research was supported by the following grants: Research Center Network for Realization of Regenerative Medicine by AMED Japan (grant Nos
the General Insurance Association of Japan Medical Research Grants 2023 and the Japan Society for the Promotion of Science (JSPS) (KAKENHI grant number 23K24464 to N.N)
Keio University Regenerative Medicine Research Center
Laboratory of Small Animal Internal Medicine
Graduate School of Medical and Dental Sciences
and N.N.; All authors read and approved the final manuscript
The authors declare no competing interests
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations
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Munn attributed her decision to the positive response she received from the <a href="https://www.instagram.com/p/DBeDx2LPKEf/?hl=en" target="_blank" rel="noreferrer noopener nofollow">SKIMS campaign</a> she posed for back in October
“Ever since I got such an amazing response from my SKIMS campaign
I stopped doing laser treatment on my scars,” she said
“I had all my appointments and I was doing them—I had all of my appointments for the next year
saying that “putting it out there” and seeing the response from other women who have also had double mastectomies
as well as family members of women who have had this surgery
inspired her to become more proud of her scars
“They’re not something I want to cover up as much anymore because everyone’s been so sweet about it,” she said
she was diagnosed with breast cancer two months later and
had a hysterectomy and a double mastectomy
In October, she posed for SKIMS’ breast cancer awareness month campaign, which helped raise money for the Susan G. Komen breast cancer foundation. While speaking about the photos on <a href="https://x.com/TODAYshow/status/1849073465652818426" target="_blank" rel="noreferrer noopener nofollow">Today</a>
Munn revealed that it was her first time showing her scars since having surgery
“We were in the middle of the shoot and we were changing an outfit that could see more of my scars
and the makeup artist was touching up my scars and we got to my double mastectomy scars and they were just really hard to cover up,” she told host Savannah Guthrie
“And then I was looking in the mirror and I just thought
‘I’m done being insecure about my scars.'”
Munn later spoke more about the photos via Instagram
“Every mark life left behind on my body is proof of how hard I fought,” she wrote
“I hope other women who have been self-conscious about their scars see these photos and feel all the love I’m sending.” 
As the state braces for wet weather arriving this week
the California Governor’s Office of Emergency Services (Cal OES) is reminding people about the dangers of mudslides and debris flows in burn scar areas
The National Weather Service is forecasting significant rain across large areas of the state
Communities in flash-flood prone areas and those still recovering from previous wildfires must prepare for a higher likelihood of mudslides
areas that are often left charred by flames and devoid of vegetation can render the soil non-permeable to rainwater
soils can develop a layer that repels water
due to the charred remnants of organic material
Rainfall that would normally be absorbed by the soil will instead quickly run off
much less precipitation is required to produce a flash flood
and the potential for mudslides and debris flows increases with the loss of organic material that holds the soil in place
locations that are downhill and downstream from burned areas are highly vulnerable to rain that can cause mudslides and debris flows
Californians who live on or below hillsides
especially in areas impacted by recent wildfires
should be aware that precipitation increases the probability of potentially dangerous debris flows
A debris flow is a fast-moving mass of material — slurries of water
and even boulders and trees – that moves downhill by sliding
Debris flows range from a few square yards to hundreds of acres in size
and from a few inches to many dozen feet deep
Imagine trying to walk through a 3-inch deep mass of wet concrete moving at 30 mph
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Scar tissue formation is a hallmark of wound repair in adults and can chronically affect tissue architecture and function
we sought to explore scar-driven imbalance in tissue homeostasis caused by a common
Deep uterine scar is associated with a rapidly increasing condition in pregnant women
characterized by aggressive trophoblast invasion into the uterus
frequently necessitating hysterectomy at parturition
recapitulating PAS-like invasive phenotype
showing that scar matrix activates mechanosensitive ion channel
through glycolysis-fueled cellular contraction
Piezo1 activation increases intracellular calcium activity and Protein kinase C activation
This inflammatory transformation of decidua leads to production of IL-8 and G-CSF
chemotactically recruiting invading trophoblasts towards scar
Our study demonstrates aberrant mechanics of scar disturbs stroma-epithelia homeostasis in placentation
relatively less is understood about the effect of existing scar or fibrosis on tissue homeostasis
We hypothesize that uterine scarring leads to a failure of normal decidualization in its proximity
which causes abnormal interaction between the decidua and the EVTs
This aberrant communication between decidua and EVTs leads to failure of maternal tissues to restrain the invading trophoblasts
suggesting that the mechanisms we identify are implicated in other scar or fibrosis-related pathologies
our data suggest that mechanical cues presented by the scar matrix alter dESF state to chemotactically recruit EVTs preferentially towards the scar
</a>A Representative immunohistochemistry images of maternal-fetal interface (MFI) tissue sections from PAS patients showing EVTs present in decidual regions proximal
and distal to collagenous acellular scar regions; Quantification of EVT density in either region in right panel; n = 5 and 3 for regions proximal and distal to scar respectively; EVTs and dESFs are marked with HLA-G (red; arrow heads) and Vimentin (green)
B KEGG pathway enrichment analysis showing signaling pathways differentially enriched in dESFs on Scar and Physio; C Gene ontologies related to inflammation enriched in dESFs on Scar and Physio
D Representative immunofluorescence images showing RelA (p65) location in dESFs on Physio and Scar; Quantification showing percentage of dESF with nuclear RelA in lower panel
n = 4 and 5 fields of view for Physio and Scar
E Immunoblot showing abundance of phosphorylated RelA (p-RelA) in dESFs on Physio and Scar
Experiments are repeated twice with similar results
F ANSIA based analysis of stromal invasion of primary EVTs into dESF compartment with scrambled
or gene silenced for NFKB1; n = 10 and 13 locations for scrambled and NFKB1KD
G Representative immunohistochemistry images of MFI tissue sections from PAS patient showing RelA intracellular localization in decidual regions proximal
and distal to scar; H Quantification of percentage of decidual fibroblasts with nuclear RelA; n = 3 and 6 locations for distal and proximal
I Pearson correlation test shows Pearson coefficient (r) of EVT number per field of view
and ratio of decidual fibroblasts with nuclear and cytoplasmic RelA and total decidual fibroblasts in PAS MFI tissue sections; a two-tailed p-value for Pearson’s r is calculated; n = 8 field of views
H are showing as mean ± s.d.; statistical significance is determined by unpaired two-tailed t-test (**p &lt; 0.01
Source data are provided as a Source Data file
aberrant matrix on scar results in activation of NF-κB signaling in decidual fibroblasts
these data showed that increased contractile force on Scar activated Piezo1-mediated Ca2+ signaling
contributing to increased IL-8/G-CSF production
</a>A Kinase enrichment analysis (KEA3) predicted top activated kinases in Scar vs Physio dESFs using Fisher’s Exact Tests (pval) on RNAseq data
B Substrate immunoblot of PKC activated targets in ESFs decidualized on Physio and Scar matrices
as well as (C) in dESFs on Scar treated with 4 µM GsMTx-4 and 2 µM PKC inhibitor Gö6983 for 4 h
D Immunoblot showing abundance of phosphorylated RelA (p65) in dESFs on Scar without
and after overnight treatment with 2 µM Gö6983
as well as (E) 10 nM PKC activator Phorbol 12-myristate 13-acetate (PMA)
and 3 µM Yoda1 plus 5 µM Gö6983; GAPDH is loading control in D
Experiments are one of the two biological replicates with similar results
F ELISA based measurement of IL-8 and G-CSF concentrations in supernatant of dESFs on Scar after overnight treatment with 2 µM Gö6983 and 10 nM PMA; n = 3 replicates; p = 0.01
G ELISA-based measurement of IL-8 and G-CSF concentrations in supernatant of dESFs on Scar after treatment with 3 µM Yoda1
and 3 µM Yoda1 plus 5 µM Gö6983; n = 3 replicates; p = 0.02
Data in F and G are showing as mean ± s.d.; statistical significance is determined by unpaired two-tailed t-test (*p &lt; 0.05
and ****p &lt; 0.0001; ns not significant)
these data suggest key role of calcium driven PKC signaling
as well as MafG-mediated transcription in regulating the inflammatory transformation of decidual fibroblasts on Scar
promoting chemotactically driven EVT invasion
Mechanistic studies are unavailable because association of scar with invasive processes is small
Potential emergence of neoplasm is also a relatively smaller concern with scars which typically emerge from significant trauma
Our findings differ from the currently held hypothesis explaining PAS pathogenesis
which posits that the acellular scar presents an empty pavement for the EVTs to rapidly invade into
A counterargument to the hypothesis is that any acellular scar region which is penetrable for EVTs is also by definition
penetrable to numerous other maternal cell types
if scar matrix is merely a spatial void which gets filled in post implantation
it should have been re-celluarized before implantation
which were not invaded by maternal or placental cells
residual decidua proximal to these acellular scar regions contained more HLA-G+ EVTs compared to distal decidua
Confirming our hypothesis even more was the observation that decidual regions proximal to scar contained maternal decidual cells with nuclear RelA
and also expressed higher Piezo1 levels than distal regions
We therefore posit that the altered mechanical cues presented by the scar matrix transform the fibroblasts into an inflammatory state
which then promote EVT recruitment via chemotactic cues
It is possible that once EVTs are recruited more than optimally proximal to the scar
other mechanisms may promote deeper invasion
including increased contractile force generation by the fibroblasts at the scar
can play a critical role in transformation of the decidual cells into inflammatory fibroblasts
We found that scar-like matrix resulted in increased expression and abundance of MafG
suggesting mechanoregulation of MafG activity
The link from cellular mechanosensation to MafG mediated inflammatory response may be more general in other mechanically active tissues
PAS is a rapidly growing concern during pregnancy
with devastating effects on maternal health and future reproductive plans
We used this model of scar owing to its standardized presentation in many women
which has also resulted in a clearly identifiable pathology caused by the scarring
deep scars resulting from trauma to other tissues are also common
and similar scar-mediated inflammatory transformation of the resident fibroblasts can contribute to pathology
Our work presents a mechanistic understanding of the long-term scar-induced effect on fibroblast phenotype
as well as avenues to prevent fibroblast inflammation
a harbinger of various chronic pathologies
Isolated ESFs were maintained in phenol red free DMEM/F12 50:50 containing 25 mM glucose
and supplemented with 10% charcoal-stripped fetal bovine serum (Thermo Fisher)
ESFs were treated with 0.5 mM 8-bromo-cyclic 3′,5′-(hydrogen phosphate)-adenosine (Cayman Chemicals) and 1 µM Medroxyprogesterone acetate (Cayman Chemicals) in DMEM/F12 medium with 2% FBS for 4 days
Chemical perturbations are implemented during the last day of decidualization unless otherwise stated
cells seeded on Physio and Scar matrices were embedded in 1 mg/ml type I collagen from rat tail (Thermo Fisher) and incubated at 37 °C for 1 h to allow 1 mm thick collagen gel formation
Decidualization medium was then added without disturbing the matrices
decidual basalis was separated from the maternal side of the termed placenta tissue and then minced
and DNase I was added to equal volume of minced tissue
The mixture was fixed on a shaker with 500 rpm at 37 °C for 1 h
Equal volume of culture medium containing 20% FBS was added to the mixture to block the digestion
The mixture was then centrifuged at 340 × g for 5 s to remove the undigested tissue
The supernatants containing isolated cells were collected and directed plated into flasks coated with 20 µg/ml fibronectin
non-attached cells were gently washed away
The isolated placental cells were then detached and blocked with 5% goat serum and 1% BSA at room temperature for 20 min
before stained with Alex Flour 488 conjugated human anit-HLA-G antibody (Biolegend
HLA-G+ cells were sorted using flow cytometry (BD FACSAria II sorter) and maintained in DMEM/F12 with 10% FBS
Human extravillous trophoblast cell line-HTR8/SVneo derived from first trimester of pregnancy were obtained from ATCC (CRL-3271)
Cells were cultured in RPMI medium supplemented with 10% FBS and 1% antibiotic/antimycotic (Gibco)
HTR8 were stably transduced with plasmid expressing H2B-bound mCherry driven by CMV promoter unless otherwise stated
Endometrial tissue samples from patients were cut into 1 cm × 1 cm × 0.4 cm pieces and half-embedded in low-melting agarose and then immersed in RPMI medium
Mechanical indentation was implemented using Mach-1 micromechanical testing system (Biomomentum) mounted with an indentation probe with a 2 mm bead at the tip
The indentation speed is 50 µm/s and the indentation depth is 500 µm
At least 20 locations were measured per sample
or fabricated from a silicone mold fabricated using electron-beam lithography followed by deep-reactive ion etching
Saline-activated coverslips for gel attachment were cleaned with ethanol and sonication
and activated with 0.5% glutaraldehyde and 0.5% (3-Aminopropyl)triethoxysilane (Sigma Aldrich)
Polyacrylamide precursor solution containing 10% acrylamide and 0.3% bis-acrylamide (Bio-Rad) was degassed for 30 min and mixed with 0.1% tetramethylethylenediamine and 0.1% ammonium persulfate (Sigma Aldrich) before sandwiched between silane-activated coverslips and PUA molds for 20 min
The physiological matrices were fabricated following similar procedures but with precursor containing 5% acrylamide and 0.12% bis-acrylamide sandwiched between saline-activated and Rain-X coated coverslips
The crosslinked gels were peeled off and coated with 40 μg/ml (Physio) and 100 μg/ml (Scar) collagen type I using sulfo-SANPAH (Thermo Fisher) overnight at 4 °C
Gels were sterilized under UV for at least 2 h before cell seeding
Tissue slides from PAS patients were stained with Picrosirius red
Collagen signals in the regions of interest were obtained after color deconvolution using ImageJ
Collagen orientation was quantified using OrientationJ plugin in ImageJ
AFM imaging of the surface topography of the Scar matrix was performed using Asylum Research Cypher AFM in PBS
A 0.08 N/m triangle PNP-TR probe (NanoWorld) was used
a custom-made polydimethylsiloxane stencil was placed on the nanogrooves-patterned substrate
The device was kept in a vacuum to remove air bubbles under the stencil
HTR8-mcherry were seeded at a density of 5 × 105 cells and allowed to attach to the substrate overnight
The stencil was removed carefully using blunt-end tweezers
The unlabeled stromal cells were seeded at a density of 5 × 105 to fill and attach that area covered by the stencil before
The unattached cells were washed off after 5 h of incubation
Invading cells were imaged by using time-lapse microcopy every 1 h for 24 h
The area occupied by the invading cells was traced manually using Region of Interest (ROI) panel in the Fiji software
The normalized extent of invasion was calculated by dividing total \(\delta {Area}(t)\) (of invading cells) by the length of the initial trophoblast–stroma interface
Automated peak identification was performed on the converted ROIs to a one-dimensional mask
The masks’ profiles were smoothed by moving the average over 20 pixels
The mean signal to either side of every point with 40 pixels each
A peak also was identified when the boundary of smoothed profile was larger than both side average
the number of invasive forks as well as the distribution of the depth of invasion in stromal monolayer were measured
1 mg/ml collagen solution were casted on ESFs and incubated at 37 °C for 1 h to form a gel layer with thickness of 1 mm
HTR8 spheroids prepared as aforementioned were suspended in 1 mg/ml collagen solution and plated on the 3D decidualization ESFs and incubated at 37 °C for 1 h to allow spheroid settle down and gel formation
dESF monolayer and HTR8 nuclear locations were recorded by Zeiss Apotome 3D scanning
Distance between each individual HTR8 nucleus and each dESF layer were calculated after deconvolution and nuclear segmentation
All animal protocols were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Connecticut Health Center before study initiation
All experiments were performed in accordance with IACUC guidelines
and abides by the ARRIVE guidelines for reporting animal experiments
temperature-controlled (22 ± 2 °C) and humidity-controlled (55 ± 5%) environment and fed a standard chow diet
Mice were anaesthetized with isoflurane and cells were subcutaneously injected into the mice
Mice were euthanized with carbon dioxide and Matrigel plugs
Decidua cells from PAS patients at the adherent and non-adherent sites
Genes of interest were visualized using violin plots with t-test
Correlation analysis of gene expression was performed using the Spearman method
Pathway enrichment analysis for differential expression genes in decidua cells was performed using GSEA on hallmark pathways
Gene silencing was achieved by using pre-prepared synthetic sgRNA (IDT)
ESFs were transfected with sgRNA and TrueCut Cas9 protein (Invitrogen) using Lipofectamine CRISPRMAX transfection reagent (Invitrogen) or Neon NxT Electroporation System (Invitrogen)
a cocktail was created by mixing (i) solution1: 24 µl Opti-MEM and 1 µL CRISPRMAX
1.5 µL CRISPRMAX Plus reagent and remaining Opti-MEM to make a 30 µL solution
Solution 1 and 2 were mixed and incubated for 10 min before being drop dispensed into one well of a 24-well plate containing cells at 50% confluency in culture medium
Cells were used after 48 h of transfection
and observation completed within 48 h thereafter
Electroporation based CRISPR/Cas9 gene editing was performed following the manufacturer’s guideline for fibroblast gene editing (1650 V/20 ms/1 pulse)
HTR8-mCherry cells were cultured in conditioned dESF medium mixed with fresh medium (1:1) and monitored using microscope for at least 9 h and time-lapse images were taken every 20 min
Single cell tracking was then performed using Fiji/ImageJ TrackMate plugin
Cell migration velocity and distance were quantified for individual cell
Cell trajectories were plotted using ibidi Chemotaxis and Migration Tool V2.0
3D Chemotaxis of HTR8-mCherry was performed using μ-Slide Chemotaxis (ibidi) following the manufacturer’s instruction
3 × 106 cells/ml HTR8 were resuspended in 1 mg/ml collagen type I
Six microliters of cell suspension was loaded into the microchannel with a width of 1 mm and a height of 70 μm
For the two chambers separated by the microchannel
one chamber was loaded with 100 ng/ml recombinant human IL-8 or G-CSF (Proteintech)
and the other chamber was loaded with vehicle
Cell migration trajectories were quantified as aforementioned
Rayleigh test was performed to determine the statistical significance of chemotaxis
Rayleigh p &lt; 0.05 is considered chemotaxis
F-actin images were enhanced using the Contrast Limited Adaptive Histogram Equalization (CLAHE) filter
then masks of actin filaments of individual cells were generated by the threshold function in ImageJ
Mean intensity value of actin was then quantified
Pre-warmed glucose-free DMEM (Thermo Fisher) with 10% FBS and 400 µM of 2-NBDG (Invitrogen) were added to cells on traction force gel at 37 °C and 5% CO2 for 30 min
and mounted on microscope for live cell imaging
GCamP6f probe was obtained from Addgene and transferred to pENTR™/SD/D-TOPO® vector (ThermoFischer Scientific)
LR reaction was used to transfer it to pLEX_307 vector (Addgene plasmid # 41392)
The virus was generated in HEK293-FT cells using packaging mix of three plasmids (pLP1
and pLP/VSVG) from ThermoFisher Scientific
The virus was concentrated using PEG-it™ Virus Precipitation Solution (SBI biosciences) and MOI was calculated using qRT-PCR
Cells were transduced using Polybrene (Millipore Sigma) using MOI 5 (multiplicity of infection)
AAT Bioquest) were premixed with 0.04% Pluronic-F127 (Sigma Aldrich) in serum-free medium and loaded to cells for 20 min
Calcium activities were imaged 20 min after dye washing out
time-lapse images were taken using light with low intensity and short exposure time at 1 Hz for 2 or 3 min
Photo bleaching of FLuo4-AM was corrected using the Bleaching Correction plugin in ImageJ
To image calcium activities for cells treated with blebbistatin
Calbryte 590-AM (AAT Bioquest) was used as a calcium indicator to avoid autofluorescence of Blebbistatin (Sigma Aldrich)
Seahorse XF analyzer (Agilent Technologies) was used to monitor cellular energetics<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 61" title="Afzal, J. et al. Cardiac ultrastructure inspired matrix induces advanced metabolic and functional maturation of differentiated human cardiomyocytes. Cell Rep. 40, 111146 (2022)." href="/articles/s41467-024-52351-0#ref-CR61" id="ref-link-section-d457249881e3116">61</a>
Cells were dissociated and cultured in a 96 wells XF plate
and 6 replicates were used for each condition
Oxygen consumption rate (OCR) was used to estimate oxidative phosphorylation while change in extracellular acidification rate (ECAR) was used to estimate glycolysis
Basal rates show changes in O2 or pH in the absence of any added compounds or metabolic inhibitors
ATP synthase was inhibited using Oligomycin (4 µM)
and rotenone (2 µM) and antimycin A (2 µM) was used to inhibit complex 1/3 respectively
Uncoupling was achieved using FCCP (500 nM) to estimate maximum respiratory capacity
and iodoacetate (100 µM) was used to inhibit glycolysis (glyceraldehyde-3-phosphate dehydrogenase)
Respiratory rates were normalized to DNA content using Picogreen DNA assay (Thermo Fisher Scientific) following manufacturer’s instructions
Human IL-8 (Biolegend) and G-CSF (SinoBiological) kits were used to test measure secreted IL-8 and G-CSF levels from dESFs culture supernatants according to the manufacturer’ instructions
a 96-well plate was coated with capture antibody overnight at 4 °C
followed by sample incubation for 2 h and detection antibody incubation for 1 h
Then the plate was incubated with Avidin-HRP for 30 min
10 mg/ml Tetramethylbenzidine for 15 min before 2 N H2SO4 was added to the plate
The absorbance signals were read using SpectraMax i3x multi-mode microplate reader (Molecular Devices) at 450 nm and background at 570 nm
IL-8 and G-CSF concentrations were quantified using SoftMax Pro
pLenti6-H2B-mCherry was obtained from Addgene (#89766)
Lentiviral particles prepared with 3rd generation packaging plasmids
as well as sorted with FACS for reduced heterogeneity of mCherry expression in the cell cultures
All cell invasion and migration assays and traction force microscopy were performed using Zeiss Axio Observer Z1 microscope with PECON Incubation System S for live cell imaging
3D imaging and deconvolution was performed using ZEISS Apotome.2 and Zen Blue 2.6 Pro software
Whole slide scanning was performed using ZEISS Axioscan 7
Statistical analyses were performed using GraphPad Prism
Two-tailed unpaired Student’s t-test was implemented for statistical significance of the differences between two groups
One-way ANOVA was performed followed by Tukey test if multiple groups were presented in a graph
Pearson correlation coefficients were provided together with two-tailed statistical significance values
All bar graphs show mean values with standard deviation as error bars
Statistical significance levels are defined as *p &lt; 0.05
P values higher than 0.05 are considered non-significant
Further information on research design is available in the <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-024-52351-0#MOESM16">Nature Portfolio Reporting Summary</a> linked to this article
The RNAseq data generated in this study have been deposited in the NCBI GEO database under accession code GSE269722. The publicly available single-cell sequencing data used in this study are available in the GEO database with GEO accession number GSE212505. <a data-track="click" data-track-label="link" data-track-action="section anchor" href="/articles/s41467-024-52351-0#Sec37">Source data</a> are provided with this paper
Extracellular matrix reorganization during wound healing and its impact on abnormal scarring
Mechanisms of pathological scarring: Role of myofibroblasts and current developments
Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies
Placenta accreta spectrum: a review of pathology
American College of Obstetricians and Gynecologists &amp; Society for Maternal-Fetal Medicine
Uterine body placenta accreta spectrum: a detailed literature review
Placenta accreta and cesarean scar pregnancy: overlooked costs of the rising cesarean section rate
Placenta previa/accreta and prior cesarean section
Placenta accreta: incidence and risk factors in an area with a particularly high rate of cesarean section
Trends and projections of caesarean section rates: global and regional estimates
Global epidemiology of use of and disparities in caesarean sections
&amp; for the FIGO placenta accreta diagnosis and management expert consensus panel FIGO consensus guidelines on placenta accreta spectrum disorders: epidemiology
Epidemiology of placenta previa accreta: a systematic review and meta-analysis
The new world of placenta accreta spectrum disorders
Classification and reporting guidelines for the pathology diagnosis of placenta accreta spectrum (PAS) disorders: recommendations from an expert panel
Recent trends in placenta accreta in the United States and its impact on maternal-fetal morbidity and healthcare-associated costs
Placenta accreta spectrum: pathophysiology and evidence-based anatomy for prenatal ultrasound imaging
Evolution of placental invasion and cancer metastasis are causally linked
The coevolution of placentation and cancer
Regulation of placental extravillous trophoblasts by the maternal uterine environment
Molecular changes on maternal–fetal interface in placental abruption—a systematic review
Histopathological evaluation of cesarean scar defect in women with cesarean scar syndrome
Surgical pathology of the lower uterine segment caesarean section scar: is the scar a source of clinical symptoms
Gynecological and obstetrical outcomes after laparoscopic repair of a cesarean scar defect in a series of 38 women
Short-term and long-term effects of caesarean section on the health of women and children
Cesarean scar pregnancy is a precursor of morbidly adherent placenta
Caesarean section scar causes myometrial hypertrophy with subsequent heavy menstrual flow and dysmenorrhoea
A framework for advancing our understanding of cancer-associated fibroblasts
A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion
Alterations of the extracellular matrix in ovarian cancer studied by Second Harmonic Generation imaging microscopy
Evaluation of the uterine scar stiffness in women with previous Cesarean section by ultrasound elastography: A cohort study
Evolution of the mammalian placenta revealed by phylogenetic analysis
Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis
Tracing the cis-regulatory changes underlying the endometrial control of placental invasion
Modes of cancer cell invasion and the role of the microenvironment
The extracellular matrix modulates the hallmarks of cancer
Role of tissue stroma in cancer cell invasion
Suppression of TGFβ-mediated conversion of endothelial cells and fibroblasts into cancer associated (myo)fibroblasts via HDAC inhibition
RUNX1 is a promising prognostic biomarker and related to immune infiltrates of cancer-associated fibroblasts in human cancers
p62-Induced cancer-associated fibroblast activation via the Nrf2-ATF6 pathway promotes lung tumorigenesis
Metastatic transition of pancreatic ductal cell adenocarcinoma is accompanied by the emergence of pro-invasive cancer-associated fibroblasts
Placenta accreta spectrum disorder at single-cell resolution: a loss of boundary limits in the decidua and endothelium
Interleukin-8 (CXCL8) stimulates trophoblast cell migration and invasion by increasing levels of matrix metalloproteinase (MMP)2 and MMP9 and integrins alpha5 and beta1
M2 macrophage-derived G-CSF promotes trophoblasts EMT
invasion and migration via activating PI3K/Akt/Erk1/2 pathway to mediate normal pregnancy
Discoveries in structure and physiology of mechanically activated ion channels
Piezos thrive under pressure: mechanically activated ion channels in health and disease
Mechanical sensitivity of Piezo1 ion channels can be tuned by cellular membrane tension
Disruption of membrane cholesterol organization impairs the activity of PIEZO1 channel clusters
Phosphorylation of NF-κB and IκB proteins: implications in cancer and inflammation
The regulation of NF-κB subunits by phosphorylation
Single-cell reconstruction of the early maternal–fetal interface in humans
Spatial multiomics map of trophoblast development in early pregnancy
Cardiac ultrastructure inspired matrix induces advanced metabolic and functional maturation of differentiated human cardiomyocytes
Traction force microscopy of migrating normal and H-ras transformed 3T3 fibroblasts
PFKFB3 inhibitors as potential anticancer agents: Mechanisms of action
Mechanical regulation of glycolysis via cytoskeleton architecture
From calcium to NF-κB signaling pathways in neurons
Regulation of the MAFF transcription factor by proinflammatory cytokines in myometrial cells1
MAFG-driven astrocytes promote CNS inflammation
Parallels between vertebrate cardiac and cutaneous wound healing and regeneration
Making better scar: emerging approaches for modifying mechanical and electrical properties following infarction and ablation
Scar carcinoma of the lung: a historical perspective
Risk of cancer development in patients with keloids
Marjolin ulcer: an observational epidemiological study from a Tertiary Care Centre in India
Marjolin’s ulcer in chronic wounds – review of available literature
Up-regulated cytotrophoblast DOCK4 contributes to over-invasion in placenta accreta spectrum
Extravillous trophoblast invasion in placenta accreta is associated with differential local expression of angiogenic and growth factors: a cross-sectional study
Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity
Activation of protein kinase C inhibits synthesis and release of decidual prolactin
Protein kinase Cα (PKCα) acts upstream of PKCθ to activate IκB kinase and NF-κB in T lymphocytes
The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG island methylator phenotype
Separation and characterization of epithelial and stromal components in vitro
gprofiler2 – an R package for gene list functional enrichment analysis and namespace conversion toolset g:Profiler
Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles
ShinyGO: a graphical gene-set enrichment tool for animals and plants
KEGG: integrating viruses and cellular organisms
KEA3: improved kinase enrichment analysis via data integration
Dissection of mechanical force in living cells by super-resolved traction force microscopy
pyTFM: A tool for traction force and monolayer stress microscopy
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Funding for project was obtained by Startup provided by UCH Department of Biomedical Engineering to Kshitiz
PI: Kshitiz) and K99 fellowship by NICHD (K99HD105973
The authors thank Joerg Nikolaus and Yale West Campus Imaging Core for their kind support on AFM imaging
performed bioinformatics and computational analyses; N.R.G.
provided clinical samples and coordinated with pathology
supervised the project and wrote the manuscript
Nature Communications thanks the anonymous
reviewer(s) for their contribution to the peer review of this work
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations
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DOI: https://doi.org/10.1038/s41467-024-52351-0
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Spinal cord injury (SCI) leads to fibrotic scar formation at the lesion site
yet the heterogeneity of fibrotic scar remains elusive
Here we show the heterogeneity in distribution
and function of fibroblasts within fibrotic scars after SCI in mice and female monkeys
Utilizing lineage tracing and single-cell RNA sequencing (scRNA-seq)
we found that perivascular fibroblasts (PFs)
rather than pericytes/vascular smooth cells (vSMCs)
primarily contribute to fibrotic scar in both transection and crush SCI
Crabp2 + /Emb+ fibroblasts (CE-F) derived from meninges primarily localize in the central region of fibrotic scars
demonstrating enhanced cholesterol synthesis and secretion of type I collagen and fibronectin
perivascular/pial Lama1 + /Lama2+ fibroblasts (LA-F) are predominantly found at the periphery of the lesion
expressing laminin and type IV collagen and functionally involved in angiogenesis and lipid transport
These findings may provide a comprehensive understanding for remodeling heterogeneous fibrotic scars after SCI
This suggests that the compositions and functions of fibrotic scar tissues are heterogeneous after SCI
Although lineage tracing strategies have been employed to investigate the origin of fibrotic scar tissue after SCI
the origin of myofibroblasts is still controversial due to the absence of recognized marker genes that distinguish these cells
The difference between meningeal and perivascular fibroblasts in both penetrating and non-penetrating SCI remains under debate
we took used of PDFGRβ-CreER in combination with the R26-TdTomato (TdT) reporter to examine the heterogeneity of pericytes/vSMCs and fibroblasts in fibrotic scar tissue after SCI
Immunostaining and single-cell RNA sequencing (scRNA-seq) results showed that PDGFRβ+ cells were distributed in the perivascular spaces and meninges of the intact spinal cord
ScRNA-seq of spinal cords from mice and monkeys revealed that PDGFRβ+ cells were pericytes/vSMCs and fibroblasts (MFs and PFs) with specific gene signatures
Combined with lineage tracing of fibroblasts (by Col1a2-CreER::R26-TdT mice)
pericytes/vSMCs (by Myh11-CreER::R26-TdT and NG2-CreER::R26-TdT mice) and meningeal fibroblasts (by Crabp2-CreER:: R26-TdT mice)
we found that the fibrotic scars formed after transection SCI and crush SCI were derived from PFs and MFs rather than pericytes/vSMCs
Crabp2+/Emb+ fibroblasts (CE-F) derived from meninges and perivascular/pial Lama1+/Lama2+ fibroblasts (LA-F) exhibited different spatial distributions and functional heterogeneity in the lesion sites of both mice and monkeys
The heterogeneous characteristics of fibrotic scars revealed in our study might help to develop strategies for remodeling fibrotic scars after SCI
</a>A Schematic showing the protocol tracing PDGFRβ progeny cells with PDGFRβ-CreER::R26-TdT mice
B Representative images showing that PDGFRβ-TdT+ cells (red) are present in the perivascular spaces and meninges of the normal spinal cord
The rectangular boxes indicate the enlarged regions in the right images
C Representative images showing PDGFRβ-TdT+ cells surrounding vessels (arrows)
Arrows indicate the adjacency of TdT (red) and CD31(green)
D After transection (top) or crush (bottom) spinal cord injury (SCI)
PDGFRβ-TdT+ cells (red) migrate into the lesion core
E Quantification of the number of PDGFRβ-TdT+ cells in the lesion core
by two-way ANOVA with Sidak’s multiple comparisons test
F Representative images showing that lesion borders are formed between PDGFRβ-TdT+ cells (red) and GFAP+ astrocytes (green) at 14 dpi
G Representative images showing that TdT+ cells express Acta2 at 5 dpi after SCI
Arrows indicate the co-localization of TdT (red) with Acta2 (green)
H PDGFRβ-TdT+ cells (red) in the perivascular space and meninges express Ki67 (green) at 5 dpi
I Representative confocal images showing the signals for Col1 (green) enriched at the location of TdT+ cells (red) 14 days post SCI
these observations indicate that PDGFRβ+ cells migrate into the lesion sites and convert into myofibroblasts after both transection and crush SCI
more PDGFRβ+ cells are recruited to the lesion sites after transection SCI compared to crush SCI
This result suggests that the more PDGFRB cells in fibrotic scar of transection SCI may be attributed to cell migration and early proliferation after injury
We speculate that these findings may be related to the activation of PDGFRβ-TdT cells
these findings indicate that both parenchymal and meningeal PDGFRβ+ cells are activated and contribute to fibrotic scar formation after either penetrating or non-penetrating SCI
these findings suggest that fibroblasts and pericytes/vSMC are the most likely candidates for secreting ECM to form fibrotic scars
and pericytes/vSMCs from scRNA-seq data of spinal cords at 0 dpi (uninjured spinal cord prior to SCI)
B Bar graph showing the proportion of dividing fibroblasts
and pericytes/vSMCs relative to the total number of cells at 0 dpi
C Violin plots showing the expression patterns of marker genes of fibroblasts
D Dot plot showing the expression patterns of ECM-associated genes in fibroblasts (including dividing fibroblasts) and pericytes/vSMCs
E UMAP projection showing the expression patterns of the myofibroblast marker genes Acta2 and Tagln at 5 dpi and 14 dpi
F Violin plot showing the different expression of Col1a2 and Myh11 in pericytes/vSMCs and fibroblasts
G Representative images showing that few TdT+ cells (red) are located in lesion center (Col1-positive cell area
green) and enwrapped by Pdx+ endothelial cells (light blue) at 14 dpi in Myh11-CreER::R26-TdT mice
Arrows indicate the adjacency of TdT (red) and Pdx (light blue)
H Representative confocal images showing that the distribution area of TdT+ cells (red) overlapped with that of Col1 (green) and Col6a1 (green) immunofluorescence signals in Col1a2-CreER::R26-TdT mice
these findings indicate that fibrotic scars primarily originate from PDGFRβ+ fibroblasts in the intact spinal cord
G–I UMAP plot showing the expression patterns of PF markers Lama1 (G) and Slc1a3 (H) and MF marker Emb (I) in crush SCI and transection SCI
J The expression patterns of Emb and Lama1 in PDGFRβ-CreER::R26-TdT mice
The immunofluorescence signal of Lama1 is located in the pia that inside of meninges and in the parenchyma
while Emb is mainly expressed in the meninges outside of Lama1
Dashed lines distinguish dura/arachnoid and pia mater
K The expression patterns of Crabp2 and Lama2 in Col1a2-CreER::R26-TdT mice
The immunofluorescence signal of Lama2 is located in the pia that inside of meninges and in the parenchyma
while Crabp2 is exclusively expressed in the outer dura matter or arachnoid
</a>A Immunostaining for Lama1 (light blue) and Emb (green) at 14 dpi in PDGFRβ-CreER::R26-TdT mice after transection SCI or crush SCI
Dashed lines distinguish the lesion regions from normal tissues
The rectangular boxes indicate the enlarged regions in the images below
B Immunostaining for Lama2 (blue light) and Crabp2 (green) at 14 dpi in Col1a2-CreER::R26-TdT mice after transection SCI or crush SCI
C Quantification of Lama1+ area index and Emb+ area index in transection SCI and crush SCI
D Representative images showing the expression pattern of TdT+ cells (red) consistent with that of Crabp2 (green) and locate outside of Lama1+ signals (green) in uninjured Crabp2-CreER::R26-TdT mice
Dashed lines distinguish dura/arachnoid from pia mater
E There is a low level of distribution of Crabp2-TdT+ cells (red) in Lama1+ (green) exterior of fibrotic scars after either transection SCI or crush SCI
the results demonstrate that the scar-forming fibroblasts can be divided into meningeal Crabp2+/Emb+ fibroblasts (CE-F) and pia/perivascular Lama1+/Lama2+ fibroblasts (LA-F) with special spatial distribution pattern following transection or crush SCI
</a>A–C GO enrichment analysis of differentially expressed genes (DEGs) among fibroblasts
and pericytes/vSMCs in the injured spinal cord
y-Axis shows the top 10 GO biological process terms
and the x-axis shows −log10 (FDR-corrected P values)
P-values (two-tailed p-value) were calculated by hypergeometric distribution method and FDR were used to estimate an adjusted p-value (qvalue)
D KEGG pathway enrichment analysis of DEGs in fibroblasts compared with dividing fibroblasts and pericytes/vSMCs showing the enrichment of the TGF-β and Wnt signaling pathways in fibroblasts at 5 dpi and 14 dpi
and x-axis showing −log10 (FDR-corrected P values)
F The algorithm of cellphoneDB was used to do cell–cell interactions analysis
and PDGF signaling pathways to assess the interactions of fibroblasts and pericytes/vSMCs with other cell types at 5 dpi (E) and 14 dpi (F)
Left axis shows the specific ligand–receptor pairs
The size of dots indicates the −log10 (P value) (two-tailed p-value)
while color of dots represents the interaction score
The rectangular boxes in the images highlight difference between FB and PC/vSMC
H Dot plots showing the expression of ligand genes (G) and receptor genes (H) associated with TGF-β
and PDGF signaling pathways in CE-F and LA-F
indicating the important role on angiogenesis of pericytes/vSMCs
our data suggested that the TGF-β and Wnt signaling pathways are primarily activated in fibroblasts and participate in fibrosis
while the PDGFB/PDGFD signaling pathway is more highly activated in pericytes/vSMCs
We also examined the activation of TGF-β, Wnt and PDGF signaling pathways in other cell types (Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-024-50564-x#MOESM1">S10</a>)
the expression level of ligand and receptor genes were higher in fibroblasts compared with other cell types
TGF-β signaling and Wnt signaling were activated in Schwann cells and endothelial cells
and Wnt signaling was also activated in astrocytes
It suggests the possible contribution of Schwann cells
endothelial cells and astrocytes for fibrotic scar
Furthermore, we analyzed expression patterns of ligand and receptor genes in CE-F and LA-F (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41467-024-50564-x#Fig5">5</a>G
Tgfb2 and Tgfb3 were higher expressed in CE-F than in LA-F
while corresponding receptor genes were higher expressed in LA-F
The expression levels of receptor genes of PDGF signaling pathway in LA-F were higher than that in CE-F
LA-F expressed higher levels of Wnt pathway ligand genes Fzd2 than CE-F
PDGF and Wnt pathway are differently activated in LA-F and CE-F
</a>A Schematic diagram depicting the dissection of spinal cord tissues in the lesion edge and lesion core at 0 dpi
Single-cell suspensions are used for subsequent 10× Genomics analysis
B UMAP plot of endothelial cells (clusters 1 and 5)
and fibroblasts (clusters 0 and 4) in uninjured spinal cord and injured spinal cord
C UMAP plot of expression patterns of canonical marker genes to identify each cell type
D UMAP plot of cells in the lesion edge (LE) and lesion core (LC) spilt by each time point
E The expression patterns of ECM genes in fibroblasts at different time points
F Expression patterns of representative DEGs in fibroblasts that distinguish monkey CE-F and LA-F
G The ratio of CE-F and LA-F in mouse and monkey SCI models
H Representative images showing the expression pattern of Crabp2 (green in left image) or Lama1 (green in right image) at 14 dpi
heterogeneity of fibroblasts in fibrotic scar tissue after SCI is observed in both mice and monkeys
</a>A Dot plot showing the expression pattern of cholesterol metabolism related genes in mouse CE-F and LA-F
B Representative images showing the distribution of Bodipy+ lipid droplets (green) in PDFGRβ-CreER:R26-TdT mice at 14 dpi after transection SCI
The rectangular boxes in the left image indicate the enlarged regions in the right images
C The percentage of Bodipy+TdT+ cells in TdT+ CE-F and LA-F
D The relative expression of marker genes of CE-F and LA-F in cultured cells in vitro by RT-qPCR
E The relative expression of cholesterol metabolism related genes in cultured CE-F and LA-F in vitro by RT-qPCR
F LA-F phagocytose myelin sheaths and forms lipid droplets (green) in vitro
G The percentage of CE-F and LA-F that containing Bodipy+ lipid droplets in vitro
</a>A Biological process terms identified from GO enrichment analysis of the top DEGs between mouse CE-F and LA-F in the injured spinal cord
B Representative confocal images showing that Pdx+ blood vessels (red) are surrounded by Lama1+ fibroblasts (green) in the lesion core
C Endothelial cell tube formation after being co-culture with CE-F or LA-F in vitro
D Biological process terms identified by GO enrichment analysis of DEGs between CE-F and LA-F after SCI in monkeys
P-values (two-tailed p-value) were calculated by hypergeometric distribution method and FDR were used to estimate a adjusted p-value (qvalue)
E Representative confocal image showing the expression pattern of endothelial cells (Pdx+
green) and perivascular fibroblasts (Lama1+
F Heat maps derived from ligand–receptor interaction counts depicting the interactions between CE-F
and EC (endothelial cell) of mice (5 dpi) and monkeys (7 dpi)
Pericytes/vSMCs are mainly located around blood vessels in spinal cord parenchyma
CE-F and LA-F migrate into the lesion core and generate ECM
CE-F express higher levels of Col1 and Fibronectin
and LA-F express higher levels of Col IV and Laminin
and LA-F are involved in lipid transportation/storage and angiogenesis
CE-F and LA-F exhibit a specific spatial distribution within the fibrotic scar region
where LA-F are found on the lateral side of CE-F
Pericytes/vSMCs contribute little to the fibrotic scar formation
We utilized Myh11-CreER::R26-TdT and NG2-CreER::R26-TdT to trace pericytes/vSMCs
Our results showed pericytes/vSMCs were minimally involved in the formation of fibrotic scar tissue
It cannot be completely ruled out that a subset of pericytes are transformed into myofibroblasts after spinal cord injury and lose their pericyte properties
Myh11+ and NG+ pericytes do not represent the whole spinal cord pericytes
More in-depth studies are needed to investigate heterogeneity of pericytes in the central nervous system
we found the heterogeneous functions of meningeal-derived CE-F and perivascular/pial LA-F after SCI on lipid synthesis and lipid transport
It suggests that specific ablation of subsets of fibroblasts may differently affect the injured microenvironment and functional recovery after SCI
019079) were also crossed with the Rosa26-tdtomato cre reporter line to generate NG2-CreER::R26-TdT mice
which are heterozygous for CreER and homozygous or heterozygous for R26-TdT
We developed Crabp2-CreER mice by using CRISPR/Cas9 to insert CreER fragments before Crabp2’s stop codon
All mice were more than 8 weeks old at the beginning of the experiments and included both males and females
Mice were housed in a barrier system with a 12 h/12 h light/dark cycle
where temperature and humidity were controlled within a range suitable for mice survival
Water and food were sterilized and freely accessible to mice
Ten female rhesus macaques (Macaca mulatta) aged 4–7 years old were housed in Beijing Institute of Xieerxin Biology Resource
Experimental procedures were performed according to Guide for the Care and Use of Laboratory Animals which were formulated by the National Institutes of Health (USA) and approved by the Animal Care and Use Committee of the Institute of Genetics and Developmental Biology
and Use Committee of Beijing Institute of Xieerxin Biology Resource
The approved animal protocol number of monkeys is no
and the approved animal protocol number of mice is AP2019003 and AP2023031
Sigma) was dissolved in 50 mL corn oil (C116023
Aladdin) to make up a solution with a concentration of 20 mg/mL
Adult mice received intraperitoneal injection of tamoxifen solution at 0.1 mg/g for 5 consecutive days
mice were intraperitoneally administered with BrdU (50 mg/kg of body weight) once a day for 13 consecutive days from 1 dpi to 13 dpi
Mice were anesthetized by intraperitoneal injection of sodium pentobarbital
and skin was washed with povidone iodine solution
Then an incision in the skin and a midline incision above the thoracic spine were made
A laminectomy was performed to expose the T10 vertebra
the exposed spinal cord was cut fully along the coronal plane with microsurgical scissors
the exposed spinal cords were completely crushed from two sides for 5 s with forceps
After the introduction of both types of SCI
the muscle layers and the skin were sutured successively
mice were placed in a heated incubator until fully awake from anesthesia
the bladders of mice who underwent surgery were artificially emptied twice a day
ketamine (1 mg/kg) was used for intramural anesthesia
and 1.5%–2.5% isoflurane was used for anesthesia
The physiological indexes of monkeys were monitored during the operation
with venous transfusion of saline solution
The SCI procedures were similar to those used for mice
an incision was made in the skin and muscle
and a cut was made through the spinal membrane
Eight millimeters of spinal cord tissue was removed to ensure complete transection of the spinal cord
Mice were euthanized by intraperitoneal injection of excess sodium pentobarbital and then transcardially perfused with phosphate-buffered saline (PBS) solution for removing all the blood
followed by perfusion with 4% paraformaldehyde (PFA)
Spinal cords were dissected and immersed in 4% PFA overnight at 4 °C
PFA-fixed tissues were then incubated with 30% sucrose overnight at 4 °C
Coronal and horizontal sections were cut at 12–15 μm thickness using a cryostat (Leica)
Sections were incubated in blocking solution (10% donkey serum and 0.3% Triton-X100) for 1 h at room temperature and then incubated in primary antibody solution diluted with 10% donkey serum (36116ES10
The primary antibodies used in the experiments are as follows
Following incubation in primary antibodies
slides were washed three times with PBS and incubated with secondary antibodies for 1 h at room temperature
tissue sections were incubated with 2 N HCl 37 °C for 25 min
then switched to 0.1 M sodium borate to neutralize for 10 minutes (pH 8.0)
The secondary antibodies used (all diluted at 1:500 in PBS) are as follows: goat anti-chicken Alexa Fluor 488 (Thermo Fisher
donkey anti-rabbit Alexa Fluor 488 (Thermo Fisher
donkey anti-rabbit Alexa Fluor 647 (Thermo Fisher
donkey anti-goat Alexa Fluor 488 (Thermo Fisher
donkey anti-goat Alexa Fluor 633 (Thermo Fisher
donkey anti-rat Alexa Fluor 488 (Thermo Fisher
and goat anti-rat Alexa Fluor 647 (Thermo Fisher
Slides were washed three times with PBS after incubation with secondary antibodies
and mounting medium with 4’,6’-diamidino-2-phenylindole dihydrochloride (DAPI) was added
All images were captured on a Leica SP8 or STELLARIS 5 confocal microscope
The fixed tissue section that had been incubated with primary and secondary antibodies and fixed cultured fibroblasts were incubated with 2 μM BODIPY (D3922
Invitrogen) staining solution at room temperature for 15 min
images were captured by using Leica SP8 or STELLARIS 5 confocal microscope
Ten male/ female PDGFRβ-CreER::R26-TdT mice per time points (0 dpi
5 dpi and 14 dpi) were euthanized by intraperitoneal injection of excess sodium pentobarbital
and then transcardially perfused with phosphate-buffered saline (PBS) solution to remove all the blood
Spinal cord segments (4 mm) centered at the lesion core were isolated and cut into small pieces with sharp scissors
The pieces were digested with papain (LK003176
Worthington Biochemical) containing DNaseI (LK003170
Worthington Biochemical) for 1 h at 37 °C with slow rotation
Then 1.0 mg/mL collagenase type II (LS004176
Worthington Biochemical) and 0.4 mg/mL neutral protease (LS02104
and the sample was incubated for 30 min at at 37 °C with slow rotation
the cell pellets were resuspended with 25% Percoll (P1644
Sigma) and centrifuged at 400×g for 10 min to remove myelin debris
cells were sorted into DPBS buffer according to tdtomato fluorescence
The FSC/SSC was adjusted to isolate single cells
then isolate target cells depending on the expression of tdtomato
The nuclei were separated from the cells using EZ Lysis Buffer (Sigma)
and then cell debris were removed by sucrose density gradient centrifugation
Tissue samples were immersed in ice-cold Nuclei EZ lysis buffer (NUC101-1KT
Sigma) and homogenized by using Dounce tissue grinder (D8938
After centrifugation at 3200 × g for 10 min and discard the supernatant
the precipitate was carefully re-suspended with 0.32 M sucrose
The suspension was then lightly covered with 1 M sucrose and centrifuged for 20 min at 3200×g
PBS was used to collect the nuclei deposited on the tube wall
resuspend cell nuclei with PBS containing 0.01% BSA
All operations should be performed on ice or at 2–8 °C
One sample containing ten spinal cords was collected from PDGFRβ-CreER::R26-TdT mice
Collected cells were passed through the 10× Genomics pipeline (v3) and sequenced on an Illumina HiSeq 4000
Low-quality cells with few genes expressed (&lt;200) and a proportion of mitochondrial genes &lt;0.05 were removed
Several cell types in addition to fibroblasts and pericytes were also observed by integrating data from 0 dpi
we captured clusters of fibroblasts and pericytes/vSMCs depending on cluster analysis and obtained a total of 33,366 cells
The sequencing files were run through the 10× Cell Ranger 7.0.0 pipeline to generate gene count data
and then Seurat (v3) and our customed R scripts were applied for sequential analyses
The FindAllMarkers function was used for gene differential expression analysis with the Wilcox method and parameters min.pct 0.25 and logfc.threshold 0.25
Using a combination of classical marker expression and calculation of differential gene expression between clusters
we obtained cell type information for all samples
We downloaded a list of all human and mouse orthologous pairs from the Ensembl database
Before loading the gene expression matrix into CellPhoneDB
we replaced mouse gene names with corresponding human orthologous gene names
After obtaining the result files (means and P values) of CellPhoneDB
we generated an R script to extract cell types and ligand–receptor pairs of interest
then cell-cell communication was visualized in a series of dot plots from ggplot2
DEGs with a P value less than 0.05 and log-transformed fold change larger than 0.25 were selected as input
The package clusterProfiler 3.18.1 and database org
Mm.eg.db 3.12.0 were used for GO enrichment analysis
Two adult SD rats weighting about 250 g were sacrificed by intraperitoneal injection of excess sodium pentobarbital
then dura/arachnoid and pia were carefully removed under a stereomicroscope
Worthington Biochemical) was used for digestion of dura and pia
The dissociated cells were collected in a 15-mL centrifuge tube after filtered through a 100-mm nylon cell strainer
Cell pellets were collected by centrifugation at 500×g for 5 min and re-suspended in culture media containing DMEM (C11330
Two adult SD rats were sacrificed by intraperitoneal injection of excess sodium pentobarbital
After peeling off the surface membrane and blood vessels
cut them into small pieces and place them in a centrifuge tube
and then use a 5 ml pipette to blow and shake
Add 6 mL 0.85 M sucrose into each high-speed centrifuge tube
and then carefully add 2 mL tissue suspension to ensure a clear boundary between the two solutions
After centrifugation at 27,000×rpm for 1 h
the protein was located in the middle separation layer
Add pre cooled water to two 15 ml centrifuge tubes
Resuspending the pellet and store at −80 °C after centrifugation at 12,000×g for 30 min
Total RNA of fibroblasts cultured in vitro was extracted using an Ultrapure RNA Kit (CW0581S, CWBIO). Reverse transcription was performed by a Hifair® II 1st Strand cDNA Synthesis Kit (11123ES, YEASEN). RT-qPCR was performed with Hieff® qPCR SYBR® Green Master Mix (11201ES, YEASEN) on a real-time PCR instrument (Bio-RAD). The list of primers used is shown in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41467-024-50564-x#Tab1">1</a>
Corning) was briefly placed in the lower chambers of a 12-well transwell plate (1 mL/well) and incubated for 30 min at 37 °C
Sigma) were then seeded at a concentration of 5 × 105/mL (800 μL/chamber)
PFs or MFs at a density of 1 × 105/mL were cultured in fibroblast culture medium and seeded on the upper chambers (500 μL/chamber)
Images were captured to examine the blood vessel formation after 12-h co-culture
To characterize TdT+ cells in the uninjured and injured spinal cord of PDGFRβ-CreER::R26-TdT mice
tissue sections from uninjured spinal cord were stained with PDGFRβ
Tissue sections from injured spinal cord were stained with Desmin
To calculate the number of TdT+ cells in the lesion core
tissue sections from PDGFRβ-CreER::R26-TdT mice at different time points in the crush and transection SCI models were stained for GFAP
which marked the astrocyte scar border between the lesion core and spared tissue
The number of TdT+ cells in the GFAP-negative area was counted using Adobe Photoshop
while the area of the corresponding section was measured using ImageJ software
To quantify the percentage of dividing cells or Nestin+ cells among TdT+ cells in the lesion core
tissue sections from PDGFRβ-CreER::R26-TdT mice subjected to crush SCI or transection SCI were stained for Ki67 or Nestin at 5 dpi
Cell nuclei were stained by incubating with DAPI
To characterize TdT+ cells in the uninjured Col1a2-CreER::R26-TdT mice
tissue sections from uninjured spinal cord were stained with PDGFRβ and Col1
Tissue sections from uninjured Myh11-CreER::R26-TdT mice were stained with CD13
tissue sections from both uninjured and injured spinal cord (14 dpi) were stained with Sox10
tissue sections from injured spinal cord were stained with Crabp2
The cell number were counted by Adobe Photoshop
Emb+ area and Lama1+ area were measured by using ImageJ software
To detect and compare the ability of LA-F and CE-F to phagocytose lipids to form lipid droplets
tissue sections from PDGFRβ-CreER::R26-TdT were stained with Bodipy and Emb
TdT+ cells in Emb+ area are identified as CE-F
TdT+ cells containing Bodipy+ signals were defined as TdT+Bodipy+ cells
Adobe Photoshop were used to count the cell number
Col1+ immunofluorescence signal area of PDGFRβ-CreER::R26-TdT mice
NG2-CreER::R26-TdT mice and Myh11-CreER::R26-TdT were measured by ImageJ software
and n values represent the number of mice or samples used in the experiment
Pairwise differences between the two groups were compared using a two-tailed Student’s t-test
The remaining data were subjected to one-way or two-way ANOVA as appropriate
Differences were regarded as significant when P values were less than 0.05
Statistical analysis was performed using GraphPad Prism 8
Further information on research design is available in the <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41467-024-50564-x#MOESM3">Nature Portfolio Reporting Summary</a> linked to this article
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rescue of primary motoneurons in somatosensory cortex and significant functional recovery
Pharmacological modification of the extracellular matrix to promote regeneration of the injured brain and spinal cord
Systemic administration of epothilone B promotes axon regeneration after spinal cord injury
Fibrosis in the central nervous system: from the meninges to the vasculature
Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury
A molecular atlas of cell types and zonation in the brain vasculature
Emerging roles for CNS fibroblasts in health
A cellular and spatial map of the choroid plexus across brain ventricles and ages
Functional characterization of the dural sinuses as a neuroimmune interface
Release of stem cells from quiescence reveals gliogenic domains in the adult mouse brain
Single-cell deconvolution of fibroblast heterogeneity in mouse pulmonary fibrosis
Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases
Heterogeneous expression of nestin in myofibroblasts of various human tissues
Nestin promotes pulmonary fibrosis via facilitating recycling of TGF-β receptor I
Nestin identifies a subpopulation of rat ventricular fibroblasts and participates in cell migration
Fibrotic scar after spinal cord injury: crosstalk with other cells
Single-cell analysis of the cellular heterogeneity and interactions in the injured mouse spinal cord
Microglia-organized scar-free spinal cord repair in neonatal mice
Wnt signaling controls pro-regenerative Collagen XII in functional spinal cord regeneration in zebrafish
Native chick laminin-4 containing the beta 2 chain (s-laminin) promotes motor axon growth
Tenascin-C is involved in motor axon outgrowth in the trunk of developing zebrafish
The extracellular matrix glycoprotein tenascin-C promotes locomotor recovery after spinal cord injury in adult zebrafish
A switch in pdgfrb(+) cell-derived ECM composition prevents inhibitory scarring and promotes axon regeneration in the zebrafish spinal cord
Understanding the NG2 glial scar after spinal cord injury
Myelinogenic plasticity of oligodendrocyte precursor cells following spinal cord contusion injury
STAT3 and SOCS3 regulate NG2 cell proliferation and differentiation after contusive spinal cord injury
A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk
Molecular anatomy of adult mouse leptomeninges
Molecular characterization of perivascular drainage pathways in the murine brain
Single-cell transcriptomic analyses of the developing meninges reveal meningeal fibroblast diversity and function
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Temporal and spatial cellular and molecular pathological alterations with single-cell resolution in the adult spinal cord after injury
Pericytes of the neurovascular unit: key functions and signaling pathways
Myelin and non-myelin debris contribute to foamy macrophage formation after spinal cord injury
Macrophage transcriptional profile identifies lipid catabolic pathways that can be therapeutically targeted after spinal cord injury
Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner
an overlooked player in vascular pathobiology
Brain and retinal pericytes: origin functions and role
Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury
Central nervous system pericytes in health and disease
Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia
Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging
PDGFRβ-P2A-CreER(T2) mice: a genetic tool to target pericytes in angiogenesis
Age-dependent fate and lineage restriction of single NG2 cells
Ligand-dependent genetic recombination in fibroblasts: a potentially powerful technique for investigating gene function in fibrosis
G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension
Single-cell analysis reveals region-heterogeneous responses in rhesus monkey spinal cord with complete injury
Isolation of adult spinal cord nuclei for massively parallel single-nucleus RNA sequencing
Single-cell reconstruction of the early maternal-fetal interface in humans
<a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/s41467-024-50564-x?format=refman&amp;flavour=references">Download references</a>
This work was supported by the National Key R&amp;D Program of China (2023YFC2412501) to Z.X
and National Natural Science Foundation of China (NSFC) (Grant Nos
We also thanked the support from Chinese Academy of Sciences for Young Scientists in Basic Research Project (Grant No
and Youth Innovation Promotion Association CAS (Grant No
and CAMS Innovation Fund for Medical Sciences (2022-I2M-3-002) to J.D
These authors contributed equally: Xiaoyu Xue
State Key Laboratory of Molecular Developmental Biology
Institute of Genetics and Developmental Biology
Tianjin Key Laboratory of Biomedical Materials
Chinese Academy of Medical Sciences &amp; Peking Union Medical College
generated transgenic mice and performed staining experiments
and Y.F analyzed scRNA-seq and snRNA-seq data
performed scRNA-seq and snRNA-seq experiments
performed mouse genotype identification and some immunostaining
and S.Z performed perfusion and some tissue dissection
prepared the samples and analyzed the sc-RNA data
Nature Communications thanks Julie Siegenthaler
<a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/s41467-024-50564-x?format=refman&amp;flavour=citation">Download citation</a>
DOI: https://doi.org/10.1038/s41467-024-50564-x
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the activation of signal transducer and activator of transcription 3 (STAT3) is considered crucial for the migration and proliferation of epithelial cells
as well as for establishing the inflammatory environment
an excessive STAT3 activation aggravates scar formation
Here we show that 450 nm blue light and 630 nm red light can differentially regulate the phosphorylation of STAT3 (p-STAT3) and its downstream cytokines in keratinocytes
Further mechanistic studies reveal that red light promotes wound healing by activating the PI3 kinase p110 beta (PI3Kβ)/STAT3 signaling axis
while blue light inhibits p-STAT3 at the wound site by modulating cytochrome c-P450 (CYT-P450) activity and reactive oxygen species (ROS) generation
skin wound healing can be significantly accelerated with red light followed by blue light to reduce scar formation
our study presents a potential strategy for regulating epithelial cell p-STAT3 through visible light to address skin scarring issues and elucidates the underlying mechanisms
The conflicting roles of STAT3 in skin wound healing and scar formation make the activation state of STAT3 an unrevealed target to solve skin trauma problems
we found a natural difference between visible red and blue light in regulating the STAT3 activation
the irradiation of the wound site with red light activated STAT3 in the skin by PI3Kβ and accelerated the wound healing
Following the red light treatment by early inflammation stage for 3 days
blue light was switched to irradiate the wound site
which activated CYT-P450 in the skin and induced massive ROS production
The phosphorylation of STAT3 was inhibited by ROS and scar formation was alleviated
Red and blue light act as the “switch” for STAT3 activity regulation to accelerate skin wound healing and alleviate scar formation
These results reveal the promising potential of STAT3 as a photo-target for an inexpensive
and noninvasive phototherapy solution for skin scar problem
</a>a Spectra of the 450 nm blue and 630 nm red LED lights used in this study
b Schematic diagram of the LED irradiation devices
d The effects of red and blue light with irradiation doses of 0 J cm−2
and 160 J cm−2 on the cell viability of PAM212 (c) and L929 (d) cell lines
The cell viability was measured by Cell Counting Kit 8 (cck-8)
f The effects of blue and red light radiation at 80 J cm−2 on the growth of PAM212 (e) and L929 cells (f)
h The effects of blue and red light radiation at 80 J cm−2 on the scratched area of PAM212 (g) and L929 cells (h)
</a>a Schematic of the treatment of the animal skin wound model
The I group and II group represent the respective red and blue light irradiation of mice skin wounds for 9 days
b Representative photographs of animal skin wounds treated in darkness or with blue light
c The wound area of mice from day 0 to day 9
n = 8) of scars in different treated groups
f H&amp;E and Masson staining in different treated groups at 14 days
The zoom view shows an enlarged field of view within the dashed box range
g The thickness of the stratum corneum at scar sites on the skin of mice in different treatment groups
</a>a Secretion of TNF-α and IL-10 in keratinocytes after red and blue light irradiation
b The transcription of Cxcl10 and Cxcl13 in Raw264.7 cells
d Anatomy photographs (c) of the inner side of mouse skin wound sites under different light treatments and the transcription of IFN-γ and IL-1b (d) of the scar skin at day 14 after injury
e Immunolocalization of CD163+ and iNOS+ macrophages in scar skin
All these results indicate the differential regulatory effects of red and blue light on the skin inflammatory environment
we suggest that red light prolongs the inflammatory cycle at the wound site which accelerates skin wound healing and increases scar formation
blue light alleviates the inflammatory response and affects cell migration and proliferation at the wound site
thereby slowing down wound healing and alleviating scar formation
</a>a Schematic diagram of the role of the p-STAT3-VEGF-A/FGF-2/Mcp-1 axis in keratinocytes during the wound healing and scar formation processes. b Immunolocalization of p-STAT3, Mcp-1, Ly6g, VEGF-A, and FGF-2 in scar-skin treatment as shown in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s42003-024-06973-1#Fig2">2a</a>
d The protein content (c) and transcription (d) of Mcp-1 in scar skin
f The transcription of VEGF-A (e) and FGF-2 (f) in scar skin
We propose that these differentially expressed genes are the fundamental reasons for the differential regulation of wound healing process by red and blue light
</a>a KEGG analysis for blue light vs dark
The volcano plot in the middle shows the significantly differentially expressed genes between the groups
The significantly upregulated and downregulated signaling pathways are shown on both sides
The signaling pathways related to CYT-P450 metabolism are emphasized in blue
c Detection of fluorescence intensity of DCFH-DA in keratinocytes using fluorescence microscopy (b) and flow cytometry (c)
d Fluorescence intensity of cytoplasmic ROS (DCFH-DA) and mitochondrial ROS (Mito-sox) in keratinocytes under different blue light irradiation doses
f ROS (DCFH-DA probe) levels in keratinocytes in different treatment groups
Galangin (10 uM): inhibitor of Cyp1b1 and Cyp1a1
and Mcp-1 in keratinocytes of different treatment groups
The line graph shows the relative expression levels of p-STAT3
and Mcp-1 in keratinocytes under different treatment conditions compared to the β-actin
Each line represents an independent repeated test
These results demonstrate that blue light can inhibit p-STAT3 in keratinocytes by inducing ROS production
Combining the previous experimental results
the mechanism for blue light is that it induces the generation of intracellular ROS by activating Cyp1b1 and Cyp1a1
which inhibits p-STAT3 and prolongs wound healing process
The volcano plot in the middle shows the differentially expressed genes between the groups
The signaling pathways related to wound healing and scar formation are emphasized in red
b Possible signal transduction pathways after red light irradiation of keratinocytes
d Immunolocalization of PI3Kβ in normal skin (c) and scar skin (d)
e The effects of red and blue light on relative protein content of PI3Kβ and p-STAT3
The line graph shows the relative expression levels of PI3Kβ and p-STAT3 in keratinocytes under different treatment conditions compared to the β-actin
f The effects of PI3K inhibitor and red light on the relative protein content of PI3K
g The effects of STAT3 inhibitor and red light on relative protein content of STAT3
</a>a Schematic of the treatment design of the skin wound model
The I group: red light irradiation of wounds from days 0 to 3 and blue light irradiation from days 4 to 9 (R + B); the II group: blue light irradiation of wounds from days 0 to 3 and red light irradiation from days 4 to 9 (B + R)
b Representative photographs of skin wounds treated with darkness
f H&amp;E and Masson staining in different groups on 14th day
The zoom view shows an enlarged field within the dashed box
g The thickness of the stratum corneum at scar sites in different treatment groups
h The body weight of mice from days 0 to 9
we have discovered and verified the regulatory ability of red and blue light to p-STAT3-VEGF-A/FGF-2/Mcp-1 axis during mouse skin wound healing and scar formation processes
we have developed a simple visible-light therapy strategy to solve the contradiction between wound healing and scar formation
Our work explored the potential of visible red and blue light for skin trauma treatment
revealed the mechanism of visible light in wound healing and scar formation
and provided a convenient and inexpensive phototherapy for skin scarring problems
nor has it revealed whether visible light has the potential to regulate scar formation
we speculate that this is the regulatory effect of some Opsin in the skin
this speculation needs further experimental verification to reveal the role of opsins in wound healing mediated by red light
and in conjunction with drug treatment are the main challenges for effective tumor phototherapies with visible light
we demonstrated the opposite effects of red and blue light on wound healing and scar formation
which were caused by the differences of red and blue light in regulating the STAT3-VEGF-A/Mcp-1/FGF-2 axis
phototherapy was developed with red and blue light as a “switch” to p-STAT3 and achieved wound healing and scar relief at the same time
This work demonstrates STAT3 as a therapeutic target for a “one-stop” solution to skin trauma and provides an inexpensive
and noninvasive phototherapy solution for treating skin scars
MZ-2610) cell lines were purchased from Ningbo Mingzhou Biotechnology Co.
CL0266) cell lines were purchased from Hunan Fenghui Biotechnology Co.
The cells were cultured in phenol red-free Dulbecco’s Modified Eagle’s Medium (DMEM
USA) with 10% (v/v) of fetal bovine serum (FBS)
and placed in the sterile intercellular chamber
SPF-grade female Balb/c mice (4–5 weeks) were purchased from Xi’an Keao Biotechnology Co.
The mice were transferred to EVC mouse mobile microbarrier (HH-MMB-1
monkey animal experimental equipment Technology Co.
Mice were adapted to the rearing environment for 7 days
and then used depilated cream to remove the hair on their back skin
Mice that did not regrow hair on the second day after depilation were selected for subsequent animal radiation experiments
a 5 mm diameter hole punch was used to create a skin wound on the back of the mice to establish a skin wound model
Sufficient water and food were provided to the mice
We have complied with all relevant ethical regulations for animal use
Anesthetize the mice by intraperitoneal injection of pentobarbital sodium at a concentration of 0.3% (w/v) dissolved in sterile PBS (inject 0.1 mL per 10 g of mouse body weight)
All animal experiments involved in this study were approved by the Animal Ethics Committee of Northwestern Polytechnical University (Ethics Number: 202201045)
and β-actin (AC026) were supplied by ABclonal Technology Co.
Ly6g (GB11229) were supplied by Service Biotechnology Co.
MK2206 (PI3K inhibitor) were supplied by Beyotime Biotechnology Co.
Cryptotanshinone (STAT3 inhibitor) was purchased from MedChemExpress (USA)
TNF-α Elisa kit were supplied by ABclonal Technology Co.
Dimethylsulfoxide (DMSO) was provided by Solarbio Science &amp; Technology Co.
Cell Counting kit 8 (CCK-8) was supplied by Gen-view (USA)
Reactive oxygen species (ROS) probes 2′,7′-Dichlorodihydrofluorescin diacetate (DCFH-DA) and N-Acetyl-l-cysteine (NAC) were obtained from Beyotime Biotechnology Co.
A mitochondrial reactive oxygen species probe (Mito-sox) was obtained from Yeasen Biotechnology Co.
In this study, ZWYC-290A illumination incubator (ZHICHENG®, Shanghai, PRC) was applied to irradiate cells and mice. The illumination incubator can provide an adjustable 450 nm blue light and 630 nm red light source (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s42003-024-06973-1#Fig1">1a</a>)
and the maximum power of illumination incubator is 3500 W
By adjusting the power and irradiation time
we can irradiate mice and cells with visible red and blue light at different gradient doses (40 J cm−2
and the control group was kept in darkness
the irradiation dose of cell samples for RNA-seq analysis was 80 J cm−2
an appropriate number of cells were seeded in 100-mm cell culture dishes and were cultured overnight
The cells were irradiated when they adhered to the bottom of the dish and the confluency of cells reached about 80%
cells were digested with trypsin and collected for RNA extraction by adding Trizol (TRleasyTM Total RNA Extraction Reagent
sterile scissors were used to cut the tissue sample into small pieces (less than 2 mm)
which were then frozen in liquid nitrogen and carefully ground into tissue fragments in a sterile quartz grinding bowl
add Trizol and homogenize with a homogenizer to extract RNA from the skin tissue
Cell Counting kit 8 was used to test cell viability
PAM212 and L929 cells were seeded in 96-well plates at a density of 5 × 104 cells/well and incubated for 24 h
DMEM containing CCK-8 solution (5 mg/mL) was added to all wells immediately and incubation for 40 min
USA) was used to detect the optical density of different treatment groups at 450 nm
The effect of red and blue light irradiation on the migration abilities of PAM212 and L929 were evaluated using wound healing analysis
2 × 105 cells were seeded in six-well plates and cultured until the cell confluence reached 80–90%
a straight scratch area was formed in the center of the well using a sterile 200 μl pipette tip
The culture dish was washed with PBS to remove scraped cells
and fresh phenol red-free serum-free medium was added
the cells were irradiated with visible red and blue light at a dose of 80 J cm−2
the migration of cells was observed and photographed under the inverted microscope
1uM) and STAT3 inhibitor (Cryptotanshinone
2 μM) or NAC (5 mM) were added to the culture medium of keratinocytes
After receiving irradiation of 80 J cm−2 red or blue light
the keratinocytes were lysed with RIPA buffer (Solarbio) containing 1% PMSF to extract proteins from the cells
The protein concentration was then determined using the bicinchoninic acid (BCA) method
Equal amounts of protein (20 μg) were separated using FuturePAGE™ 4–12% 12-well precast gels (ET12412Gel
and then transferred into PVDF (polyvinylidene fluoride) membranes
The membranes were rapidly blocked using NcmBlot Blocking Buffer (P30500
and then incubated with diluted primary antibodies: PI3Kβ
Appropriate secondary antibodies (1:10000) were then chosen for incubation for 1 h at room temperature
protein blotting was observed on the chemiluminescence imaging system (JS-M6
To detect the effects of red and blue light irradiation treatment on the levels of relevant cytokines in cells and skin
and TNF-α (RK00027) Elisa kit purchased from ABclonal Technology Co.
Ltd (PRC) to measure the levels of relevant cytokines in PAM212
samples/standards (100 μl) were added to the antibody-coated wells and incubated for 2 h
After washing the unbound samples/standards
biotinylated secondary antibodies (100 μl) were added and incubated for 1 h
excessive secondary antibody was washed off
100 μl of horseradish peroxidase (HRP) was added to each well
followed by the addition of 100 μl of substrate solution TMB (3
5′-Tetramethylbenzidine) and incubated in the dark for 15 min
The optical density at 450 nm was measured using the Multiscan GO spectrophotometer (1510
after visible red and blue light irradiated
the cells were stained with 10 μM DCFH-DA at 37 °C for 0.5 h
the fluorescence status of DCFH-DA fluorescence probe in the cells was identified using flow cytometry (EasyCell103A0
and Muti-Mode Microplate Reader (SpectraMax M5
cells were incubated with 5 μM Mito-sox for 15 min
and the fluorescence status of Mito-sox fluorescence probe in the cells was identified using fluorescence confocal microscope (SP8
treated with red and blue light or darkness
were taken and frozen with liquid nitrogen
then the skins paraffin sections and ROS fluorescence staining (Dihydroethidium
DHE) were commissioned by Service Biotechnology Co.
To amplify the PBM induced by red and blue light in organisms
we increased the times of irradiation treatments (once a day for 1 week) in mice with shaved backs
and then the Mouse XL Cytokine Array Kit (ARY028
USA) was used to analyze the cytokine changes in peripheral blood serum of irradiated mice
The normal skin and scar skin of mice were treated with 4% PFA fixation and paraffin embedment
The treated skin sample slices (5 µm) were subjected to H&amp;E dyeing procedures after deparaffinized and subjected to rehydration
Imaging was performed via tissue slice scanner (Science
The mice skin samples were fixed under room temperature with 4% PFA and embedded in paraffin
The thickness of the treated tissue slices was 5 μm
The corresponding skin slices were subjected to immunohistochemical staining using diluted antibodies Mcp-1
Imaging was performed via tissue slice scanner
The thickness of the treated tissue slices was 5μm
The corresponding skin slices were subjected to immunofluorescence staining using diluted antibodies VEGF-A
Imaging was performed by commissioned Service Biotechnology Co.
GraphPad Prism 9 software was used for data statistics
and the repetition number of all experimental settings was ≥3
Student’s t test or one-way ANOVA were performed to determine the statistical significance
P value &lt; 0.05 was considered a significant difference (*P &lt; 0.05; **P &lt; 0.01; ***P &lt; 0.001; ****P &lt; 0.0001)
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article
Microbiota and maintenance of skin barrier function
Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense
Pine pollen polysaccharides promote cell proliferation and accelerate wound healing by activating the JAK2-STAT3 signaling pathway
Therapeutically exploiting STAT3 activity in cancer—using tissue repair as a road map
Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling
Functional involvement of Stat3 in skin remodeling including hair cycle and wound healing
Stat3 regulates genes common to both wound healing and cancer
Oncometabolite succinate to promote angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation
FGF2-induced STAT3 activation regulates pathologic neovascularization
Photobiomodulation promotes angiogenesis in wound healing through stimulating the nuclear translocation of VEGFR2 and STAT3
The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells
Stat3: linking inflammation to epithelial cancer—more than a “gut” feeling
STAT3 but not STAT4 is critical for γδT17 cell responses and skin inflammation
Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling
Modulation of wound scar formation by monocyte chemoattractant protein-1 (MCP-1)
Minimizing skin scarring through biomaterial design
Carrier-free 5-Fu nanoparticle-mediated domestication therapy for scar treatment: a preclinical and first-in-human study
Human skin wounds: a major and snowballing threat to public health and the economy
Aspirin inhibits inflammation and scar formation in the injury tendon healing through regulating JNK/STAT-3 signalling pathway
Effect of different wavelengths of laser irradiation on the skin cells
Analysis of the systemic effect of red and infrared laser therapy on wound repair
Advances in phototherapy for psoriasis and atopic dermatitis
Effect of red and near-infrared wavelengths on low-level laser (light) therapy-induced healing of partial-thickness dermal abrasion in mice
Disclosure of the culprits: macrophages-versatile regulators of wound healing
Therapeutic hydrogel patch to treat atopic dermatitis by regulating oxidative stress
The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury
Inflammation in wound healing and pathological scarring
PI3Kβ controls immune evasion in PTEN-deficient breast tumours
Mitochondrial reactive oxygen species drive proinflammatory cytokine production
Gene expression profiling reveals aryl hydrocarbon receptor as a possible target for photobiomodulation when using blue light
Regulation of reactive oxygen species generation in cell signaling
Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer
Nox2 impairs VEGF-A-induced angiogenesis in placenta via mitochondrial ROS-STAT3 pathway
Celastrol elicits antitumor effects by inhibiting the STAT3 pathway through ROS accumulation in non-small cell lung cancer
Intramacrophage ROS primes the innate immune system via JAK/STAT and Toll activation
Revisiting STAT3 signalling in cancer: new and unexpected biological functions
Systemic alteration induced in mice by ultraviolet light irradiation and its relationship to ultraviolet carcinogenesis
Regulation of immune activity by mild (fever-range) whole body hyperthermia: effects on epidermal Langerhans cells
Sunlight effects on immune system: is there something else in addition to UV-induced immunosuppression
Blue light-triggered Fe2+-release from monodispersed ferrihydrite nanoparticles for cancer iron therapy
Immunoactivation by cutaneous blue light irradiation inhibits remote tumor growth and metastasis
gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis
Differential immunological effects of infrared irradiation and its associated heat in vivo
Biological effects and medical applications of infrared radiation
Skin DNA photodamage and its biological consequences
Protective effect of infrared-A radiation against damage induced by UVB radiation in the melan-a cell line
RNA-Seq analysis revealed the molecular mechanisms of photobiomodulation effect on human fibroblasts
In vitro and in vivo efficacy of new blue light emitting diode phototherapy compared to conventional halogen quartz phototherapy for neonatal jaundice
Red (660 nm) or near-infrared (810 nm) photobiomodulation stimulates
green (540 nm) light inhibits proliferation in human adipose-derived stem cells
Biostimulation of wound healing by low-energy laser irradiation—a review
The role of macrophage phenotype in vascularization of tissue engineering scaffolds
Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo
STAT proteins in cancer: orchestration of metabolism
Essential role of Stat3 in PI3K-induced oncogenic transformation
The expression of opsins in the human skin and its implications for photobiomodulation: a systematic review
Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision
Illumination of the melanopsin signaling pathway
Under the spotlight: mechanisms of photobiomodulation concentrating on blue and green light
Melanopsin signalling in mammalian iris and retina
A neuropsin-based optogenetic tool for precise control of G(q) signaling
Neuropsin (OPN5) mediates local light-dependent induction of circadian clock genes and circadian photoentrainment in exposed murine skin
Mammalian G proteins and their cell type specific functions
The structure and function of G-protein-coupled receptors
Illuminating insights into opsin 3 function in the skin
Adaptive thermogenesis in mice is enhanced by Opsin 3-dependent adipocyte light sensing
Implantable micro-scale LED device guided photodynamic therapy to potentiate antitumor immunity with mild visible light
Low-level laser therapy promoted aggressive proliferation and angiogenesis through decreasing of transforming growth factor-β1 and increasing of Akt/hypoxia inducible factor-1α in anaplastic thyroid cancer
Light-emitting diode irradiation induces AKT/mTOR-mediated apoptosis in human pancreatic cancer cells and xenograft mouse model
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This work was supported by the National Natural Science Foundation of China (31971315)
and the China Postdoctoral Science Foundation (2024M754229)
Key Laboratory for Space Bioscience &amp; Biotechnology
Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation
All authors contributed to the article and approved the submitted version
Communications Biology thanks Takako Chikenji
Primary Handling Editors: Jesmond Dalli and Dario Ummarino
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DOI: https://doi.org/10.1038/s42003-024-06973-1
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Scar formation is a common end-point of the wound healing process
particularly in relation to abnormal scars such as hypertrophic scars and keloids
This study unveils a novel mechanistic insight into scar formation by examining the differential expression of Homeobox (HOX) genes in response to mechanical forces in fibroblasts derived from normal skin
We isolated fibroblasts from different scar types and conducted RNA sequencing (RNA-Seq) to identify differential gene expression patterns among the fibroblasts
Computational modeling provided insight into tension alterations following injury
and these findings were complemented by in vitro experiments where fibroblasts were subjected to exogenous tensile stress to investigate the link between mechanical tension and cellular behavior
Our study revealed differential HOX gene expression among fibroblasts derived from normal skin
Computational simulations predicted injury-induced tension reduction in the skin
and in vitro experiments revealed a negative correlation between tension and fibroblast proliferation
we discovered that applying mechanical tension to fibroblasts can modulate HOX gene expression
suggesting a pivotal role of mechanical cues in scar formation and wound healing
This study proposes a model wherein successful wound healing and scar formation are critically dependent on maintaining tensional homeostasis in the skin
Our findings highlight the potential of targeting mechanotransduction pathways and tension-sensitive HOX gene expression as therapeutic strategies for abnormal scar prevention and treatment
offering a new perspective on the complex process of scar formation
(e) The average log2(normalized RC) values for total gene expression plotted on the 2D plane and R-squared values for normal skin vs
This finding suggests that the observed phenotypic differences are driven by focused transcriptional changes in specific gene subsets
rather than broad-scale shifts in global gene expression
</a>Differentially expressed genes (DEGs) demonstrate the different morphogenetic features of fibroblasts from normal skin
(a) Principal component analysis (PCA) of 219 DEGs plotted on the 2D domain (first and second principal components)
(b) Hierarchical clustering of log2(FC) values and the sub-gene group with average values
FC stands for fold change and is calculated with the normalized read count
and K indicate fibroblasts from normal skin
and keloids; the numbers represent different patient groups
(c) Gene Ontology (GO) analysis of DEGs with wound healing- and morphogenesis-related biological processes
(d) Markov clustering of DEGs using STRING
Network analysis revealed two distinct clusters
The nodes represent the proteins encoded by the DEGs
The whole 219 DEGs were used for the analysis but only connected nodes are shown
with disconnected nodes containing 165 genes removed from view
These findings suggest that keloid formation may involve alternative pathways or mechanisms that are not predominantly associated with morphogenesis-related genes
To further elucidate how these differences might manifest in vivo
particularly in the context of disrupted skin architecture
we next investigated the role of injury-induced tension changes and their impact on fibroblast behavior across normal skin
Excessive tension at the wound site has been thought to cause abnormal scar formation in the form of hypertrophic scars and keloids
Data represent the mean ± standard deviation (SD)
This suggests that the reduction of tension in the tissue following an injury could result in increased proliferation
we may consider that tension changes induced by injury could serve as a contributing factor to stimulate fibroblasts for wound healing
leading to an increase in their proliferation
</a>Positive correlation between tension and selected genes (HOXA9, HOXC10, and COL1A1). (a) HOXA9, HOXC10, and COL1A1 relative mRNA expressions of fibroblasts from the last donor group (third donor of normal skin, hypertrophic scars, and keloid, respectively, Supplementary Table <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/s12967-025-06191-1#MOESM1">5</a>)
+ and – represent with and without tension
Statistical significance was evaluated via two-way ANOVA with post hoc tests (HOXA9 and HOXC10: n = 5
(b) Schematic of the suggested model of genetic response to tension in fibroblasts from normal skin
Fibroblasts from normal skin express HOX and collagen synthesis genes in their normal state
when the existing tension is lost due to injury
the expression of these genes is decreased via mechanotransduction
the positive PBC values for HOXA9 and HOXC10 support a direct association between tension and HOX gene upregulation
Hypertrophic scar fibroblasts exhibited similarly elevated HOX expression under tension
but the PBC values did not reach statistical significance (p &gt; 0.05)
suggesting that while these cells follow the same trend
keloid fibroblasts showed no significant difference in HOX expression between tension states
paralleling their tension-insensitive proliferation behavior
COL1A1 levels were significantly higher under tension
hypertrophic scar fibroblasts did not achieve statistical significance despite an apparent increase in COL1A1 expression under tension
Keloid fibroblasts remained largely unresponsive to tension
reflecting an intrinsic divergence in their mechanotransduction pathways
Because the cells are in a quiescent state
their collagen synthesis gene expression is upregulated
if an injury compromises the skin’s integrity
fibroblasts can sense the changes in tension and alter their response via hierarchical tensegrity
As a result of the disruption of positional identity
and collagen synthesis is temporally ceased
the same mechanism appears to function but with greater variability
possibly explaining why PBC values did not reach statistical significance
keloid fibroblasts show minimal changes in HOX/COL1A1 expression under tension
consistent with their hyperproliferative and tension-insensitive phenotype
We also note that while HOX and COL1A1 expression in keloid fibroblasts may correlate (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12967-025-06191-1#Fig2">2</a>d)
further exploration is needed to establish a direct functional linkage; correlation alone does not confirm causation
The etiology of hypertrophic scars and keloids remains unclear
While many investigations have suggested that keloids have a significant hereditary susceptibility
it is essential to recognize that this genetic predisposition may still lack a clear causal link
This study showed distinct expression levels of HOX genes in fibroblasts from different scar types
whose mechanosensitivity to exogenous tension varied markedly
Physical factors like excessive tension have been thought to influence hypertrophic scar and keloid formation. This is because most of those scars are found in regions with relatively high tension (the neck, chest, and similar sites), and patients can also feel the unpleasant tension around the wound. To our surprise, this study demonstrated that the tension near the wound site decreased dramatically based on FEM analysis.
and keloid scar formation scenarios with respect to tension-sensitive HOX gene expression
a material in natural tensional homeostasis
experiences a decrease in tensile stress upon injury
the injury’s periphery can be pulled outward
This phenomenon can be viewed as tension acting on the wound
even though there is no active tension on the material (i.e.
Based on the negative feedback loop of proliferation-ECM deposition suggested by Rognoni et al..
we can speculate that excessive deposition of ECM can lead to scar formation
decreased expression of HOX can be viewed as a threat to this maintenance program
resulting in systematic responses to restore the program
We view this process as the potential role of HOX genes in postnatal wound healing processes
in which fibroblasts restore the original dermal architecture through the regulation of HOX expression levels
which aim to stabilize or restore local tension
these interventions help minimize pathological scarring
With the proposed model, we can delineate how the same tension-driven mechanism results in distinct outcomes in normal, hypertrophic, and keloid scars (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12967-025-06191-1#Fig5">5</a>b). In normal skin (top row, Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12967-025-06191-1#Fig5">5</a>b)
fibroblasts maintain moderate HOX and COL1A1 expression under natural tensile stress
these cells shift into a proliferative mode with transiently downregulated HOX expression
ECM-depositing state to complete the remodeling phase
In hypertrophic scars (middle row, Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12967-025-06191-1#Fig5">5</a>b)
elevated baseline tension—particularly in high-tension areas such as the chest or neck—sustains increased HOX gene expression and active ECM deposition
In contrast, keloid fibroblasts (bottom row, Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12967-025-06191-1#Fig5">5</a>b) exhibit a fundamental insensitivity to changes in mechanical tension
These cells continue proliferating and depositing collagen regardless of mechanical cues
Injury to local tissue further exacerbates this process by damaging or dysregulating other ECM-regulating cells
The result is an aggressive overgrowth that extends beyond the original wound boundaries
forming the invasive lesions characteristic of keloids
This model explains how keloids can form in low-tension environments
While these areas experience less macroscopic tension
local micro-strains from factors like ear piercings
or head and neck movements may still trigger scar formation in genetically or epigenetically predisposed individuals
keloids do not rely exclusively on high-tension environments but instead stem from an intrinsic dysfunction in fibroblast mechanotransduction that enables aggressive growth in both high- and low-tension sites
It is plausible that fibroblasts from keloid exhibit an intrinsic dysfunction of HOX gene expression in response to injury-induced tension reduction
and this intrinsic issue related to HOX gene expression might be regarded as genetic susceptibility in the field
keloids are reported more common in darker-skinned individuals
suggesting a complex interplay between genetic predispositions and environmental or phenotypic factors
known for their crucial roles in regulating tissue repair and fibrosis
have recently been implicated in keloid pathology
the direct correlation between HOX gene expression and skin color in the context of keloid susceptibility remains underexplored
We recognize that our study does not directly address the potential correlation between HOX gene expression and skin color in keloid formation
This represents a limitation of our current study
as the genetic mechanisms underlying keloid predisposition in individuals of varying skin colors are likely multifaceted and warrant detailed investigation
We propose that future studies could specifically explore the interaction between skin pigmentation
and keloid susceptibility to further elucidate this relationship
the suggested wound healing model and scar formation scenarios are the first demonstration of the mechanisms by which different hypertrophic and keloid scars can form in terms of mechanical cues and gene expression
our study presents several notable limitations that warrant discussion
We suggested that the differential expression of HOX genes observed in our study is more closely associated with the type of scar (hypertrophic vs
keloid) rather than the anatomical location from which the sample was obtained
Although analyzing additional samples from similar body regions would strengthen our argument
we were unable to include these in the current study
hypertrophic scars predominantly manifest in areas of the skin subject to higher tension
procuring cells from normal and keloid tissues that are anatomically congruent with regions affected by hypertrophic scars poses significant logistical challenges
the feasibility of obtaining donors with specific conditions at designated anatomical locations is often limited
complicating the collection of fibroblasts from individuals of the same age group
Enhanced examination of HOX genes within more homogenous cohorts (i.e.
and injury site) and in more heterogeneous populations (e.g.
ethnicity) would help establish the generalizability of our tension-based HOX model across diverse patient backgrounds
While keloid formation is known to be more prevalent in darker-skinned populations, our current study was conducted in South Korea, where the patient pool is relatively uniform in ethnicity and skin tone (Supplementary Table <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/s12967-025-06191-1#MOESM1">5</a>)
we could not directly evaluate potential differences in HOX gene expression or mechanosensitivity attributable to pigmentation levels
including sample-sharing agreements with international biobanks
may enable larger and more ethnically diverse cohorts
Such efforts could clarify whether genetic or pigmentation-linked factors modulate the tension-based HOX model presented here
because in vitro experiments cannot fully recapitulate the long-lasting and complex wound healing phenomena
our in vitro tensile stimulation experiments were designed to maximize the effect of tension on the cells
even though we believe that the time frame set up in our experimental design was appropriate to observe the different behaviors of cells upon tensile stimulation
one should be noted that there could be remodeling and changes to mechanics that occur at the wound site in vivo
which could influence the wound healing process
Another limitation pertains to our focused analysis on two specific HOX genes
within the scope of our tensile stimulation experiments
While these findings provide valuable insights into the etiology of hypertrophic scar and keloid formation
a comprehensive understanding of tension-induced HOX gene regulation remains elusive
the site-specific expression patterns of HOX genes—integral for predicting cellular origins—suggest a complex regulatory mechanism that demands further exploration
although our DEGs were primarily HOX-related
other genes implicated in scar biology—such as LOXL2
and other collagen crosslinking factors—likely contribute to ECM remodeling and should be investigated in future studies
Our findings aim to contribute to a more nuanced understanding of fibroblast behavior in specific wound-healing contexts
particularly where decreased tension is a factor
We acknowledge that our models and experiments do not encompass all wound healing scenarios
We acknowledge that the reliance on in vitro tensile stimulation limits the full replication of the in vivo wound environment
The in vitro setups offer controlled conditions that facilitate the observation of mechanobiological interactions but do not fully capture the complex
long-term dynamics of tissue repair in the body
these results lay essential groundwork by elucidating core mechanisms in a controlled setting
inviting future studies to extend this model in vivo or in clinical settings to validate and expand upon the molecular framework presented here
Future studies should indeed explore these conditions in more detail
examining the fibroblast response over extended periods and under various mechanical stresses to fully understand their role in wound healing and scar formation
our study advances the understanding of tension-sensitive genetic regulation in scar formation
providing a blueprint for future investigations into scar pathology and potential treatments aimed at reducing or preventing abnormal scar formation through mechanotransduction-targeted strategies
Three normal skin tissues, three hypertrophic scar tissues, and three keloid scar tissues were obtained from plastic and reconstructive surgery patients, and the information about donors were described in Supplementary Table <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/s12967-025-06191-1#MOESM1">5</a>
Hypertrophic scars and keloids were diagnosed by plastic surgeons
scars that have not overgrown the original wound boundaries are defined as hypertrophic scars
scars that have overgrown the original wound edges are defined as keloids
and some samples were histologically verified
all patients were informed of the purpose and procedure of this study
and the patients agreed to donate excess tissue
written informed consent was obtained from all participants or their legal representatives
This study was approved by the institutional review board (IRB) of KAIST (KH2017-75) and performed
and keloid scar tissue were washed several times with phosphate-buffered saline (PBS
pH 7.4) and incubated with 2.4 units of Dispase® (Sigma
the dermis and epidermis were separated using forceps
the separated dermal tissue was cut into small pieces and incubated with 0.2% collagenase type II (Worthington Biochemical Corp
and the cells were precipitated using centrifugation at 1000 rpm for 5 min
the cell suspension was filtered through a cell strainer (pore size 75 μm
The filtered cells were grown in Dulbecco’s modified Eagle’s medium (DMEM
and 10% fetal bovine serum (Gibco/BRL) in 100-mm culture dishes in an incubator at 37 ℃ and 5% CO2
Once the cells had reached 70–80% confluence
they were treated with Trypsin 0.25% (1x) solution (Hyclone Laboratories Inc.
Cells were washed with PBS and fixed for 15 min in 4% (v/v) paraformaldehyde
cells were permeabilized for 20 min in 0.2% or 1% (v/v) Triton-X (Sigma Aldrich) and blocked for 60 min in 3% (v/v) bovine serum albumin (BSA)
cells were incubated with diluted primary antibodies (α-SMA and Ki67
Abcam) for 12 hours and secondary antibodies (Alexa Flour 488 and 568-fluorescence
Invitrogen) for 1 hour at room temperature
Actin filaments were stained with phalloidin (Alexa Fluor 568-phalloidin
Molecular Probes) was treated in the cells for 3 min
Cells were then imaged using multichannel fluorescence microscopy (Carl Zeiss)
Cells were cultured on polydimethylsiloxane (PDMS) (Dow Corning
which were pretreated with oxygen plasma (Convance
Korea) for 1 min at a pressure of 0.7 Torr followed by 1 µg/cm2 of fibronectin (Invitrogen
USA) coating for 120 min at room temperature
which typically occurred within approximately two days
and total RNA was extracted using a Trizol reagent (Invitrogen
RNA purity was assessed by Agilent 2100 bioanalyzer with the RNA 6000 Nano Chip (Agilent Technologies
and RNA was quantified at 260 nm with ND-2000 Spectrophotometer (Thermo Inc.
The STRING network analysis parameters were set to all the sources with a high confidence score (0.7)
Markov clustering with an inflation parameter setting of 3 was used to visualize the network analysis
which is the same percent strain used in our experiments
to the one wall and set fixed support conditions for the confronting wall for boundary conditions to simplify the problem
Because the fibroblasts were attached to the fibronectin-coated-PDMS chambers and cells produce other matrix proteins during the pre-incubation period
the attached cells can be stretched by applying tension on a flexible membrane via a variety of ligand/receptor interactions
including integrin linkages at focal adhesions
where we applied six cycles of intermittent tensile stimulation to the fibroblasts (5% strain
where each cycle consisted of a 10-minute stretching followed by a 60-minute resting period
While we acknowledge that anatomical differences may lead to variations in tension levels
our primary goal was to investigate the mechanobiological responses of fibroblasts under controlled conditions
All stretch experiments were carried out inside an incubator at 37 °C in 5% CO2
Unstretched cells were incubated under the same conditions as the samples undergoing cyclic tension
At the end of tensile stimulation experiments
total RNA was isolated from fibroblasts with RNAiso reagent (Takara Bio
Japan) according to the manufacturer’s instructions
Extracted RNAs were reverse transcribed to cDNA using iScript cDNA Synthesis Kits (Bio-Rad
USA) and Biometra T-personal Thermal Cycler for the synthesis
Real-time qPCR was performed in duplicates with iQ SYBR green supermix (Bio-Rad
USA) and a Bio-Rad CFX96 real-time detection system
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used for the reference gene
ΔCt values were used for hypothesis testing and used to express relative mRNA expression
ΔCt = Ct(reference gene) - Ct(gene of interest)
Rev: CCTGCCAACAGGTTGTTCC) COL1A1(For: GTGCGATGACGTGATCTGTGA
RNA-seq data have been deposited in the Gene Expression Omnibus under accession code GSE210434
All data generated or analyzed during this study are included in the article and supplemental files
or available from the corresponding author on reasonable request
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Biomechanical modeling of the forces applied to closed incisions during single-use negative pressure wound therapy
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Chapter 17 - skin mechanobiology and biomechanics: from homeostasis to wound healing
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Kim M, Shin DW, Shin H, Noh M, Shin JH. Tensile stimuli increase nerve growth factor in human dermal fibroblasts independent of tension-induced TGFbeta production. Exp Dermatol. 2013;22:72–4. <a href="https://doi.org/10.1111/exd.12064" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1111/exd.12064">https://doi.org/10.1111/exd.12064</a>
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This research was supported by National Research Foundation granted by the Korean Government (NRF-2017R1A2B2007673
Korea Advanced Institute of Science and Technology
Department of Plastic &amp; Reconstructive Surgery
This study was approved by the institutional review board (IRB) of KAIST (KH2017-75) and performed All participants provided written informed consent
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest
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DOI: https://doi.org/10.1186/s12967-025-06191-1
but The Last of Us has actually been quite kind to viewers in its adaptation of the video game
The show explained Abby (Kaitlyn Dever) and her motivation for murdering Joel (Pedro Pascal) up front
The Last of Us Part II waits much longer to reveal why Abby killed Joel
preferring instead to linger on Ellie’s (played on the show by Bella Ramsey) rage and confusion over Joel’s death
That’s kind of the whole deal of The Last of Us: It’s a franchise about flawed people with imperfect information who are driven by emotion to do terrible things
The audience can expect to eventually get a more complete picture of why they’ve done those things
The tension of the story—and the adaptive choices that showrunners Craig Mazin and Neil Druckmann are making—lie in when that information comes
All this is to say: The mysterious new group of bow-wielding hunters we meet this week
and The Last of Us will explore them in time
it might be a long time before the show explains exactly who they are and what they want
So if you’re looking for a little clarity and limited spoilers
As the man at the head of the pack of Seraphites explains to the young girl he’s teaching—it’s unclear if she’s his daughter—the Seraphites are a religious cult who believe in a prophet
We’re not told much more about this prophet
other than the fact that she’s been dead for years
the Seraphite prophet viewed the cordyceps infection as divine judgment
It inspired her to begin a practice of nomadic asceticism
eschewing modern technology and living off the land
the Seraphites we met are seemingly killed by Abby’s people—known as the WLF
or the Wolves—which gets at some of the thematic groundwork being laid here
Those two Seraphites might have been in a religious cult
and his own complicated feelings about Israel and Palestine
the fight between the Wolves and the Scars (which is what the Wolves call the Seraphites) could be likened to the conflict between Israel and Palestine
Whether or not the game successfully pulls this off is an extremely subjective question
and it will be fascinating to watch it play out in a new medium
and Gross all have their work cut out for them
In the brief glimpse we get of them to start
the Seraphites on the show appear extremely faithful to the way they’re presented in the game
with their handmade ponchos and facial scarring
The important thing to take away is that they have been in a long war of attrition with the Washington Liberation Front—the WLF—for control of what was Seattle
Which means that Ellie is on a collision course with both factions
now that she’s left on a mission to find and kill Abby
Ellie’s storyline this episode is largely original to the show
as she takes time to absorb and process the horror of “Through the Valley.” We pick up three months after the events of that devastating hour
In one of last week’s more interesting departures from the game
Jackson suffered a devastating attack at the same time that Joel was murdered—which means that this week
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it becomes easier to appreciate all the time this week’s episode takes to show Jackson’s efforts to rebuild and recover—and how the community is responding to its angriest member
When Ellie appears before the Jackson town council and proposes that they form a posse to find justice for Joel
believes Ellie will settle for that answer—not Tommy (Gabriel Luna) or Gail (Catherine O&#x27;Hara)
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rather than watching Ellie ride off half-cocked
has spent the last three months doing all the research she knows her friend won’t—learning about the WLF
It’s really worth pausing for a moment and celebrating just how great Merced is in the role of Dina
Not just because she brings a healthy amount of spunk to an otherwise pretty dour show
but for the way she lingers even between chipper moments
Dina is making a difficult decision for the sake of love
and hoping that her support will get through to Ellie at a time when nothing else will
where Ellie leaves a few coffee beans in tribute—the 2013 video game took a moment to stress that coffee is basically gone post-pandemic
and Joel really missed it—the two make it to Seattle in no time at all
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What Caused This Seven-Mile Scar in Australia&rsquo;s Outback
A man scouring Google Earth found a mysterious scar in the Australian outback
By <a class="article_authors__link--mMFB" href="/author/matej-lipar/">Matej Lipar</a> &amp; <a class="article_authors__link--mMFB" href="/author/the-conversation-us/">The Conversation US</a> 
This Google Earth image shows a mysterious scar etched into Australia's barren landscape
The following essay is reprinted with permission from <a href="https://theconversation.com/" target="_blank">The Conversation</a>
an online publication covering the latest research
a caver was poring over satellite images of the Nullarbor Plain when he came across something unexpected: an enormous
mysterious scar etched into the barren landscape
The find intrigued scientists, including my colleagues and I. Upon closer investigation, we realised the scar was created by a ferocious tornado that no-one knew had occurred. We outline the findings in <a href="https://doi.org/10.1071/ES24023">new research</a> published today
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Tornadoes are a known threat in the United States and elsewhere. But they also <a href="https://doi.org/10.1016/j.atmosres.2016.03.011">happen in Australia</a>
this remarkable example of nature&rsquo;s ferocity would have gone unnoticed
It&rsquo;s important to study the tornado&rsquo;s aftermath to help us predict and prepare for the next big twister
<a href="https://doi.org/10.1007/978-3-642-05381-8">Tornadoes</a> are violent
spinning columns of air that drop from thunderstorms to the ground
bringing wind speeds often exceeding 200 kilometres an hour
They can cause massive destruction &ndash; uprooting trees
tearing apart buildings and throwing debris over large distances
Tornadoes have been reported on every continent except Antarctica
They most commonly occur in the Great Plains region of the United States
and in the north-east region of India&ndash;Bangladesh
The earliest tornado observed by settlers in Australia occurred in 1795 in the suburbs of Sydney
But a tornado was not confirmed here by Western scientists until the late 1800s
In recent decades, documented instances in Australia include a <a href="https://knowledge.aidr.org.au/resources/tornado-murray-river-townships-victoria-2013/#:%7E:text=Tornado%20%2D%20Murray%20River%20townships%2C%202013&amp;text=At%20approximately%208.00pm%20on,border%20of%20New%20South%20Wales.">2013 tornado</a> that crossed north-east Victoria and travelled up to the New South Wales border
It brought winds between 250&ndash;300 kilometres an hour and damaged Murray River townships
And in 2016, a severe storm produced <a href="https://theconversation.com/severe-thunderstorms-are-sweeping-through-southern-australia-but-what-makes-a-thunderstorm-severe-241555#:%7E:text=In%202016%2C%20huge%20rotating%20supercell,after%20taking%20down%20six%20towers.">at least seven tornadoes</a> in central and eastern parts of South Australia
It&rsquo;s important for scientists to accurately predict tornadoes
That&rsquo;s why the Nullarbor tornado scar was useful to study
The Nullarbor Plain is a remote, dry, treeless stretch of land in southern Australia. The man who discovered the scar had been using Google Earth satellite imagery to search the Nullabor for <a href="https://doi.org/10.1007/978-3-031-24267-0_11">caves</a> or other karst features
Karst is a landscape underlain by limestone featuring distinctive landforms
The discovery of the scar came to the attention of my colleagues and I through the collaborative network of researchers and explorers who study the Nullarbor karst
The scar stretches from Western Australia over the border to South Australia. It lies 20 kilometres north of the <a href="https://www.nma.gov.au/defining-moments/resources/trans-australian-railway">Trans-Australian Railway</a> and 90 kilometres east-north-east of Forrest
We compared satellite imagery of the site over several years to determine that the tornado occurred between November 16 and 18
Blue circular patterns appeared alongside the scar
indicating pools of water associated with heavy rain
My colleagues and I then travelled to the site in May this year to examine and photograph the scar and the neighbouring landscape
Our results have been <a href="https://doi.org/10.1071/ES24023">published </a>in the Journal of Southern Hemisphere Earth Systems Science
The scar is 11 kilometres long and between 160 and 250 metres wide. It bears striking patterns called &ldquo;cycloidal marks&rdquo;, formed by tornado suction vortexes. This suggests the tornado was no ordinary storm but in the strong <a href="https://ntrs.nasa.gov/citations/19720008829">F2 or F3</a> category
spinning with destructive winds of more than 200 kilometres an hour
The tornado probably lasted between seven and 13 minutes
Features of the scar suggest the whirling wind within the tornado was moving in a clockwise direction
We also think the tornado moved from west to east &ndash; which is consistent with the direction of a strong cold front in the region at the time
"Cycloidal marks" can be seen in the tornado scar
Local weather observations also recorded intensive cloud cover and rainfall during that period in November 2022
eroding soil and vegetation and reshaping the Earth&rsquo;s surface
the scar was still clearly visible 18 months after the event
both in satellite images and on the ground
This is probably because vegetation grows slowly in this dry landscape
This fascinating discovery on the Nullarbor Plain shows how powerful and unpredictable nature can be &ndash; sometimes without us knowing
Only three tornadoes have previously been documented on the Nullarbor Plain
This is likely because the area is remote with few eye-witnesses
and because the events do not damage properties and infrastructure
those three tornadoes occurred in November
Our research provides valuable insights into the tornadoes in this remote and little-studied region
It also emphasises the importance of satellite imagery in identifying and analysing weather phenomena in remote locations
and in helping us predict and prepare for the next big event
the results are a stark reminder that extreme weather can strike anywhere
This article was originally published on <a href="http://theconversation.com/">The Conversation</a>. Read the <a href="https://theconversation.com/a-man-scouring-google-earth-found-a-mysterious-scar-in-the-australian-outback-and-now-scientists-know-what-caused-it-239867">original article</a>
<a class="bioLink-kqdDv" href="/author/matej-lipar/">Matej Lipar</a> is an adjunct research fellow in Curtin University&rsquo;s School of Earth and Planetary Sciences
and head of the Department of Physical Geography at the Research Centre of the Slovenian Academy of Sciences and Arts (ZRC SAZU)
Curated by professional editors, <a class="bioLink-kqdDv" href="/author/the-conversation-us/">The Conversation</a> offers informed commentary and debate on the issues affecting our world
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Scientific American maintains a strict policy of editorial independence in reporting developments in science to our readers
The following essay is reprinted with permission from The Conversation
\\"Cycloidal marks\\" can be seen in the tornado scar
Matej Lipar is an adjunct research fellow in Curtin University&rsquo;s School of Earth and Planetary Sciences
The Conversation offers informed commentary and debate on the issues affecting our world
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Hypertrophic scar (HS) is a plaque fibrous and indurated dermal lesion that may cause physical
Intralesional injection of triamcinolone acetonide (TA) is commonly used in clinical practice
which cause unbearable pain and uneven drug delivery within HS tissue
we developed a paper battery powered iontophoresis-driven microneedles patch (PBIMNP) for self-management of HS
The high integration of PBIMNP was achieved by incorporating a paper battery as the power source for iontophoresis
The transdermal drug delivery strategy of PBIMNP combined microneedles and iontophoresis techniques
which can actively deliver 90.19% drug into the HS tissue with excellent in vitro drug permeation performance
PBIMNP administration effectively reduced the mRNA and protein levels
leading to a decrease in the expression of TGF-β1 and Col I associated with HS formation
demonstrating its efficacy in HS treatment
The microneedles and wearable design endow the PBIMNP as a highly promising platform for self-administration on HS treatment
the integration of MN with iontophoresis techniques in a wearable drug delivery patch holds great potential to synergistically enhance the efficacy of drug administration for HS treatment
c The solid-liquid transformation mechanism of gelatin
and blue (α3) lines represent the three branches of the gelatin triple helix structure
d The drug delivery strategy of PBIMNP: pressing and poking
The PBIMNP was developed for HS self-management and personalized treatment, as shown in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41378-024-00823-0#Fig1">1</a>a. PBIMNP mainly consists of three modules (as shown in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41378-024-00823-0#Fig1">1</a>b): (1) Drug storage module: an impermeable ring
The impermeable ring separates the anode and cathode for iontophoresis and provides resilience to MN
The agarose gel and gelatin are served as the anode and cathode of iontophoresis
(2) MN module: The MN is employed to puncture the thickened corneum and create the microchannels for drug diffusion
(3) Iontophoresis module: the paper battery connected with the flexible PCB provides a consistent current for iontophoresis
the solid gelatin loaded with TA is gradually transformed into a liquid state due to the heat transfer from the skin
Then the iontophoresis-driven drug delivery is triggered due to the formation of a closed conductive loop between the reservoir and the agarose gel through skin
The paper battery and the flexible PCB for iontophoresis circuit is extremely simple
the exceptional flexibility of the paper battery and PCB allows the PBIMNP closely conform to the skin
contributing to its outstanding adaptability
The reservoir exhibits a temperature-sensitive property
enabling efficient storage and controlled release of TA at physiological temperature (37 °C)
The iontophoresis-driven delivery rate is primarily determined by the drug concentration
and the current and duration of iontophoresis
the combination of passive diffusion and active iontophoresis-driven penetration may synergistically enhance the efficacy of transdermal drug delivery
</a>a The image of PBIMNP fixed on the upper arm
d The iontophoresis-driven circuit on a flexible PCB
e The optical image of gelatin at approximately 25 °C
g The solid gelatin on the skin at t = 0 s
h The liquid gelatin due to the phase transformation at t = 180 s
i The SEM image of gelatin wrapped with TA
b The current density of PBIMNP during drug delivery
c Impedance performance of PBIMNP during drug delivery
d The penetration performance of PBIMNP on HS
g OCT image of the microchannels in HS skin recovery at 15 min after puncture
h HE image of the microchannels in HS skin recovery at 15 min after puncture
i OCT image of the microchannels in normal skin recovery at 15 min after puncture
j HE image of the microchannels in normal skin recovery at 15 min after puncture
k Heat mapping on the back of a New Zealand rabbit treated with PBIMNP at 0 min
guaranteeing the safety of MN without broken in the skin
thereby effectively preventing foreign body and inflammatory reactions
The initial temperature of PBIMNP was at 4 °C as it had been stored in a refrigerator
the skin temperature rapidly decreased and the average temperature of PBIMNP gradually increased to 34.7 °C within 15 min due to heat conduction from the skin
the PBIMNP temperature remained stable at 35.5 °C without any further increase
indicating minimal influence of iontophoresis current on thermal damage to the skin
</a>Cell viability of HSFBs treated with TA
gelatin and gelatin-wrapped TA at 24 h (a) and 48 h (b) (n = 3)
c Cell viability of HSFBs incubated with MN for 24 h and 48 h
Fluorescence images of HSFBs stained by live/dead assay in control (d)
where live and dead cells show green and red fluorescence
</a>a Schematic diagram of in vitro transdermal drug delivery of PBIMNP using Franz diffusion cells
b In vitro permeability of the four administration approaches at 60 min
c In vitro permeability of the four administration approaches at 1440 min
d The intra-scar retention in HS after in vitro permeability tests
e Schematic illustration of the FEA model of PBIMNP
f The calculated cumulative amount administrated with different methods at 60 min
g The calculated cumulative amount administrated with different methods at 1440 min
h Comparison of the final cumulative amount at 24 h between the in vitro experimental and calculated groups (data are mean ± SD
i The calculated transdermal delivery process administrated with different methods
MNP and PBIMNP can increase drug diffusion depth in the skin
the PBIMNP group showed the most significant effect
indicating its higher potential to promote the deep diffusion of drugs
PBIMNP further enhanced the drug permeability and increased the delivery depth in the HS skin by introduction of iontophoresis with MN
demonstrating the effectiveness and controllability of active iontophoresis on HS treatment
</a>a Time point of drug administration process of PBIMNP on rabbit ear scar
b Heat map of VSS before and after administration
c Brightness of HS skin before and after administration
The L represents the brightness of the scar
d Color of HS skin before and after administration
e SEI changes of HS skin before and after administration
f Hardness changes of HS skin before and after administration
</a>a Relative mRNA expression of TGF-β1 in HS tissues before and after treatment
b Relative mRNA expression of Col I in HS tissues before and after treatment
c Protein expression of TGF-β1 and Col I in HS tissues
d Relative protein expression of TGF-β1 in HS tissues before and after treatment
e Relative protein expression of Col I in HS tissues before and after treatment
the same group of the previous week; $$p &lt; 0.01 vs
the same group of the previous week; $$$p &lt; 0.001 vs
Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41378-024-00823-0#Fig8">8</a>c shows the protein expression of TGF-β1 and Col I in HS tissues measured by western blotting (WB). Prior to administration, all groups showed high expression of both proteins (almost 1.5–2.5 times of normal tissues). Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41378-024-00823-0#Fig8">8</a>d
e shows the gray scale of TGF-β1 and Col I
The expression of TGF-β1 and Col I in the PBIMNP group was 1.69 ± 0.11 times and 1.88 ± 0.37 times than that of normal tissues on day 30
the protein expression of TGF-β1 and Col I significantly decreased in PBIMNP administration
It demonstrates that PBIMNP can significantly reduce the protein expression of TGF-β1 and Col I
further confirming the effectiveness of PBIMNP in HS treatment
relative molecular weight: 434.5 g/mol) was purchased from Shanghai Macklin Biochemical Co.
Gelatin (gum strength of 100g Bloom) was purchased from Shanghai Aladdin Biochemical Technology Co.
Human hypertrophic scar fibroblasts (HSFBs) was obtained from Shanghai Qiansi Biotechnology Center (Shanghai
Dulbecco’s Modified Eagle Medium:Nutrient Mixture F-12 (DMEM/F-12) (Gibco)
and Penicillin - streptomycin (10,000 U/mL) were purchased from Thermo Fisher Scientific Co.
Cell Counting Kit-8 (CCK-8) was got from Dojindo Molecular Technologies
Rabbit Anti-GAPDH (bs-2188R) and Rabbit Anti-TGF beta 1 antibody (bs-0086R) were purchased from Beijing Bioss Antibodies Biotechnology Co.
Anti-collagen I Rabbit pAb (WL0088) was provided by Wanleibio Co.
BCA protein detection kit was purchased from Beijing Pureland Gene Technology Co.
Female New Zealand rabbits weighing 2.2 kg was obtained from Guangdong Medical Experimental Animal Center (Guangdong
China) and maintained under standard conditions with a 12-h light/dark cycle
All procedures used in the animal study were approved by the Animal Ethical and Welfare Committee of Sun Yat-sen University (Approval No
SYSU-IACUC-2023-B0929) and followed the National Institutes of Health guidelines for laboratory animal care and use
The paper battery for powering the PBIMNP was purchased from Jiangsu Enforsai Flexible Electronics Co.
The paper battery has an initial voltage of 1.5 V
A flexible PCB for the iontophoresis-driven drug delivery was fabricated from Shenzhen Senmi Zhizhuo circuit Technology Co.
The MN was fabricated by micro-milling technology from aluminum alloy
The morphology of MN and TA was observed using a field emission scanning electron microscope (SEM) (JSM-6380LA
The temperature-sensitive gelatin was prepared for drug encapsulation
0.176 g gelatin was dissolved in 1 ml of saline and subsequently incubated at room temperature for 30 min
The swollen gelatin was incubated at 70 °C for 5 min and stirred until fully dissolved
1 mg/ml TA powder was added and shaken for 60 s
A 200 μl mixture was refrigerated at 4 °C for 3 min to allow the formation of a drug-loaded gelatin matrix
The PBIMNP includes three modules: drug storage module
The drug storage module consists of three parts: an impermeable ring
The reservoir was prepared by the gelatin loaded with TA
The agarose gel and the reservoir were embedded in the impermeable ring
The MN was inserted into the drug storage module
The flexible PCB was connected with the paper battery for iontophoresis
The HSFbs were cultured in DMEM/F-12 medium supplemented with 10% fetal bovine serum at 37 °C
HSFbs were seeded in 96-well plates at a density of 5 × 103 cells/well and incubated for 24 h to promote adhesion
the original medium was replaced with 100 μL of fresh medium containing TA
the absorption at 450 nm of each well was measured using an ELISA kit from the CCK-8 assay to determine cell viability
the MN were exposed to MN-soaked medium by replacing the medium in the 96-well plate
the absorption of each well was measured using CCK-8 assay
while cell viability was determined using enzyme-linked immunosorbent assay (ELISA)
HS skin treated by microneedles patch loaded with 200 μg TA
HS skin administrated with PBIMNP loaded with 200 μg TA using MN penetration and 1.5 V iontophoresis,(4) Injection group
HS skin injected with 200 μg TA suspension
The Cream group was evenly applied TA cream on HS surface
1 ml of PBS was added after each sampling to maintain consistency
the HS tissue was collected and gently wiped with a cotton
2 ml of methanol was added for lysing and grinding in a mortar
The resulting supernatant after centrifugation represented the TA concentration in HS tissue
The samples were filtered through a microporous filter membrane (pore size of 0.22 μm) and then tested using a HPLC analysis (LC-20AT binary pump
The content level for target TA was monitored specifically at 240 nm
The New Zealand rabbits were anesthetized via the ear marginal vein using pentobarbital sodium (1%
Three wounds with a diameter of 10 mm were created in the auricular abdominal region
with excision of the subcutaneous periosteum while preserving the cartilaginous structure
the wounds were disinfected with povidone-iodine for 7 days
saline was used to soften the wound and remove scabs for promoting wound healing
the rabbit ear scar models were created at the 30th day
The HS model were randomly divided into 7 groups, as listed in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41378-024-00823-0#Tab2">2</a>: (1) NS group
HS skin treated by MNP loaded with 400 μg TA
HS skin administrated by PBIMNP loaded with 400 μg TA using MN penetration and 1.5 V iontophoresis for 30 min
HS skin injected with 400 μg TA suspension
The normal skin of the rabbit ear was employed as the control
The administration of each cycle lasts for 7 days
Twelve female New Zealand rabbits weighing approximately 2.2 kg were selected and randomly divided into 4 groups (n = 3)
Each group represented a administration cycle
the HS tissue was photographed and measured
and histological and biological tests were conducted on day 37 (7 days after the 1st administration)
day 44 (7 days after the 2nd administration)
and day 51 (7 days after the 3rd administration) following establishment of the HS model on day 30
After the HS model was established (day 30)
7 days after the 1st administration (day 37)
7 days after the 2nd administration (day 44) and 7 days after the 3rd administration (day 51)
the HS tissues were photographed and measured for histological and biological tests
The appearance of HS tissue was recorded using a macro-camera
Following a 2 s pressure on the HS tissue with a slide
the changes in HS were observed and evaluated based on the Vancouver Scar Scale (VSS)
The brightness and color changes of HS tissue were quantify using Image J
the thickness of HS tissue was measured using a Vernier caliper and converted into a scar index (SEI)
the hardness of HS tissue was assessed using a Shore hardness tester (Shore HT-6510OO
The HS tissues were wrapped in tin foil and fixed in 4% paraformaldehyde for 48 h
The embedded sections underwent histological staining with HE
The HE was employed to visualize tissue distribution
quantify somatic cell density per unit area
The Masson’s trichrome was utilized to evaluate collagen volume fraction (CVF) within the tissues
The HE and Masson sections were observed using EVOS FL Auto microscope (Life Technologies Co.
The Sirius red staining was employed to determine the ratio of type I to type III collagen proteins in the tissues
The stained sections with Sirius red staining were observed using NIKON digital sight DS-FI2 camera (Nikon Instrument Co.
Japan) and analyzed with Image-Pro Plus 6.0 software to calculate the collagen protein ratio
Total RNA was isolated from the collected samples using TRIzol reagent
the RNA was reverse transcribed to cDNA using the agarose gel electrophoresis
The same amount of cDNA was used for RT-qPCR
Cycles were performed at 95 °C for 3 min followed by 40 cycles of 95 °C for 5 s and 60 °C for 30 s
The fold change was calculated using the 2−ΔΔCT method
The oligonucleotide primers used for PCR amplification were as follows:
Forward primer: ACC ATC TTC CAG GAG CGA GAT
Reverse primer: TGA TGA CCC TTT TGG CTC CG
Forward primer: GTG GAC ATC AAC GGG ATC AG
Reverse primer: GCA GTT CTT CTC TGT GGA GC
Forward primer: CCA GAG TGG AGC AGT GGT TAC
Reverse primer: TGC AGG TTT CGC CAG TAG AG
The skin tissues were digested and grounded with presselly 24 (Bertin
France) in RIPA lysate and total proteins were extracted with a mixture of protease inhibitors
The total protein concentration was then detected with BCA protein detection kit
Skin tissue bundle proteins were isolated by 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred to PVDF membrane
which was sealed with 5% emulsion at room temperature
The proteins and primary antibodies were incubated at 4 °C overnight
The PVDF membrane was washed with 0.1% Tween PBS (PBST)
the secondary antibodies were incubated at room temperature for 2 h
and the PVDF membrane was washed with PBST again
The protein signals were detected by an automated chemiluminescence image analysis system and gray analysis was performed using Image J
The data were presented as mean ± standard deviation
Statistical comparisons were performed using one-way analysis of variance (ANOVA) after normality and homogeneity tests using SPSS (version 26.0
International Business Machines Corporation
The Turkey test was used for post analysis of individual groups
with p &lt; 0.05 considered statistically significant
we developed a paper battery powered iontophoresis-driven microneedles patch for HS treatment with a delivery strategy that involves “pressing and poking
The microchannels in HS created by PBIMNP puncture were lasted for 420 min without closure (30 min for normal skin)
thereby significantly enhances the efficiency of transdermal drug delivery into HS tissues
The storage and controlled release of TA powder was accomplished through the phase transformation of gelatin
The iontophoresis-driven drug delivery of PBIMNP was powered using a thin paper battery
In vitro experiments demonstrated that PBIMNP could deliver 90.19% of the drug effectively into HS tissue and retained 51.78% of the drug in HS tissue
In vivo administration of rabbit ear scars also demonstrated the significant efficacy of PBIMNP in the HS management
the PBIMNP effectively avoid the side effects associated with injection
reduced the mRNA and proteins expression of HS
and facilitated a regular arrangement of collagen fibers
the highly integrated PBIMNP provides a possibility for home-care management of HS
Molecular features of hypertrophic scars after thermal injury: is there a biologic basis for laser therapy
Therapeutic targeting of mechanical stretch-induced fak/erk signaling by fisetin in hypertrophic scars
An updated review of hypertrophic scarring
Microneedle-mediated biomimetic cyclodextrin metal organic frameworks for active targeting and treatment of hypertrophic scars
Desferrioxamine enhances 5-aminolaevulinic acid-induced protoporphyrin ix accumulation and therapeutic efficacy for hypertrophic scar
Mapping the 3d remodeling of the extracellular matrix in human hypertrophic scar by multi-parametric multiphoton imaging using endogenous contrast
Modulation of hypertrophic scar formation using amniotic membrane/electrospun silk fibroin bilayer membrane in a rabbit ear model
Hypertrophic scarring: the greatest unmet challenge after burn injury
Transdermal delivery of chinese herbal medicine extract using dissolvable microneedles for hypertrophic scar treatment
Efficacy of a triamcinolone acetonide-loaded dissolving microneedle patch for the treatment of hypertrophic scars and keloids: a randomized
Combining scar-modulating agents for the treatment of hypertrophic scars and keloids: a systematic review
Strategy for hypertrophic scar therapy: improved delivery of triamcinolone acetonide using mechanically robust tip-concentrated dissolving microneedle array
The safety and efficacy of intralesional triamcinolone acetonide for keloids and hypertrophic scars: a systematic review and meta-analysis
Advances of microneedles in biomedical applications
Down-regulating scar formation by microneedles directly via a mechanical communication pathway
Microneedle physical contact as a therapeutic for abnormal scars
Bilayer dissolving microneedle array containing 5-fluorouracil and triamcinolone with biphasic release profile for hypertrophic scar therapy
Co-delivery of triamcinolone acetonide and verapamil for synergistic treatment of hypertrophic scars via carboxymethyl chitosan and bletilla striata polysaccharide-based microneedles
Enhanced in vitro efficacy for inhibiting hypertrophic scar by bleomycin-loaded dissolving hyaluronic acid microneedles
Iontophoresis-mediated direct delivery of nucleic acid therapeutics
to internal organs via non-blood circulatory pathways
Iontophoresis of basal insulin controlled delivery based on thermoplastic polyurethane
Transdermal delivery of insulin using combination of iontophoresis and deep eutectic solvents as chemical penetration enhancers: In vitro and in vivo evaluations
Iontophoretic drug delivery for the treatment of scars
Acetic acid iontophoresis for recalcitrant scarring in post-operative hand patients
Permeation effect analysis of drug using raman spectroscopy for iontophoresis
Portable iontophoresis device for efficient drug delivery
The impact of sugar alcohols and sucrose on the physical properties
Long-term storage stability of type a and type b gelatin gels: the effect of bloom strength and co-solutes
Characterization of the thermal behavior and structural properties of a commercial high-solids confectionary gel made with gelatin
Small and large oscillatory shear behaviors of gelatin/starch system regulated by amylose/amylopectin ratio
Riboflavin mediated uv crosslinking of chitosan-gelatin cryogels for loading of hydrophobic bioactive compounds
Agar/gelatin bilayer gel matrix fabricated by simple thermo-responsive sol-gel transition method
In-vitro characterization of buccal iontophoresis: the case of sumatriptan succinate
Correlation between elastic modulus and clinical severity of pathological scars: a cross-sectional study
Iontophoresis-driven porous microneedle array patch for active transdermal drug delivery
Transdermal delivery of sumatriptan succinate using iontophoresis and dissolving microneedles
Gelatin/nanofibrin bioactive scaffold prepared with enhanced biocompatibility for skin tissue regeneration
Treatment of keloids: a meta-analysis of intralesional triamcinolone
Efficacy and safety of intralesional triamcinolone versus combination of triamcinolone with 5-fluorouracil in the treatment of keloids and hypertrophic scars: a systematic review and meta-analysis
Iontophoresis-driven microneedle patch for the active transdermal delivery of vaccine macromolecules
Smartphone-powered iontophoresis-microneedle array patch for controlled transdermal delivery
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This research was financially supported by the Shenzhen Science and Technology Program (Project No
the National Natural Science Foundation of China (Project No
the Natural Science Foundation of Guangdong Province (Project No
the Shenzhen Medical Research Fund (Project No
and the Foundation of Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument (Project No
Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument
State Key Laboratory of Optoelectronic Materials and Technologies
School of Electronics and Information Technology
designed and performed most of the experiments
contributed to the in-vivo experiments and collected data
helped with the in-vivo experiments and developed the control circuit design
contributed to the COMSOL numerical simulations
contributed to the revision of the manuscript
helped with the evaluation of the data analysis
contributed to the evaluation of hypertrophic scar treatment and interpretation
contributed to the evaluation of references and graphics
guided the research and provided advice on this work and revision of the manuscript
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper
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DOI: https://doi.org/10.1038/s41378-024-00823-0
Newborns with heart complications can rely on their newly developed immune systems to regenerate cardiac tissues
most adults struggle to regenerate healthy heart tissue
A new Northwestern Medicine study in experimental animals reveals a critical difference in how macrophages — a part of the immune system — help repair the heart in newborns versus adults after a heart attack
highlights a fundamental difference in how the immune system drives healing based&nbsp;on age
We might one day improve tissue repair after a heart attack in adults.”
“Understanding why newborns can regenerate their hearts while adults cannot will open the door to developing treatments that could ‘reprogram’ adult macrophages,” said first and co-corresponding author Connor Lantz
lead scientist of the bioinformatics core at the Comprehensive Transplant Center at Northwestern University Feinberg School of Medicine
macrophages perform a process called&nbsp;efferocytosis
This process triggers the production of a bioactive lipid called&nbsp;thromboxane
signaling nearby heart muscle cells to divide
and allowing the heart to regenerate damaged&nbsp;heart muscle
we might one day improve tissue repair after a heart attack in adults,” Lantz said
The study examined how the immune system responds to heart injury in mice of different ages
including newborn mice (one day old) and adult mice (eight weeks old)
The researchers found the ability of macrophages to engulf dying cells was enhanced in newborn mice due to increased expression of MerTK
when the scientists blocked this key receptor
newborn mice lost their ability to regenerate their hearts
resembling adult hearts after a heart attack
Engulfment of dying cells by newborn macrophages triggered a chemical chain reaction that produced a molecule called thromboxane A2
which unexpectedly stimulated heart muscle cells to multiply and repair the damage
nearby muscle heart cells in newborns are primed to respond to thromboxane A2
leading them to change their metabolism to support their growth and healing
this process did not work the same way — after an injury
their macrophages did not produce enough thromboxane A2
limiting their ability to regenerate heart tissue
<a href="https://www.feinberg.northwestern.edu/faculty-profiles/az/profile.html?xid=21261">Edward B. Thorp</a>
professor of experimental pathology at Feinberg
<a href="mailto:news@northwestern.edu">news@northwestern.edu</a>
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All codes used in this article are available from the corresponding authors upon request
Bound-state eigenfunctions of classically chaotic Hamiltonian systems: scars of periodic orbits
Quantum Chaos: An Introduction (American Association of Physics Teachers
Chaos in Classical and Quantum Mechanics Vol
Scattering and absorption of surface electron waves in quantum corrals
Imaging fractal conductance fluctuations and scarred wave functions in a quantum billiard
Imaging electron wave functions inside open quantum rings
Periodic scarred states in open quantum dots as evidence of quantum Darwinism
Direct imaging of electron states in open quantum dots
Recurrent quantum scars in a mesoscopic graphene ring
Imaging quantum interference in stadium-shaped monolayer and bilayer graphene quantum dots
Imaging electrostatically confined Dirac fermions in graphene quantum dots
Visualization and manipulation of bilayer graphene quantum dots with broken rotational symmetry and nontrivial topology
Strong quantum scarring by local impurities
Controllable quantum scars in semiconductor quantum dots
Chiral scars in chaotic dirac fermion systems
Quantization of massive Dirac billiards and unification of nonrelativistic and relativistic chiral quantum scars
Keski-Rahkonen, J., Graf, A. &amp; Heller, E. Antiscarring in chaotic quantum wells. Preprint at <a href="https://arxiv.org/abs/2403.18081" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="https://arxiv.org/abs/2403.18081">https://arxiv.org/abs/2403.18081</a> (2024)
Zum quantensatz von Sommerfeld und Epstein
Einstein’s unknown insight and the problem of quantizing chaos
Ubiquitous quantum scarring does not prevent ergodicity
Genuine many-body quantum scars along unstable modes in Bose–Hubbard systems
Quantum scars and regular eigenstates in a chaotic spinor condensate
Probing many-body dynamics on a 51-atom quantum simulator
The Semiclassical Way to Dynamics and Spectroscopy (Princeton Univ
Uniform distribution of eigenfunctions on compact hyperbolic surfaces
Characterization of chaotic quantum spectra and universality of level fluctuation laws
Experimental observation of scarred eigenfunctions of chaotic microwave cavities
Experimental determination of billiard wave functions
Experimental visualization of acoustic resonances within a stadium-shaped cavity
Quantum mirages formed by coherent projection of electronic structure
Confinement of electrons to quantum corrals on a metal surface
An on/off Berry phase switch in circular graphene resonators
Measuring and tuning the potential landscape of electrostatically defined quantum dots in graphene
Giant orbital magnetic moments and paramagnetic shift in artificial relativistic atoms and molecules
Creating and probing electron whispering-gallery modes in graphene
Klein tunnelling and electron trapping in nanometre-scale graphene quantum dots
Coexistence of electron whispering-gallery modes and atomic collapse states in graphene/WSe2 heterostructure quantum dots
Wave function scarring effects in open stadium shaped quantum dots
Two-dimensional gas of massless Dirac fermions in graphene
Chiral tunnelling and the Klein paradox in graphene
Neutrino billiards: time-reversal symmetry-breaking without magnetic fields
Electron optics with pn junctions in ballistic graphene
Dielectric microcavities: model systems for wave chaos and non-Hermitian physics
Quantum interference and Klein tunnelling in graphene heterojunctions
Wavefunction Mapping and Magnetic Field Response of Electrostatically Defined Graphene Quantum Dots
A transfer technique for high mobility graphene devices on commercially available hexagonal boron nitride
Ge, Z. et al. Source data for “Direct visualization of relativistic quantum scars”. Zenodo. <a href="https://doi.org/10.5281/zenodo.13751637" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.5281/zenodo.13751637">https://doi.org/10.5281/zenodo.13751637</a> (2024)
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Zettl for discussions about quantum chaos at the initial stages of the project; D
Liu for assistance with STM cryogen refilling at the beginning of the project; and the Hummingbird Computational Cluster team at UC Santa Cruz for providing computational resources for the numerical tight-binding calculations performed in this work
acknowledge support from the National Science Foundation under award DMR-1753367
acknowledges support from the Army Research Office under contract W911NF-17-1-0473 and the Gordon and Betty Moore Foundation award 10.37807/GBMF11569
acknowledge support from the Research Collaborations grant 1185409051 under the International Science Partnerships Fund
acknowledges support from Lloyd Register Foundation Nanotechnology Grant
acknowledge support from the JSPS KAKENHI (grant numbers 21H05233 and 23H02052) and the World Premier International Research Center Initiative (WPI)
acknowledges support from the Harvard Quantum Initiative
acknowledges support from the Emil Aaltonen Foundation and the Oskar Huttunen Foundation
Paulson School of Engineering and Applied Sciences
Department of Chemistry and Chemical Biology
Research Center for Materials Nanoarchitectonics
Research Center for Electronic and Optical Materials
Henry Royce Institute for Advanced Materials
conceived of the work and designed the research strategy
fabricated the samples and performed data analysis under the supervision of J.V.J
carried out tunnelling spectroscopy measurements with assistance from P.P
performed quantum dynamics simulations under the supervision of E.J.H
performed classical dynamics and tight-binding simulations with input from S.S
All authors discussed the paper and commented on the paper
a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law
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DOI: https://doi.org/10.1038/s41586-024-08190-6
Here’s what you need to know about eczema and scarring
as well as scar treatment and prevention.&nbsp;
Scarring is a natural part of your skin’s healing process. “Scars are secondary to something like scratching, itching, digging in the skin or infection,” says <a href="https://pariserderm.com/aboutpariserdermatology/meet-our-providers/david-m-pariser-m-d/" target="_blank" rel="noreferrer noopener">Dr. David Pariser</a>
dermatologist at Pariser Dermatology Specialists in Norfolk
Virginia and a former President of the American Academy of Dermatology.&nbsp;
a board-certified dermatologist at Massachusetts General Hospital in Boston
Skin infections are also a common problem for people with eczema. “Scratching also increases the risk of infection, which can further damage the skin and contribute to an eczema flare,” said <a href="https://www.uwmedicine.org/bios/vivian-shi" target="_blank" rel="noreferrer noopener">Dr. Vivian Shi</a>
professor of dermatology and director of clinical trials at the University of Washington in Seattle
The damage from skin infections can lead to scarring
These changes in skin color can look like scars (even though they are not scars)
There is no magic cure to get rid of scars completely. The best option is to avoid getting them in the first place. If you have eczema, this means having an effective <a href="https://nationaleczema.org/blog/6-essential-products-and-ingredients-for-eczema/" target="_blank" rel="noreferrer noopener">eczema care routine</a> to help prevent itch
which can all lead to skin injury and infections
“Try to treat the eczema and itch so as not to scratch,” said Dr
I would recommend thick emollients on the broken skin
and out of the sun is important to prevent discoloration
there may be a concern for infection and topical antibiotics may be necessary,” advised Dr
Shi also said using gentle pressure or cool compresses can help prevent scratching
She also advised people with eczema to “keep nails trimmed short to minimize damage if scratching does occur.”
According to the <a href="https://www.plasticsurgery.org/news/blog/scar-treatment-101-what-are-the-first-steps" target="_blank" rel="noreferrer noopener">American Society of Plastic Surgeons</a>
scars may improve and fade over the first two years depending on the severity and location on the body
it’s not likely the scar will fade anymore
there are some treatment options that can help improve the appearance of scars
“Unfortunately all scar treatments currently on the market do not have robust scientific evidence saying they are better than just using Vaseline,” said Dr
patients have told me that topicals such as Mederma
Bio-Oil and hydrocolloid bandages are helpful.”
silicone gel sheets or scar creams can help soften scars while being gentle on sensitive skin.” She also suggested using petroleum jelly on open sores or wounds to facilitate and speed-up wound healing
fragrance-free moisturizer daily can support the skin’s natural repair process,” she said
it’s important that you talk to a dermatologist or plastic surgeon who has expertise in eczema
You should go to someone who understands eczema
can assess your scars and make the most appropriate recommendation (while not aggravating or irritating your already-sensitive skin).&nbsp;
Here are some basic ways to prevent injuries from scarring:&nbsp;
“Preventing eczema flares is the best scar prevention,” said Dr
“Flares can be prevented by strategically avoiding known triggers and keeping the skin well moisturized
Flares should be treated promptly with prescribed medications to reduce inflammation and itching.”
NEA is a qualified 501(c)(3) EIN 93-0988840
&copy; 2002-2025 National Eczema Association
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Quantum many-body scars are rare eigenstates hidden within the chaotic spectra of many-body systems
representing a weak violation of the eigenstate thermalization hypothesis (ETH)
as well as other non-thermal states in complex quantum systems
the nature of other non-thermal states lacking simple analytical characterization remains an open question
we employ tools from quantum machine learning—specifically
(enhanced) quantum convolutional neural networks (QCNNs)
to explore hidden non-thermal states in chaotic many-body systems
Our simulations demonstrate that QCNNs achieve over 99% single-shot measurement accuracy in identifying all known scars
we successfully identify new non-thermal states in models such as the xorX model
and the far-coupling Su-Schrieffer-Heeger model
some of these non-thermal states can be approximately described as spin-wave modes of specific quasiparticles
We further develop effective tight-binding Hamiltonians within the quasiparticle subspace to capture key features of these many-body eigenstates
we validate the performance of QCNNs on IBM quantum devices
achieving single-shot measurement accuracy exceeding 63% under real-world noise and errors
with the aid of error mitigation techniques
Our results underscore the potential of QCNNs to uncover hidden non-thermal states in quantum many-body systems
These dynamics blend regular and complex behavior
sitting between full integrability and complete chaos
</a>The wave functions inside and outside the scar subspace are treated as two classes that are input to the QCNN as training data
The QCNN consists of convolution layers(C)
pooling layers(P) and a fully connected layer(F)
Then QCNN is able to identify a larger subspace (dashed circles) of special states that are potential candidates for approximate scars
where \({{\mathcal{N}}}_{m}\) is the normalization factor and the operator
with projectors \({P}_{i}^{0}={\left\vert 0\right\rangle }_{i}\left\langle 0\right\vert\) and \({P}_{i}^{1}={\left\vert 1\right\rangle }_{i}\left\langle 1\right\vert\)
The domain wall number in the xorX model is conserved as \(\left[H,{\sum }_{i}{\sigma }_{i}^{z}{\sigma }_{i+1}^{z}\right]=0\)
The far-coupling Ising SSH model is realized on the platform of superconducting circuit<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Zhang, P. et al. Many-body hilbert space scarring on a superconducting processor. Nat. Phys. 19, 120 (2023)." href="/articles/s41534-025-01005-0#ref-CR33" id="ref-link-section-d454151672e1883">33</a>
The serpentine routing makes it flexible to tune the coupling between different qubits
where \({\sigma }^{+}=| 1\left.\right\rangle \left\langle \right.0|\) and \({\sigma }^{-}=| 0\left.\right\rangle \left\langle \right.1|\) represent the raising and lowering operators
Je and Jo denote the coupling strengths at even and odd positions
Jnn is the next-next-nearest-neighbor coupling strength which breaks integrability
Both numerical simulations and experimental data provide evidence for the existence of scar states in this model
which exhibit a significant overlap with the reference state \({\left\vert {Z}_{1001}\right\rangle = \left\vert 1001\right\rangle }^{\otimes n/4}\)
The red crosses are the eigenstates marked by the QCNN
The number of spins is 12 while two of them at the boundaries are fixed
</a>The plot shows fidelity as a function of time, with the initial state being an equal-amplitude superposition of exact scar states (blue dashed line), additional states marked by QCNN (red solid line), and non-marked states (green dash-dotted line). The parameters are the same as in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41534-025-01005-0#Fig2">2</a>
</a>The results are shown for architectures with 2 (blue solid line) and 3 (orange dashed line) convolutional layers before the pooling layers
The numerical results presented in the previous section suggest a more detailed study on the nature of the additional non-thermal states found by QCNN in the xorX model in Eq. (<a data-track="click" data-track-label="link" data-track-action="equation anchor" href="/articles/s41534-025-01005-0#Equ1">1</a>)
The PR indicates that these states are predominantly localized within a small subregion of the full Hilbert space
we demonstrate that some of these non-thermal states can be understood in terms of quasiparticles
We will construct effective tight-binding Hamiltonians that approximately describe the spin-wave modes of these quasiparticles
reproducing key features of the exact many-body eigenstates
where i is the position of the domain wall. In this subspace, the dynamics is fully integrable.
</a>These eigenstates are characterized by distinct eigen-energies with similar entanglement entropy
The above effective Hamiltonian can be readily diagonalized
the Hamiltonian in momentum space takes the form:
The QCNN successfully identifies states within this integrable subspace
marking those with energies similar to the exact scar states
</a>a, c ndw = 2; b, d ndw = 3. The red crosses indicate the eigenstates identified by the QCNN. The green solid curves represent analytical results from the ferromagnetic magnon bound state approximation, while the purple dashed curves correspond to those obtained from the anti-ferromagnetic magnon bound state approximation. Other parameters are λ = J = 10Δ.
The red crosses indicate the eigenstates identified by the QCNN
The green solid curves represent analytical results from the ferromagnetic magnon bound state approximation
while the purple dashed curves correspond to those obtained from the anti-ferromagnetic magnon bound state approximation
blue spins form a ferromagnetic background for the propagation of the bound state
blue spins are trapped in an antiferromagnetic configuration
a The motion of a ferromagnetic bound state (red spins)
b The motion of an anti-ferromagnetic bound state (red spins)
We begin by analyzing the motion of a single magnon in a background of down spins, as depicted in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41534-025-01005-0#Fig8">8</a>a. In Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41534-025-01005-0#Fig9">9</a>a
we present the total weight of each eigenstate within the single-magnon configuration subspace
The data reveal that certain marked states exhibit significantly larger weights in this subspace
The motion of this single magnon will necessarily involve intermediate configurations where the magnon first grows into longer strings and then shrinks
consider the following intermediate configurations (totaling four configurations): { ⋯ 00111100 ⋯ 
The effective Hamiltonian within this subspace has the following form in momentum space (assuming PBC):
</a> The weights of the ferromagnetic magnon bound state are shown in a and b while the weights of the anti-ferromagnetic magnon bound states are shown in c and d
The special states marked by QCNN have anomalously large weight on the subspace of a particular type of quasiparticle
we can similarly write down an effective Hamiltonian:
these trivial states are not marked by the QCNN
The non-thermal states discussed in this section
are situated in the middle of the energy spectrum
We demonstrate the performance of our QCNN on IBM’s quantum hardware
with the training process carried out classically via noise-free simulations
We then prepare the exact scar state \(| {{\mathcal{S}}}_{1}\left.\right\rangle\) using a shallow circuit
which is fed into the trained QCNN on the quantum device to evaluate its performance
we introduce a shallow general layer as a preprocessing step to enhance hardware efficiency
the learning circuit is optimized by reducing the number of two-qubit gates
</a>The experiment was conducted in 12 groups
each spaced hours apart to assess drift error
Each group involved 104 measurement repeats to determine the success probability
Error bars indicated by the shaded region represent the standard error across different groups
b Two different methods for boosting errors in the circuit: a adding single-qubit Pauli errors; b replacing U with \(U{\left({U}^{\dagger }U\right)}^{r}\)
c Error mitigation according to input fidelity
Linear regression suggests P1 ≈ 67 ± 1% in the limit of a perfect input state
The red and blue dots correspond to Monte Carlo sampling of single-qubit Pauli errors (averaged over 103 noise realizations) and repeating U†U
d Error mitigation according to error rate in the second approach
Linear regression using data prior to saturation suggests P1 ≈ 63 ± 1% in the limit of a perfect input state
we instead plot the success rate P1 against the number of appended layers r in the second approach
By repeating the gates using \(U\to U{\left({U}^{\dagger }U\right)}^{r}\)
the error is assumed to be 1 + 2r times that of U
The success probability decreases with increasing r and eventually saturates due to the finite size of the Hilbert space
Regression analysis before saturation suggests that the success rate of the QCNN
Although experimental errors weaken the performance of QCNN
the classification signal is not completely drowned out by the noise
Our experimental results demonstrate that QCNN can still achieve a good success rate in the presence of noise
which we recover by using error mitigation
In this work we mitigate the state preparation noise
while the QCNN circuit error mitigation will be deferred to future works dedicated to full experimentation
a symmetric subspace \({\mathcal{K}}\) can be constructed
The quasimodes within this subspace can be viewed as approximations of certain eigenstates
The subspace \({\mathcal{K}}\) is spanned by the basis states
</a>a Overlap between the eigenstates and the \(| {Z}_{2}\left.\right\rangle\) state
with red crosses marking the states identified by the QCNN
The yellow squares are the eigenstates of quasimodes in the symmetric subspace \({\mathcal{K}}\)
b Weights of each eigenstates within the symmetric subspace \({\mathcal{K}}\)
c Density of QCNN-identified states based in (a)
d Density of energy differences between the QCNN-identified states in (a)
only states with non-zero overlap with the \(| {Z}_{2}\left.\right\rangle\) state are counted
with smoothing applied using Gaussian broadening of each points set to 0.1Ω/2
indicating that their linear superposition can lead to stable oscillations
</a>a Overlap between the eigenstates and the Z1001 state
b Density of QCNN-identified states based in (a)
c Density of energy differences between the QCNN-identified states in (a)
only states with non-zero overlap with the \(| {Z}_{1001}\left.\right\rangle\) state are counted
with smoothing applied using Gaussian broadening of each points set to 0.25Je
We extend the QCNN approach to other models and discover additional states
The energy difference spectrum reveals that these identified states are non-thermal with relatively small dispersion
This demonstrates the QCNN’s capability to identify non-thermal states across various models
Analytical understanding of these non-thermal states
similar to that presented for the xorX model in this work
A deeper exploration of this correspondence and its underlying mechanisms remains an open avenue for further investigation
the QCNN trained on scar states effectively identifies additional non-thermal states
Some of them primarily occupy a small fraction of the Hilbert space and can be approximately described as spin-wave modes of various quasiparticles
We construct effective Hamiltonians based on this framework
capturing key features of the exact many-body eigenstates
we validate our approach on a quantum device
achieving a notable success rate with the use of error mitigation techniques
This study highlights the potential of QCNNs in uncovering hidden non-thermal states within the many-body spectrum
paving the way for future research into more complex quantum systems and their non-thermal behavior
Our approach utilizes QML by feeding known scar states as the training data set
as their number grows linearly with the number of qubits
whereas the Hilbert space expands exponentially
we include superpositions of QMBS states in our training dataset
enhancing the model’s ability to learn from a small set of scar states
The pooling layers measure a subset of qubits after the quantum gates
reducing the number of operations needed in subsequent steps
This not only makes the quantum circuit shallower but also reduces noise
The fully connected layer then consolidates the information from the remaining qubits at the end of the process
</a>The rate of marked states rm is the ratio of marked states to the total dimension of the Hilbert space
Each point represents a distinct set of circuit parameters and a corresponding training iteration
The orange dashed line indicates the rate of marked (scar) states in the input data
The number of trainable parameters is given by nθ = 12 + 3(9nl + 3)
where nl is the number of convolutional layers preceding the pooling layers
Our study focuses on this transition to identify previously unknown non-thermal states with scar-like characteristics
The data supporting the findings of this study are available from the first author upon reasonable request
The theoretical results of the manuscript are reproducible from the analytical formulas and derivations presented therein
Additional code is available from the first author upon reasonable request
Proof of the ergodic theorem and the h-theorem in quantum mechanics: Translation of: Beweis des ergodensatzes und des h-theorems in der neuen mechanik
Foundation of statistical mechanics under experimentally realistic conditions
Pseudointegrable systems in classical and quantum mechanics
Quantum statistical mechanics in a closed system
Thermalization and its mechanism for generic isolated quantum systems
Entanglement and the foundations of statistical mechanics
Testing whether all eigenstates obey the eigenstate thermalization hypothesis
Quantum many-body scars and weak breaking of ergodicity
Quantum many-body scars and hilbert space fragmentation: a review of exact results
Disorder-tunable entanglement at infinite temperature
Quantum many-body scar states with emergent kinetic constraints and finite-entanglement revivals
Microscope for quantum dynamics with planck cell resolution
Quantum dynamical tunneling breaks classical conserved quantities
Weak integrability breaking perturbations of integrable models
Volume-entangled exact eigenstates in the pxp and related models in any dimension
Mordacci, M., Ferrari, D. &amp; Amoretti, M. Multi-class quantum convolutional neural networks. Preprint at <a href="https://arxiv.org/abs/2404.12741" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="https://arxiv.org/abs/2404.12741">https://arxiv.org/abs/2404.12741</a> (2024)
Branching quantum convolutional neural networks
Realizing quantum convolutional neural networks on a superconducting quantum processor to recognize quantum phases
Model-independent learning of quantum phases of matter with quantum convolutional neural networks
Unsupervised detection of decoupled subspaces: Many-body scars and beyond
Unsupervised learning of quantum many-body scars using intrinsic dimension
Cenedese, G. et al. Shallow quantum circuits are robust hunters for quantum many-body scars. Preprint at <a href="https://arxiv.org/abs/2401.09279" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="https://arxiv.org/abs/2401.09279">https://arxiv.org/abs/2401.09279</a> (2024)
Weak ergodicity breaking from quantum many-body scars
Exact quantum many-body scar states in the rydberg-blockaded atom chain
Many-body hilbert space scarring on a superconducting processor
Quantum many-body scar models in one-dimensional spin chains
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Graph-theoretical proof of nonintegrability in quantum many-body systems: Application to the PXP model
Buhrman, H., Linden, N., Mančinska, L., Montanaro, A. &amp; Ozols, M. Quantum majority vote. Preprint at <a href="https://arxiv.org/abs/2211.11729" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="https://arxiv.org/abs/2211.11729">https://arxiv.org/abs/2211.11729</a> (2022)
Fate of quantum many-body scars in the presence of disorder
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Correspondence principle for many-body scars in ultracold rydberg atoms
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Meta-machine-learning-based quantum scar detector
Bermejo, P. et al. Quantum convolutional neural networks are (effectively) classically simulable. Preprint at <a href="https://arxiv.org/abs/2408.12739" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="https://arxiv.org/abs/2408.12739">https://arxiv.org/abs/2408.12739</a> (2024)
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and quantum many-body scars in constrained models: Matrix product state approach
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Cost function dependent barren plateaus in shallow parametrized quantum circuits
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The authors acknowledge discussions with Zlatko Papic on quasi-modes in the PXP model
acknowledge support from University of Southern California
acknowledges support from Peking University
This research was conducted using IBM Quantum Systems provided through USC’s IBM Quantum Innovation Center
Ming Hsieh Department of Electrical and Computer Engineering
proposed the study of scar states using quantum machine learning
designed the framework of quantum machine learning
performed numerical analyses and experiments
provided insights on quantum many body scars
with inputs and contributions from all authors
<a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/s41534-025-01005-0?format=refman&amp;flavour=citation">Download citation</a>
DOI: https://doi.org/10.1038/s41534-025-01005-0
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forming protective scar tissue around the damaged area to stabilize and protect it
too much scarring can prevent nerves from regenerating
impeding the healing process and leading to permanent nerve damage
Now, UC San Francisco researchers have discovered how a rarely studied cell type controls the formation of scar tissue in spinal cord injuries. Activating a molecular pathway within these cells, the team showed in mice, lets them control levels of spinal cord scarring. The new research appears Sept. 18 in <a href="https://www.nature.com/articles/s41586-024-07889-w">Nature</a>
“By illuminating the basic signaling biology behind spinal cord scarring, these findings raise the possibility of one day being able to pharmacologically fine-tune the extent of that scarring,” said <a href="https://profiles.ucsf.edu/david.julius">David Julius</a>
and winner of the 2021 Nobel Prize in Physiology or Medicine
Spinal cord injuries – caused by physical trauma such as vehicle accidents
or sports collisions – can damage the nerves that run down the length of the spinal cord and coordinate messages between the brain and the rest of the body
Treatments largely revolve around surgery or braces to stabilize the spine
drugs to control pain and swelling and physical therapy
Julius and his colleagues were studying the function of a poorly understood group of neurons
called cerebrospinal fluid (CSF)-contacting neurons
These neurons are found along the hollow channel that runs through the center of the cord
and they extend into the spinal fluid that fills the channel
This image shows cerebrospinal fluid-contacting neurons genetically labeled with a fluorescent green marker
These neurons are found in the ependymal layer shown in blue
which is a thin layer of specialized epithelial cells surrounding the central canal
a hollow space in the spinal cord that is filled with fluid
This image shows cerebrospinal fluid-contacting neurons
genetically labeled with a fluorescent marker (green)
These neurons are found in the ependymal layer (shown in blue)
The team developed a new method to label these neurons
isolate them and measure which genes were active in the cells
That led them to discover that the cells express a receptor that senses κ-opioids
which are naturally produced by the human body
The group went on to identify the spinal cord cells that produce κ-opioids
and show how the molecules excite the CSF-contacting neurons
Further experiments revealed that signaling through these κ-opioids decreased in the aftermath of a spinal cord injury
transforming nearby cells into scar tissue for protection
The researchers tried delivering extra κ-opioids to the mice
and the scarring was reduced; but the spinal cord injuries were more severe
and the mice did not recover their motor coordination as well
“κ-opioids might give us a way, after a spinal cord injury, to pharmacologically modulate the fine balance between producing enough scar tissue and having excessive scarring,” said <a href="https://profiles.ucsf.edu/wendy.yue">Wendy Yue</a>
a former postdoctoral research fellow in Julius’ lab who is now an assistant professor of physiology at UCSF and the first author of the new paper
κ-opioids are different from commercial opioid drugs such as oxycodone and hydrocodone
Scientists must do more work to understand why κ-opioid levels drop after spinal cord injuries
as well as what the ideal levels of scarring are to support optimal healing
Further preclinical studies also would be required before testing κ-opioid-related drugs in humans with spinal cord injuries
Julius said the new findings underscore the importance of carrying out basic scientific research on how various cell types and signaling molecules work
“We were not looking for a way to control spinal cord healing,” he said
“This came out of asking questions about this mysterious cell type
and then running into a mechanism that is both biologically interesting and could eventually have some therapeutic potential.”
Authors: The other authors were Kouki Touhara
Funding: The work was supported by a Howard Hughes Medical Institute Hanna Gray Fellowship
a Croucher Fellowship for Postdoctoral Research
a Damon Runyon Cancer Research Foundation Fellowship (DRG-2387-30)
a New Frontier Research Award from the UCSF Program for Breakthrough Biomedical Research
and the National Institutes of Health (R01EY030138
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Hypertrophic scars arise from aberrant wound healing and can lead to functional and aesthetic impairments
One of the common interventions for treating hypertrophic scars is fractional carbon dioxide (CO2) laser
which employs narrow laser beams to stimulate dermal collagen deposition
Recent studies and reports have suggested that combining laser therapy with other interventions such as botulinum toxin type A (BTX-A) and topical growth factors may enhance treatment outcomes
we examine the efficacy and safety of a sequential combination of BTX-A
for treating hypertrophic scars compared with only using fractional CO2 laser and topical growth factors
Our retrospective study includes 128 patients with hypertrophic scars (56 underwent monotherapy and 72 underwent combined therapy)
which were followed-up for up to 15 months after the initiation of treatment to collect demographic and clinical data
Our analysis showed that the combined therapy significantly outperformed monotherapy in improving Vancouver scar scale scores (P &lt; 0.05) and in the reduction of scar thickness (P &lt; 0.05)
Repeated treatments further augmented the efficacy of the combined therapy
Subgroup analysis revealed that combined therapy was notably more effective in reducing Vancouver scar scale scores and scar thickness in early-stage scars compared to late-stage (P = 0.023 and P = 0.045
Our study suggests that including BTX-A treatment before fractional CO2 laser and topical growth factors offers superior efficacy in reducing hypertrophic scars
We encourage early intervention and repeated treatments for optimal treatment outcomes
safe and effective medical interventions are in demand for the patient’s mental and physical health
enhancing the efficacy of fractional CO2 laser without increasing adverse reactions
has become a critical research area in dermatology
the effectiveness and safety of this sequential combined therapy in treating hypertrophic scars remain unexplored
we evaluate the safety and efficacy of a sequential combination of BTX-A
for treating hypertrophic scars in 128 patients compared with only using fractional CO2 laser and rbFGF
Our goal is to show the effect of the pre-treatment with BTX-A for hypertrophic scar treated with fractional CO2 laser and rbFGF
No statistical differences were observed between the groups in terms of scar location
Patients underwent one to three treatment sessions based on their individual improvement
Inclusion criteria were individuals aged 18 to 70 years without serious underlying conditions
while exclusion criteria included patients under 18 or over 70
All participants provided written informed consent (supplementary material)
and intervals between treatments were collected with the approval of the Ethics Committee of the General Hospital of Ningxia Medical University (No.: KYLL-2021-601)
All methods were performed in accordance with the relevant guidelines and regulations
Representative images of hypertrophic scars before and immediately after fractional CO2 laser treatments are provided in Supplementary Fig
the scar area was cleansed and anesthetized with Lin compound lidocaine cream (Guoyao Zhunzi
Fractional CO2 laser treatment was performed using the AcuPulse Fractional King device (Lumenis Medical Laser Company
A preliminary scan was conducted using Deep FX mode
Scars were categorized by thickness as mild
and treatment parameters were adjusted accordingly
Medium and heavy scars were treated with a 2 mm spot diameter
while mild scars were treated with a 10 mm spot diameter
This classification only determined laser parameters
Treatment duration ranged from 10 to 30 min
ice was applied to the treated area for 30 to 40 min
followed by recombinant bovine basic fibroblast growth factor (rbFGF) gel (Zhuhai Yisheng Biopharmaceutical Co.
approval number: S20020113) applied twice daily for a week to promote wound healing
Each application included 25,000 IU (50 µg) per 5 g
Patients were advised to keep the treated area clean and dry for the first three days
The average interval between sessions is three months
The decision to schedule a subsequent treatment is contingent upon the evaluation of the results from the previous session
A 2-week interval between treatments was selected to avoid potential inactivation of BTX-A by laser
The injection was administered intradermally at the periphery before targeting the body of the scar
Follow-ups were scheduled at one- and six months post-injection
The decision to use BTX-A was made by the dermatologist based on a comprehensive evaluation of the scar
Patients were followed up on an outpatient basis for up to 15 months with an average of 7.2 ± 2.2 months
Scar treatment was evaluated at 1 month after each treatment session
Scar treatment efficacy was gauged using the Vancouver scar scale
and swelling were recorded after the completion of all treatment sessions
a trained medical professional applied a specialized ultrasound gel to the center of the scar
operating at a frequency of 20 MHz and positioned perpendicular to the subject’s skin surface
Particular care was taken to ensure minimal pressure was applied to the subject’s skin during the procedure
and pliability in each image were measured
The average value of these measurements was calculated
the ultrasound images of both normal skin and scar tissue were processed using the DFY-1 ultrasound image diagnosis and analysis software to analyze the characteristics of the scar
Three distinct areas were selected within each image to measure the echo intensity
and the average value of these measurements was computed
Subgroup analyses were conducted to examine variations in the efficacy and safety of combined therapy among scar patients at distinct stages
Patients were divided into early-stage (treatment within six months post-injury) and late-stage (treatment after six months post-injury) groups
The effectiveness and safety of the combined therapy in these distinct subgroups were then compared
Continuous variables were presented as mean with standard deviation (SD) \(\left( {\overline{\chi } \pm s} \right)\) 
Comparisons between groups and subgroups were tested for significance using the two-tailed Mann-Whitney U test
Categorical data were presented as frequencies and percentages and assessed with chi-square \(\chi ^{2}\) tests
P value &lt; 0.05 was considered indicative of statistical significance
A sketch showing the patients involved in this study
Inclusion criteria: individuals aged between 18 and 70 years with no serious underlying conditions
Exclusion criteria: individuals under 18 or over 70 years of age
and those presenting with abnormal mental states
</a>Bar plots showing the reduction in hypertrophic scar size and thickness after mono- and combined therapy
Data was presented as mean with standard deviation (SD)
Comparisons were made between mono- and combined therapy groups
Statistical significance was tested as mentioned in the method section
We then evaluate the safety of mono- and combined therapy by analyzing the incidence of adverse complications among patients (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41598-024-78094-y#Tab3">3</a>)
there was no significant difference in the occurrence of adverse complications between patients receiving monotherapy (62.5%
35 cases) and those undergoing combined therapy (68.1%
the most common complication was pruritus (monotherapy
these results indicate that combined therapy is as safe as monotherapy while demonstrating enhanced effectiveness in reducing hypertrophic scars
</a>Performance of combined therapy in multiple treatment sessions
(A) Changes in Vancouver scar scale after repeated treatments; (B) Changes in scar thickness after multiple treatments
Comparisons were by comparing each treatment to the baseline
We next evaluated the performance of combined therapy in early- and late-stage scars. We stratified patients receiving combined therapy into two subgroups: an early-stage subgroup and a late-stage subgroup based on the time after scar formation. Notably, there are no significant demographic differences between the two groups (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41598-024-78094-y#Tab4">4</a>)
</a>Bar plots showing the reduction in hypertrophic scar size and thickness after combined therapy at early and late stages
Comparisons were made between early- and late-staged scars
we demonstrated that a sequential combination of BTX-A
and topical growth factors offers superior efficacy in reducing hypertrophic scars compared to only using fractional CO2 laser and topical growth factors
Our results suggest that combined therapy is particularly effective in the early stages (within 6 months) of scar formation
with its performance further enhanced by repeated treatments
given the combined therapy did not increase any complications at least
we still recommend the use of the combined therapy over monotherapy for treating hypertrophic scars
we recommend the inclusion of growth factors
we recommend clinicians apply at least two repeated treatments of combined therapy at early stages to achieve optimal outcomes
it is important to recognize certain limitations
the hypertrophic scars analyzed were caused by various etiologies
which might have influenced the effectiveness of therapies
focused studies on hypertrophic scars with uniform etiology may be a better choice
such studies could be very challenging as limiting the study to a single etiology might significantly reduce the available sample size
the majority of participants involved in the study received treatment within 12 months post-injury
Future studies may be needed to explore the performance of combined therapies on older scars
The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request
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The study was supported by the Ningxia Natural Science Foundation (No: 2022AAC03534)
Jin Wang and Lijun Huang contributed equally to this work
General Hospital of Ningxia Medical University
University of Rochester School of Medicine and Dentistry
and JL) contributed to the conception and study design
and JZ coordinated and managed all experiments of the study
and JZ conducted data collection and performed preliminary data preparations
and JL conducted data analyses and all the authors contributed to the interpretation of data
and LW wrote the draft of the paper and all authors provided substantive feedback on the paper and contributed to the final manuscript
All authors have read and approved the final manuscript
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DOI: https://doi.org/10.1038/s41598-024-78094-y
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Glial scar formation represents a fundamental response to central nervous system (CNS) injuries
It is mainly characterized by a well-defined spatial rearrangement of reactive astrocytes and microglia
The mechanisms underlying glial scar formation have been extensively studied
yet quantitative descriptors of the spatial arrangement of reactive glial cells remain limited
we present a novel approach using point pattern analysis (PPA) and topological data analysis (TDA) to quantify spatial patterns of reactive glial cells after experimental ischemic stroke in mice
We provide open and reproducible tools using R and Julia to quantify spatial intensity
cell covariance and conditional distribution
which collectively disentangle the arrangement patterns of the glial scar
This approach unravels a substantial divergence in the distribution of GFAP+ and IBA1+ cells after injury that conventional analysis methods cannot fully characterize
PPA and TDA are valuable tools for studying the complex spatial arrangement of reactive glia and other nervous cells following CNS injuries and have potential applications for evaluating glial-targeted restorative therapies
current methods for analyzing glial scar formation primarily rely on qualitative assessments that lack spatiotemporal resolution/information and limit the examination of the patterns of cellular rearrangement
no direct applications of PPA/TDA exist for analyzing the dynamics of cell rearrangement following brain injuries
which is critical for assessing scar formation and tissue integrity
The approach presented in this article provides reproducible pipelines/codes to quantify the spatial intensity of cells
and short and long-scale cumulative cell distributions in the context of ischemic stroke
This allowed us to thoroughly quantify the divergent allocation of reactive GFAP+ and IBA1+ cells
revealing a double-layered glial scar with unique dynamics over the course of the injury that eludes the scrutiny of traditional methods for glial scar assessment
This also enabled us to build a machine-learning model to predict the time post-ischemia based on the position of GFAP+ and IBA1+ cells
To ensure the reliability/reproducibility of our results
and to encourage the use of PPA and TDA-based analyses in other disease models
we provide raw microscopy images/data sets
together with fully annotated notebooks/scripts for R and Julia/Python in accompanying Zenodo and GitHub repositories
All animal procedures and handling were performed according to the Canadian Council on Animal Care guidelines
as implemented by Comité de Protection des Animaux de l’Université Laval-3 (CPAUL-3)
The experimental procedures were approved by the Université Laval under the protocol # 20–470)
An incision was then made between the permanent and temporal ligatures to insert a silicone resin-coated nylon monofilament (MCAO suture
The monofilament was advanced into the CCA to block the MCA fork at the polygon of Willis and tied tightly to prevent retraction
the monofilament was removed through the entry incision and the upper segment of the CCA was permanently ligated
Postoperative care was provided in the home cage by subcutaneous injection of 1 mL Ringer’s lactate twice daily for at least three days or until the preoperative weight was regained
We provided wet food and diet gel boost (DietGel® Boost
Cat #72–04-5022) in the bottom of the cage to facilitate feeding
The pre-processing (.ijm) script to generate .tif images and enhance cell detection is available in the OSF repository
To delineate the observation windows for PPA
we sharpened the sections using FIJI and manually removed blank regions
and IBA1-expressing cells in the cortex (CTX)
and inter-brain (IB) using .groovy QuPath scripts (see OSF repository)
we detected NeuN+ cells using machine learning-based classifiers that segregated cells with abnormal NeuN intensity (characteristic of the ischemic area)
we used the integrated watershed algorithm to segregate the circular/oval nuclear shapes
we segregated highly reactive IBA1+ cells from cells with normal IBA1 reactivity (resting microglia) in the healthy brain
The specific parameters used for the detection/segmentation of each marker are available in the .groovy QuPath scripts in the OSF repository
while the marker-specific classifiers are available in the QuPath projects folders in the OSF repository
We also provide high-resolution (.tif) images with segmentation overlays in the ‘Images_Segmentation’ folder of the OSF repository
showing normal NeuN+ and reactive IBA1/GFAP+ cells with green overlay
we highlight two limitations of this approach
due to the inherent challenges in segmenting ramified
non-uniform cells in regions of high cell density
such as reactive glial cells and macrophages
we clarify that our detection/segmentation strategy for GFAP and IBA1 is not intended to be an accurate mapping of individual cells
an estimation of the location of reactive cells based or marker expression
although the term “cells” is used throughout the text for simplicity
the individual points in the point patterns can be whole cells or stained cell fragments
we judged it necessary to threshold the markers
instead of using histogram normalization strategies (such as CLAHE) that make the cell detection invariant to the marker expansion
This was motivated by the high density of cells in the injured regions and the formation of a “continuum” of glial branching
our detection/segmentation strategy is based on a trade-off between marker threshold and quantity to detect/segment objects with lower and upper size limits
The shared images with overlays (see OSF) and row data allow contrast
the available scripts ensure that the user can test different parameter sets on this or other datasets
We applied comparable cell detection and quantification to 10× magnification images at the level of the MCA territory
without alignment to the Allen Mouse Brain Atlas
The classifiers and .groovy scrips are available in the Zenodo and OSF repository respectively
we acknowledge that GFAP+ cells comprise a heterogeneous population of astrocytes and progenitor cells located in cell niches such as the ventricular zone
Our approach based on conventional GFAP staining
does not allow us to distinguish between these different cell types
but assumes GFAP expression as a general sign of astroglial reactivity following injury
IBA1 labels myeloid cells at the lesion site
including resident microglia and infiltrating monocyte-derived macrophages
Our study does not aim to differentiate between these cell types
but to use this marker as a general indicator of the location of microglia and microglia-like macrophages after injury
We analyzed these GFAP+ and IBA1+ cells independently of the brain regions in which they are located
using the injured area as a single and common reference point for PPA-TDA-based analysis
The analyzed point patterns are available in the Zenodo and OSF repositories
We performed PPA on section # 3 (bregma 0.44– − 0.06) of each brain
which includes the MCA territory imaged at 10× 
We downsampled to 10% of the detected cells to improve computational efficiency and visualization
Subsampling influences the raw counts per unit area (and corresponding scales) but does not affect the assessment of spatial covariates and the implications of the statistical models developed
The available raw data and QN allow interested parties to verify/reproduce the results in the full set of cells
(5) Calculation of the inhomogeneous L-function
which is Besag’s transformation of Ripley’s K-function
to assess cell-to-cell interactions within point patterns and deviations from complete spatial randomness (CSR) (QN
we randomly split the dataset into training and testing sets
with 80% of the data used for training and 20% for testing
and computed the mean and standard deviation of the prediction error across the 10 folds
We performed scientific inference using the entire posterior distribution and calculated the probability of falling within the ROPE using the entire posterior
we used Betti curves to represent the Betti numbers of the dataset against a parameter
We analyzed the Betti curves using the non-parametric two-sample Kolmogorov–Smirnov (KS) test to compare the cumulative distribution functions (CDFs)
We also employed permutation tests to randomly permute the labels of the data points and compute the Betti curves for each permutation
We repeated this process many times to obtain a null distribution of the test statistic
and complete results from statistical and spatial models are also shared as markdown or latex syntax in the OSF repository
the analysis of spatial intensity for NeuN captures the complex variations in neuronal density associated with brain atrophy and cell antigenicity
This indicates that these cells are preferentially positioned in low-intensity neuronal regions as the injury progresses
We excluded control animals from this analysis given the absence of reactive glia labeling in healthy brains
These results highlight the potential of the relative distribution (rhohat) and cell covariance (tessellations
quadrant counts) calculations to elucidate the complex interactions and spatiotemporal dynamics of different cell types in response to brain injury
This approach can quantitatively characterize the positioning over time of reactive glial cells relative to the position and density of neurons or other spatial features of interest
and allows precise spatiotemporal modeling of interventions aiming at modulating the distribution of cells at the glial scar
The preceding pattern is consistent with the resolution of inflammatory cascades and implies that GFAP+ cells (including reactive astrocytes) consistently position surrounding IBA1+ cells/macrophages (including activated microglia) populating injured areas
GFAP+ cells allocation is strongly influenced by low-density microglial regions
these data support a model where GFAP+ and IBA1+ cells intermingle progressively during the injury course
astrocyte allocation is prominent in low-intensity IBA1 areas
This is consistent with a compartmentalized glial scar where GFAP+ cells (including reactive astrocytes) in the healthy tissue enclose IBA1+ cells (including activated microglia) in an inner layer at the injury core
our results provide a quantitative and reproducible assessment of the progressive mixing of GFAP+ and IBA1+ cells at the glial scar
Our approach based on PPA shows that GFAP+ cells surround IBA1+ cells after the second week after injury and that the distribution of IBA1+ cells in the healthy tissue is strongly associated with the position and dispersion of GFAP+ cells
Contrary to standard qualitative assessments
our approach enables the precise and reproducible examination of cell covariance at specific spatial locations and different resolution scales
To gain further insights into the structure of the glial scar, we focused our analysis on injured regions (QN, Section 8). We defined rectangular ROIs comprising the MCA territory, from the ventricular zone to the outer edge of the dorsolateral cerebral cortex (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41598-024-69426-z#Fig1">1</a>C)
we analyzed the distribution of GFAP+ cells conditioning on the distance to IBA1+ cells
These outcomes imply that the distribution of GFAP+ cells is more dynamic than that of IBA1+cells
We ponder that this facet may be driven by the more “flexible” allocation of GFAP+ cells at the edges of the injured tissue
The preceding provides a reproducible/validatable model of a compartmentalized glial scar formed by an outer layer of GFAP+ cells bordering a degraded/liquefied tissue in the dorsolateral cortex entirely populated by IBA1+ cells
To quantify the spatial organization of NeuN+
we first used the Vietoris-Rips filtration to compute persistent homology from 3D cell positions
consisting of the number of connected components (dimension 0 homology) and the number of loops enclosing empty regions of space (dimension 1 homology)
This 200-dimension representation was obtained by counting the number of topological features at 200 different values of the filtration parameter
we provide a primer in the Supplementary Materials
the distribution of IBA1+ cells appears to be correlated with the high-density neuronal regions where GFAP+ cells initially aggregated
Analysis of Betti curves obtained from TDA of NeuN+
and IBA1+ cell positions and pairwise combinations of cell types revealed that GFAP+ and IBA1+ cells are present in regions of low neuronal density
by using the Betti curves as input features for machine learning-based classification and regression tasks
We constructed the input feature vector by concatenating the 200-dimensional Betti curves representing dimension-0 and dimension-1 homological features for each of the three cell types
</a>Recovery of DPI and cell type from topological features
(A) Confusion matrix for the prediction of days post-injury with an overall accuracy of 77.8% using dimension 0 topological features
(B) Confusion matrix for the prediction of cell type with 100% accuracy using dimension 0 and dimension 1 topological features
(C) Betti curves of all mice at 30 days post-injury computed using 3D positions of NeuN+
(D) Principal component analysis of Betti curves reveals clustering by mouse identity
Embedding distance between cell types over time
Lower embedding distance implied greater similarity in Betti curves
which in turn indicates spatial distribution profiles
The embedding distances reveal a consistent increase in similarity of spatial distributions of IBA1+ and NeuN+ cells over time
and an initial increase followed by a decrease in similarity of spatial distributions between GFAP+/NeuN+ cells and GFAP+/IBA1+ cells over time
all topological features were computed using 5 independent subsamples obtained from each experimental replicate (mouse)
our results demonstrate the effectiveness of our topological machine learning-based approach for predicting the post-ischemia time point using point cloud data of NeuN+
This allows the use of the topological features of glial cell distribution to inform about injury progression in CNS diseases
we provide a fully reproducible and extrapolable approximation that researchers can use to uncover distribution patterns of cells at different scales
in diverse disease models addressing cell positioning and redistribution
we show that TDA is also a suitable tool for the analysis of the topological arrangement of nervous cells (point clouds) extracted from widefield microscopy images
This entails a step towards an unbiased and reproducible analysis of cell distribution in fixed brain tissue
which can be validated and extrapolated to other body organs
the fluctuations in fluorescent signal are broad
they substantially influence the number of cells/fragments automatically detected
While performing histogram equalization techniques such as CLAHE (that make detection invariant to fluorescence intensity) is suitable for well-separated cells
this approach strongly compromises the segmentation of highly ramified and packaged reactive glial cells
The segmentation of these cells is a challenge that has not been fully addressed by the research community and remains a frontier in image processing
it must be noted that the estimation of spatial intensity depends on the size and shape of the observation window
The window size can influence the detection of clustering patterns and density calculation
we remark that our spatial intensity calculations are derived from a mixture of stained fragments of whole cells detected by the specified parameters in QuPath
This is an approximation to estimate local cell density but does not constitute a representation of the absolute number of cells in the observation window
interpreting ppm and mppm models requires careful consideration of the assumptions and parameters
there are still no tools in spatstat for mppm diagnostics or goodness-of-fit
we complete our analysis with Bayesian models
running ppm models to large datasets can be computationally intensive and time-consuming
which may limit its scalability for some applications involving many cells
the interpretation of spatial intensity maps can be influenced by the choice of color scales and contour lines
which emphasize the importance of proper modeling
Our study shows that the limitations of 2D PPA for studying reactive glia and scar formation in the CNS are surpassed by 3D TDA
which captures the full complexity of the 3D microenvironment in which cells interact and migrate
indicating that GFAP+ cells initially aggregate in high-density neuronal regions during the first week post-injury
before shifting to low-density neuronal regions in the second week
particularly through using persistent homology
relies on the creation of simplicial complexes from the data
these complexes can capture spurious topological features that do not reflect the underlying geometry or structure of the data
the scale at which the data is analyzed plays a crucial role; small-scale features might be missed
while large-scale features might overshadow more intricate details
and tracking persistence across scales can be computationally demanding
As the size and dimensionality of the data increase
the computational cost associated with TDA can escalate rapidly
This can limit the real-time or on-the-fly applications of TDA for big datasets
we used a sampling strategy to subset our data
We found the brms and emmeans R-packages fundamental to contrasts grouping variables of interest
and we promote its use for proper statistical inference based on estimation and uncertainty
which is particularly relevant for small sample sizes such as those typical of biomedicine
our study has successfully applied PPA and TDA to investigate the spatial distribution and evolution of NeuN+ (neurons)
and IBA1+ cells (including activated microglia) in the injured brain after ischemic stroke
it demonstrated the power and versatility of machine learning techniques to predict days post-injury from cell positions with high accuracy
This outcome not only validates the robustness of TDA for analyzing complex biological data but also highlights its potential for aiding in the development of novel diagnostic and therapeutic strategies for neurological disorders and injuries
Our findings contribute to a better understanding of the dynamic cellular interactions occurring in the brain following ischemic stroke and provide a foundation for future research
Maintenance is performed by the Laboratory of Neurovascular Interactions (Université Laval)
Glial scar borders are formed by newly proliferated elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury
Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury
Spatiotemporal dynamics of the cellular components involved in glial scar formation following spinal cord injury
Fibrinogen regulates lesion border-forming reactive astrocyte properties after vascular damage
Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS
Microglial inflammation after chronic spinal cord injury is enhanced by reactive astrocytes via the fibronectin/β1 integrin pathway
Depletion of microglia exacerbates injury and impairs function recovery after spinal cord injury in mice
Dissecting the dual role of the glial scar and scar-forming astrocytes in spinal cord injury
Spatio-temporal overview of neuroinflammation in an experimental mouse stroke model
ionized calcium-binding adapter molecule 1
after transient focal cerebral ischemia in rat brain
Tenascin-C preserves microglia surveillance and restricts leukocyte and more specifically
GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer’s disease
Ezrin deficiency triggers glial fibrillary acidic protein upregulation and a distinct reactive astrocyte phenotype
Gramine promotes functional recovery after spinal cord injury via ameliorating microglia activation
Methods to determine and analyze the cellular spatial distribution extracted from multiplex immunofluorescence data to understand the tumor microenvironment
Spatial point pattern analysis of neurons using Ripley’s K-function in 3D
Characterizing microglia activation: a spatial statistics approach to maximize information extraction
Spatial clustering analysis in neuroanatomy: Applications of different approaches to motor nerve fiber distribution
Topological data analysis of collective and individual epithelial cells using persistent homology of loops
Topological analysis of interaction patterns in cancer-specific gene regulatory network: persistent homology approach
Tracking collective cell motion by topological data analysis
Malavasi, M. et al. Ecology meets archaeology: Past present and future vegetation-derived ecosystems services from the Nuragic Sardinia. People Nat. <a href="https://doi.org/10.1002/pan3.10461" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1002/pan3.10461">https://doi.org/10.1002/pan3.10461</a> (2023)
A multimethod approach for county-scale geospatial analysis of emerging infectious diseases: A cross-sectional case study of COVID-19 incidence in Germany
Spatial metrics of interaction between CD163-positive macrophages and cancer cells and progression-free survival in chemo-treated breast cancer
Using the R package Spatstat to assess inhibitory effects of microregional hypoxia on the infiltration of cancers of the head and neck region by cytotoxic T lymphocytes
Multiparameter persistent homology landscapes identify immune cell spatial patterns in tumors
Persistent homology for the quantitative evaluation of architectural features in prostate cancer histology
The shape of things to come: Topological data analysis and biology from molecules to organisms
Representation of molecular structures with persistent homology for machine learning applications in chemistry
A topological representation of branching neuronal morphologies
Topological data analysis distinguishes parameter regimes in the Anderson-Chaplain model of angiogenesis
The role of ECA transection in the development of masticatory lesions in the MCAO filament model
Fiji: An open-source platform for biological-image analysis
QuPath: Open source software for digital pathology image analysis
Spatial Point Patterns (Apple Academic Press
raster: Geographic data analysis and modeling
GPU-Accelerated Computation of Vietoris-Rips Persistence Barcodes
in 36th International Symposium on Computational Geometry (SoCG 2020) (Schloss Dagstuhl-Leibniz-Zentrum für Informatik
A survey of topological machine learning methods
Support vector machines and kernels for computational biology
Large-scale evaluation of k-fold cross-validation ensembles for uncertainty estimation
Multiple predicting K-fold cross-validation for model selection
Advanced Bayesian multilevel modeling with the R package brms
Spatstat: An R-package for analyzing spatial point patterns
Understanding and interpreting confidence and credible intervals around effect estimates
A studentized permutation test for the comparison of spatial point patterns
Loss of NeuN immunoreactivity after cerebral ischemia does not indicate neuronal cell loss: A cautionary note
Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury
Spatial Point Patterns: Methodology and Applications with R
Microglial depletion impairs glial scar formation and aggravates inflammation partly by inhibiting STAT3 phosphorylation in astrocytes after spinal cord injury
Conditional ablation of reactive astrocytes to dissect their roles in spinal cord injury and repair
STAT3 is a regulator of astrogliosis and scar formation after spinal cord injury
Abrogation of -catenin signaling in oligodendrocyte precursor cells reduces glial scarring and promotes axon regeneration after CNS injury
Proliferating NG2-cell-dependent angiogenesis and scar formation alter axon growth and functional recovery after spinal cord injury in mice
Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model
Early monocyte modulation by the non-erythropoietic peptide ARA 290 decelerates AD-like pathology progression
Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntingtons disease
Discrepancy between distribution of alpha-synuclein oligomers and Lewy-related pathology in Parkinson’s disease
Glial scar borders are formed by newly proliferated
elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury
The fibrotic scar in neurological disorders
Role of immune responses for extracellular matrix remodeling in the ischemic brain
Tenascin-C restricts reactive astrogliosis in the ischemic brain
Applications of topological data analysis in oncology
Topological data analysis in medical imaging: Current state of the art
Topological data analysis of spatial patterning in heterogeneous cell populations: Clustering and sorting with varying cell-cell adhesion
Characterizing emerging features in cell dynamics using topological data analysis methods
Topological data analysis (TDA) enhances bispectral EEG (BSEEG) algorithm for detection of delirium
Precision dynamical mapping using topological data analysis reveals a hub-like transition state at rest
Topological data analysis of human brain networks through order statistics
Microglia and monocyte-derived macrophages in stroke
Phenotypic and functional heterogeneity of GFAP-expressing cells in vitro: Differential expression of LeX/CD15 by GFAP-expressing multipotent neural stem cells and non-neurogenic astrocytes
Unbiased quantification of the spatial distribution of murine cells using point pattern analysis
A deep learning-based algorithm for 2-D cell segmentation in microscopy images
Whole-cell segmentation of tissue images with human-level performance using large-scale data annotation and deep learning
Cellpose: a generalist algorithm for cellular segmentation
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This work is supported by grants from the Canadian Institutes of Health Research (CIHR) (#169062; #186148) (all to A.EA.)
is founded by Fonds de recherche du Québec (FRQS)-Santé (case—318466)
is funded by the Yale—Boehringer Ingelheim Biomedical Data Science Fellowship
holds a Tier 2 Canada Research Chair in molecular and cellular neurovascular interactions
Research Center of CHU de Québec-Université Laval
All the authors are compliant with the latest version of the text
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also acknowledged as the myometrium of uterus defects
which commonly results in myometrial discontinuity between the uterine and cervical cavity
Current literatures have indicated the efficacy of MSCs and MSC-derived exosomes (MSC-Exos) for diverse refractory disease administration
yet the feasibility of MSC-Exos for PCSD treatment is largely obscure
we took advantage of the in vivo myofibrotic model for mimicking the typical manifestation of PCSD and the assessment of fertility
the ex vivo scratch wound healing model is used for exploring the underlying molecular mechanism
we took advantage of the TGF-β-induced in vitro myofibrotic model and the full-thickness uterine injury rat model to verify the efficacy of human umbilical cord MSC-derived exosomes (hUC-MSC-Exos)
with the aid of CHK1 overexpression and β-TrCP knockdown
together with multifaceted biological analyses (e.g.
we further dissected the underlying regulatory mechanism
We identified hUC-MSC-Exos and verified the suppressive effect of hUC-MSC-Exos upon TGF-β-induced in vitro myofibrotic model and full-thickness uterine injury in rats via delivering β-TrCP
we found that β-TrCP in hUC-MSC-Exos facilitated the ubiquitination degradation of CHK1 and inhibited the myofibrosis
our data indicated the preferable ameliorative effect of hUC-MSC-Exos upon both the in vitro and in vivo myofibrotic models
together with the β-TrCP and CHK1-mediated regulatory mechanism
Our findings provided new references of hUC-MSC-Exos-based regimens for PCSD management in future
the treatment prospects and the underlying mechanism of MSCs and the MSC-Exos upon PCSD are largely obscure
our data suggested the feasibility of hUC-MSC-Exos for previous cesarean scar defect management
which would benefit the further development of hUC-MSC-Exos-based regimens in future
HUC-MSCs were purchased from Stem Cell Bank of Guizhou Province (Guizhou Health-Biotech Biotechnology Co.
HUC-MSCs at passages 3–8 were cultured in DMEM/F12 basal medium (Invitrogen
USA) supplemented with 1% L-glutamine (Gibco
HUC-MSCs were isolated with 0.25% Trypsin/EDTA (Gibco
the supernatant after 72 h culture was filtered (0.22 μm
USA) and centrifuged at 120,000×g (Sorvall WXULTRA series
the enriched hUC-MSC-exos were resuspended by precooled 100 µl 1×PBS and stored at -80 ℃
hUC-MSC-exos were turned to particle size identifications with the Zetasizer Software 7.11
HESCs were purchased from Hunan Fenghui Biotechnology Co.
ESCs were cultured in DMEM basal medium (Gibco
USA) supplemented with 10% fetal bovine serum (FBS) (Australia) in 37 ℃
hESCs were isolated with 0.25% Trypsin/EDTA (Gibco
USA) and resuspended in hESCs culture medium (DMEM basal medium with 10%FBS)
Equipment and settings were as following: the proteins were turned to SDS-PAGE gel and transferred onto a PVDF membrane (GE Healthcare Life Sciences) for detection
the membranes were incubated with the indicated primary and secondary antibodies for developing
the bands were detected using the ECL Detection Reagent (Thermo Fisher Scientific
the bands were developed by using the Super-Signal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific
the blot images were gathered at the same time from the location (As to the protein samples collected at diverse time points
all blots were gathered at the same time from the same location)
and the borders were clearly demarcated in the figure and described in the legend
ESCs were seeded on slide and fixed with 4% paraformaldehyde (PFA
ESCs were treated with 0.5% Triton X-100 (Sigma-Aldrich
USA) for 15 min and incubated with the fluorescent-coupled primary and secondary antibodies
and the nuclear was stained with DAPI (Sigma-Aldrich
Immunofluorescent images were captured under fluorescent microscope (Laica Mateo FL
Population doubling (Pd) was calculated by using the formula: PdT=(t-t0) × log2/log(N-N0)
population doubling number; N is the number of harvested cells; N0 is the initial number of seeded cells; t-t0 is time of cell culture)
ESCs in the indicated groups were washed with 1×PBS (Gibco
ESCs were photographed at different time points
and the gap area in the indicated groups was quantitatively calculated with Image J software (NIH
USA) according to the formula: % of area repopulation = 1- clear area of Tn/clear area of T0
For the assessment of the fertility after ameliorating the scarred uterus
the female rats were fertilized with the male rats
single infusion (multipoint injection along the edge of the incision with 1 mL syringe
25µL per point) of 200 µL PBS or hUC-MSC-exo was instantly conducted after modeling in the indicated groups
pathologic analysis was conducted for the scarred uterus
all rats were euthanized by 3.5% isoflurane to oxygen mixture according to the commonly accepted norms of veterinary best practice for the detection of embryos including the number of fetal rats in each side of uterus
and the implantation rate of embryos in the damaged area
together with the indicated histopathological examinations (e.g.
hematoxylin and eosin (H&amp;E) staining and Masson’s staining)
considering the thickness of the endometrium can differ depending on the location in the uterus and the phase of the estrous cycle
lactating endometrium in all groups was collected and measured at 30 days postpartum
the endometrial thickness was measured by the micrometer of the optical microscope
5 sections were randomly selected in each group
and four directions of the visual field (the upper
left and right) in each section were randomly selected for measurement
and the endometrial thickness was calculated
The experiments were approved by the Ethical Committee of The Affiliated Hospital of Guizhou Medical University (approval number: 2101490)
and all methods were performed in accordance with the relevant guidelines and regulations
the slides with the indicated cells were washed with 1×PBS (Gibco
USA) and fixed with 4% paraformaldehyde (PFA
the cells were treated with 0.5% Triton X-100 at room temperature (RT) for 15 min
and followed by incubation with primary antibodies for 30 min and secondary antibodies for 1 h
the cells were incubated with DAPI for 5 min in dark and observed under the fluorescence microscope
All data were represented as mean ± SD (N = 3 independent experiments)
the Student’s unpaired t test was used for analyzing the data of two unpaired groups
One-way ANOVA was applied to analyze the data of multiple unpaired groups
Two independent samples t test was used for the comparison between two groups
while single factor analysis of variance was used for the comparison among multiple groups
X2 test and Fisher exact probability method were used for counting data
Differences were recognized as statistically significant only when P &lt; 0.05
</a>Identification of hUC-MSC-exo and the ameliorative effect upon TGF-β-induced in vitro myofibrotic model
(a) The distribution of hUC-MSC-exo concentration according to the diameter
(b) Representative ultrastructural structure of hUC-MSC-exo under transmission electron microscope (TEM)
(c) Western-blotting analysis of the indicated proteins (CD9
β-actin) expressed in hUC-MSC-exo and hUC-MSC by using the Super-Signal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific
USA) as described in the “Materials and Methods” section
All blots were gathered at the same time from the same location
(d) Immunofluorescent staining of ESCs with PKH67 and DAPI
(e-f) Scratch assay revealed the migration of ESCs in the indicated groups from 0 h to 12 h (e) and 24 h (f)
TGF-β + hUC-MSC-exo (TGF-β + hUC-MSC-exo) treatment
(g) The migration rate of ESCs in the indicated groups
(h) CCK-8 assay of ESCs in the indicated groups under OD 450 nm
(i) qRT-PCR analysis of α-SMA and Collagen I expression in ESCs in the indicated groups
and β-actin expression in ESCs in the indicated groups by using the Super-Signal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific
USA) as described in the “Materials and methods” section
All data were shown as mean ± SD (N = 3 independent experiments)
*P &lt; 0.05; **P &lt; 0.01; ***P &lt; 0.001
hUC-MSC-exo administration could efficiently alleviate the deficiency of TGF-β-induced in vitro myofibrotic model
</a>HUC-MSC-exo suppresses myogenic fibrosis in TGF-β-treated ESCs with CHK1 overexpression
(a) qRT-PCR analysis of CHK1 expression in ESCs with the indicated treatment (Control
(b,c) Western-blotting analysis (b) and gray scanning (c) showed the expression level of CHK1 protein by using the Super-Signal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific
(d) qRT-PCR analysis of α-SMA and Collagen I in ESCs with the indicated treatment (Control
(e,f) Western-blotting analysis (e) and gray scanning (f) showed the expression level of α-SMA and Collagen I protein in ESCs with the aforementioned treatment
All blots were gathered at the same time from the same location by using the Super-Signal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific
</a>HUC-MSC-exo with TrCP knockdown revealed decline in ameliorating myogenic fibrosis in ESCs
(a) Western-blotting analysis and gray scanning showed the expression level of β-TrCP protein in the indicated hUC-MSC-exo by using the Super-Signal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific
(b) qRT-PCR analysis showed the expression level of β-TrCP protein in the indicated groups (Control
(c,d) Western-blotting analysis and gray scanning showed the expression level of β-TrCP protein in HUC-MSCs (c) and hUC-MSC-exo (d)
(e) Representative images of scratch assay revealed the migration of ESCs in the indicated groups (Control
(f) The migration rate of ESCs in the indicated groups (Control
Then, we took advantage of the scratch wound healing assay, and observed that the rescue effect of hUC-MSC-exo upon the migration of TGF-β-treated ESCs was sharply abolished (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41598-024-84689-2#Fig3">3</a>e and f)
our findings suggested the suppressive effect of hUC-MSC-exo upon TGF-β-induced in vitro myofibrotic model by delivering β-TrCP
</a>HUC-MSC-exo with TrCP knockdown revealed decline in ameliorating full-thickness uterine injury in rats
(a,b) H&amp;E staining (a) and statistical analysis (b) showed the thickness of endometrium of rat uterus in the indicated groups
(c,d) Masson staining (c) and statistical analysis (d) showed the thickness and collagen deposition variations of endometrium of rat uterus in the indicated groups
Imaging J software was used for quantitative analysis of collagen deposition according to Masson staining
and the percentage of collagen deposition was calculated for further statistical analysis
(e,f) IHC staining (e) and statistical analysis (f) showed α-SMA expression in the endometrium of rat uterus in the indicated groups
(g,h) Phase contrast images (g) and statistical analysis (h) of embryos in rat uterus in the indicated groups
β-TrCP knockdown could efficiently abolished the alleviative effect of hUC-MSC-exo in full-thickness uterine injury in rats
</a>HUC-MSC-exo with TrCP knockdown showed minimal rescue effect upon TGF-β-induced in vitro myofibrotic model
(a) The growth curve showed the proliferation of ESCs in the indicated groups (Control
CHK1 expression in ESCs with the indicated treatment
(c,d) Western-blotting analysis (c) and gray scanning (d) showed the expression level of α-SMA
CHK1 and β-actin protein in the indicated groups
</a>TrCP in HUC-MSC-exo could facilitate the degradation of CHK1 by ubiquitination
(a) Co-IP analysis of β-TrCP and CHK1 in ESCs in the indicated groups (IgG
(b,c) Western-blotting (b) and gray scanning (c) analysis of CHK1 and β-actin protein in ESCs with the indicated treatment (DMOS
(d,e) Western-blotting analysis (d) and gray scanning (e) showed the expression level of CHK1 and β-actin protein in the indicated groups
The protein samples were collected at the indicated time points and all blots were gathered at the same time from the same location by using the Super-Signal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific
(f) Ubiquitination analysis of CHK1 protein in the indicated groups (DMSO
our data indicated the benefiting effect of β-TrCP in hUC-MSC-exo upon TGF-β-treated ESCs via orchestrating CHK1 protein degradation
Despite the considerable progress in diagnosis and treatment
yet the outcomes of PCSD patients are still largely insufficient
we enriched hUC-MSC-Exos and verified the preferable efficacy for the administration of both in vitro and in vivo myofibrotic models
our data indicated the ameliorative effect of hUC-MSC-Exos via delivering β-TrCP and orchestrating CHK1 protein degradation
our findings for the first time clarified the feasibility and the concomitant regulatory mechanism of hUC-MSC-Exos for PCSD management
which would accelerate the further development of hUC-MSC-Exos-based cell-free regimens and novel drug application for conquering PCSD in the near further
our findings highlighted the preferable efficacy as well as the concomitant regulatory mechanism of the cell-free hUC-MSC-Exos upon PCSD treatment
which would help gain deeper insight into clinical practice and the impact of hUC-MSC-Exos upon patient outcomes in future
we enriched hUC-MSC-Exos and verified the efficacy upon PCSD via delivering β-TrCP and suppressing CHK1 expression
Our data for the first time highlighted the superiority of hUC-MSC-Exos for alleviating the clinical manifestations and pathological variations during PCSD
which would provide overwhelming new references for hUC-MSC-Exos serving as novel therapeutic strategies upon PCSD
All data generated or analysed during this study are included in this published article and its supplementary information files
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request
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The coauthors thank all the doctors and nurses in The Affiliated Hospital of Guizhou Medical University for their professional assistance
We also thank Guizhou Health-Biotech Biotechnology Co.
This work was supported by grants from The Guizhou Provincial Science and Technology Projects (Foundation of Guizhou Science and Technology Cooperation [2020]1Y149)
the National Natural Science Foundation of China (82260031
Taishan Scholar Special Funding (tsqnz20240858)
Medical and Health Technology Project of Shandong Province (202402050122)
Science and Technology Development Plan of Jinan Municipal Health Commission (2024301008)
Clinical Medical Science and Technology Innovation Program of Jinan Science and Technology Bureau (202430055)
the Science and technology projects of Guizhou Province (QKH-J-ZK[2021]-107)
Postdoctoral Program of Natural Science Foundation of Gansu Province (23JRRA1319)
Natural Science Foundation of Jiangxi Province (20224BAB206077)
Jiangxi Provincial leading Talent of “Double Thousand Plan” (jxsq2023102017)
The 2022 Master/Doctor/Postdoctoral program of NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor (NHCDP2022008)
Xiaoling Zeng and Yuan Liao have contributed equally to this work
The Affiliated Hospital of Guizhou Medical University
The First Affiliated Hospital of Jinan University
Shandong Provincial Key Medical and Health Laboratory of Blood Ecology and Biointelligence
Jinan Key Laboratory of Medical Cell Bioengineering
Cardio- cerebrovascular Disease Hospital of Jinan
The Teaching Hospital of Shandong Second Medical University
National Health Commission (NHC) Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor
The Third Hospital of Lanzhou University (The Third Clinical College)
and D.H.: designed and performed the experiments
and X.L.: helped with collection and assembly of data; L.Z.
and S.H.: data analysis and interpretation
All coauthors have read and approved the final manuscript
The experiments were approved by the ethical Committee of The Affiliated Hospital of Guizhou Medical University (approval number: 2101490). The coauthors confirmed that the study was reported in accordance with ARRIVE guidelines (<a href="https://arriveguidelines.org">https://arriveguidelines.org</a>)
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keratinocytes that underwent the epithelial-mesenchymal transition (EMT) regain their epithelial characteristics
epidermal cells persist in a mesenchymal state
the regulatory mechanisms governing this reversion are poorly understood
and the impact of persistent mesenchymal-like epidermal cells in scar tissue remains unclear
the regulatory factor GRHL2 is highly expressed in normal epidermal cells
and upregulated again during the process of mesenchymal-epithelial transition (MET)
We further demonstrated that interfering with GRHL2 expression in epidermal cells can effectively induce the EMT
the overexpression of GRHL2 in EMT epidermal cells resulted in partial reversion of the EMT to an epithelial state
To investigate the effects of failed MET in epidermal cells on skin wound healing
we interfered with GRHL2 expression in epidermal cells surrounding the cutaneous wound
The results demonstrated that the persistence of epidermal cells in the mesenchymal state promoted fibrosis in scar tissue
manifested by increased thickness of scar tissue
as well as the activation of myofibroblasts
the miR-200s/Zeb1 axis was perturbed in GRHL2 knockdown keratinocytes
and transfection with miR-200s analogs promoted the reversion of EMT in epidermal cells
which indicates that they mediate the EMT process in keratinocytes
These results suggest that restoration of the epithelial state in epidermal cells following the EMT is essential to wound healing
providing potential therapeutic targets for preventing scar formation
we still incompletely understand the regulatory mechanisms orchestrating the transition of mesenchymal-like keratinocytes back to an epithelial state
which is termed the mesenchymal epithelial transition (MET)
the implications of persisting mesenchymal-like keratinocytes for scar remodeling remain uncertain
The results of our study show that the compromised epithelialization of mesenchymal-like keratinocytes regulated by GRHL2 leads to fibrosis of the scar tissues after wounds have healed
</a>A HE staining of mouse skin sections from different stages of cutaneous wound healing
B The total protein extracted from the epidermis at the wound edge and normal epidermis was analyzed for fibronectin
C Quantification of protein bands from the western blot in Fig
D Immunofluorescence analysis of E-cadherin
fibronectin and GRHL2 expression in the epidermis during cutaneous wound healing
White dotted lines indicate the epidermis determined by immunofluorescence of keratin 14
These results offer strong evidence that there is a dynamic and reversible transition of epidermal cells between epithelial and mesenchymal states during wound healing
which is accompanied by dynamic changes of GRHL2 expression
</a>A Schematic diagram of the construction of the dynamic EMT-MET model in human keratinocytes
B Morphological changes of keratinocytes undergoing the EMT
C Expression levels of the epithelial and mesenchymal markers in the control group as well as the group treated with TGF-β and EGF according to RT-qPCR
D Expression levels of EMT-related markers in control group as well as keratinocytes treated with TGF-β and EGF according to western blotting for fibronectin
E Quantification of protein bands from the western blot in D
F Expression levels of EMT-related markers in keratinocytes in the control
EMT and MET groups according to western blotting for E-cadherin and fibronectin
G Quantification of protein bands from the western blot in F
After withdrawal of cytokines, RT-qPCR (Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41419-024-07121-7#MOESM1">2</a>) and western blot (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-024-07121-7#Fig2">2F, G</a>) analyses revealed that some of the keratinocytes in the mesenchymal state reverted to the epithelial state
suggesting that oscillatory changes of GRHL2 expression levels are correlated with the EMT-MET dynamics of epidermal cells
</a>A The knockdown efficiency of GRHL2 in keratinocytes according to RT-qPCR
Control: Double-stranded small RNAs that do not target any known mammalian genes
B Morphological changes of keratinocytes with GRHL2 knockdown
C Cluster analysis of transcriptomic datasets
D Transcriptomic analysis of differential gene expression (GRHL2 KD cells compared with control keratinocytes)
E Gene set enrichment analysis (GSEA) of keratinocytes with GRHL2 knockdown compared to the control group
we observed that G2-M phase related genes were significantly upregulated
especially carboxypeptidase A4 (CPA4) and amelotin (AMTN)
</a>A Wound healing assay to determine cell migration
Photos of the scratch for analysis were taken at 0 h
24 h and 32 h in monolayers of control and GRHL2 KD keratinocytes
The remaining scratch area was determined based on microscopic images using ImageJ
B Expression levels of EMT-related markers in normal and GRHL2 KD keratinocytes according to western blotting for fibronectin
C Quantification of protein bands from the western blot in B
D Expression levels of epithelial and mesenchymal genes according to RT-qPCR in control and GRHL2 KD keratinocytes
E-cadherin and ZO-1 in control and GRHL2 KD keratinocytes
GRHL2 knockdown effectively induced the EMT in keratinocytes
interference with GRHL2 expression in the epidermis surrounding wounds could prevent the MET of keratinocytes
Transcriptomic analysis further indicated that the downregulation of GRHL2 expression is associated with phenotypic changes in cells at the migrating epidermal tongue
while EMT keratinocytes with low GRHL2 expression may affect scar remodeling by enhancing the secretion of cytokines such as IL-6 and MMPs
After investigating the effects of gene knockdown, we attempted to overexpress GRHL2 to see if it would promote the MET of keratinocytes. To achieve this, we constructed a cassette for doxycycline (Dox)-induced expression of GRHL2 and introduced it into the HaCaT keratinocyte cell line on a lentiviral vector (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-024-07121-7#Fig5">5A</a>).
</a>A Schematic of doxycycline (Dox)-inducible overexpression of GRHL2 in EMT keratinocytes
B Morphological changes of EMT keratinocytes following GRHL2 overexpression
C Overexpression efficiency of GRHL2 in EMT keratinocytes according to RT-qPCR
D Expression levels of EMT-related markers according to RT-qPCR in EMT keratinocytes treated with Dox or left untreated
E Expression levels of fibronectin and E-cadherin according to western blot analysis in EMT keratinocytes treated with Dox or left untreated
F Quantification of protein bands from the western blot in E
Since induction with TGF-β and EGF can substantially reduce the protein expression level of GRHL2
but has little effect on the amount of GRHL2 mRNA
this treatment likely inhibits translation
thus impeding the ability of GRHL2 overexpression to reverse the EMT phenotype
Although some cells spontaneously reverted to an epithelial state after removing the cytokines
our results still indicated that the upregulation of GRHL2 promoted the EMT of keratinocytes
</a>A Schematic diagram showing the exploration of impaired MET in epidermal cells during cutaneous wound healing
B Morphological changes of murine keratinocytes with GRHL2 knockdown
C The knockdown efficiency of GRHL2 shRNA in murine keratinocytes according to RT-qPCR
D The scar surface area on day 24 of the control and GRHL2 KD group
determined based on photographs of the scars using ImageJ software
E HE staining of mouse skin sections of the control and GRHL2 KD groups
Scale bar = 1000 μm (global view) or 200 μm (detailed view)
F The depth of scar tissue of the control and GRHL2 KD group
determined based on microscopy images using ImageJ software
G Picrosirius red staining (Scale bar = 200 μm)
immunohistochemistry for α-SMA (Scale bar = 100 μm)
and immunofluorescence for fibronectin in the control and GRHL2 KD group (Scale bar = 1000 μm)
Then, we delivered the AAV virus to the wound-adjacent skin via intradermal injection. Twenty-four days after the injection, we collected samples of the scar tissue. The area of the scar was diminished in the group of mice with GRHL2 knockdown (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-024-07121-7#Fig6">6D</a>)
We hypothesize that this phenomenon may be attributed to an acceleration of re-epithelialization or activation of myofibroblasts by EMT epidermal cells through paracrine pathways
Myofibroblasts are known to facilitate wound contraction
these results demonstrate that the persistence of EMT epidermal cells promoted the formation of scar tissue
</a>A Schematic illustration of the regulation of EMT in keratinocytes by GRHL2 through the Zeb1/miR-200s axis
B Expression levels of EMT transcription factor Zeb1 in the control and GRHL2 KD keratinocytes according to western blot analysis
D Expression levels of EMT transcription factor Zeb1 according to RT-qPCR in the control and GRHL2 KD keratinocytes
according to RT-qPCR in normal and GRHL2 KD keratinocytes
F Western blot analysis of the expression levels of fibronectin
and E-cadherin in GRHL2 KD keratinocytes transfected with miR-200b analogue or control small RNA
This indicates that GRHL2 at least partially regulates the EMT of keratinocytes by modulating the Zeb1/miR200s axis
Since GRHL2 is subject to post-transcriptional regulation
the delivery of miR-200s may more effectively reverse the mesenchymal phenotype of epithelial cells in vivo compared with mRNA transfection or introducing a DNA vector overexpressing GRHL2
Our results establish a theoretical basis for intervening with the EMT in epidermal cells and treating scarring through miR-200 delivery
achieving scarless cutaneous wound healing through medical intervention remains elusive
it is imperative to focus on how the process of wound healing ceases in order to prevent excessive scar formation
Our experimental findings indicate that the persistence of EMT epidermal cells after wounds heal promotes the formation of scar tissue
there is a pressing need to better understand the EMT of keratinocytes in aberrant tissues such as keloids
we cannot conclusively determine that the loss of GRHL2 is the cause of keloid formation
studies of cancer and embryonic development have shown that the EMT can promote the invasion of cells into surrounding tissues
suggesting a potential association between epidermal EMT and keloid pathogenesis
the reduction of GRHL2 expression can affect the TGF-β
and IL-6 signaling pathways of keratinocytes
thereby potentially influencing their interaction with the keloid microenvironment
we found that GRHL2 KD keratinocytes only exhibited an enhanced migratory ability compared to control cells when treated with TGF-β
This experimental result underscores the phenotypic impact of GRHL2 knockdown on keratinocyte responsiveness to TGF-β
preventing us from exploring their potential treatment by inducing the MET in keratinocytes
further research is needed to determine whether the decreased expression of GRHL2 in keloid keratinocytes can enhance the regulation of cellular EMT by IL-17
GRHL2 may have a dual role in the development of non-melanoma skin cancers
Understanding how the abnormal phenotype of keratinocytes affects their communication with other components of the skin as well as the complex signaling pathways involved in regulating abnormal ECM deposition will lead to new treatments for scarring and keloids
The C57BL/6 J mice were aged 6 weeks at the beginning of experiments
They were bred and housed at the Tsinghua University Animal Facilities
The Animal Experiments Committee of Tsinghua University approved all of the experiments reported in this study (Approval No
Group allocation was randomized with no blinding
The mice were anesthetized using an intraperitoneal injection of avertin (200 mg/kg)
The dorsal surface was shaved with an electric clipper followed by a hair removal cream to remove the remaining hair
The skin as disinfected with iodine solution
A sterile 10-mm punch biopsy tool was used to outline the wounds on the dorsum
the full-thickness wounds extending through the panniculus carnosus were made using iris scissors
The adeno associated virus (AAV) vector was purchased from GeneChem Inc (Shanghai
Intradermal injections of approximately 20 μL per site were administered to deliver 1 × 1013 transducing units (TU) at 6 sites around the newly created wound in mice
The control group received the adeno associated virus expression vector with no inserted shRNA sequence in the same manner
Mice that died or had a significantly lower weight compared to others were excluded
The mouse scar tissue was carefully removed wish scissors
the tissue was placed in a tube filled with PBS containing 200 IU penicillin and 200 mg/L streptomycin
the skin tissue was cut thoroughly into small pieces and digested with Dispase II (2 mg/mL
China) in a tube or dish for more than 2 hours in a 37 °C water bath
a new scalpel blade was used to scrape off the epidermis and hairs into the buffer
The total protein of the epidermis was extracted using Lysis Buffer for WB/IP Assays (Yeasen Biotechnology) according to the manufacturer’s instructions
The scar tissue was surgically removed and fixed in 4% paraformaldehyde
The sections were stained with hematoxylin and eosin (HE) or subjected to picrosirius red staining
the tissue sections or coverslips with cells were blocked with QuickBlock™ Blocking Buffer for Immuno Staining (Beyotime
the rat primary antibodies against mouse fibronectin (1:100
China) were incubated with the sample at 4 °C overnight
an Alexa Fluor 555-labeled donkey anti-rabbit IgG secondary antibody (1:500
China) was used to stain the samples for 60 min at room temperature in the dark
the sections were washed with TBS solution and incubated with the Alexa Fluor 488-conjugated rabbit monoclonal antibody against cytokeratin 14 (1:200
The sections were mounted with mounting medium containing DAPI and covered with a glass slip
The stained sections were observed using a laser scanning confocal microscope (Zeiss
The quantification of fluorescence and the intensity profile were performed using ImageJ
Immortalized human HaCaT keratinocytes (Beina Chuanglian Biotechnology
China) were cultured in DMEM-high glucose medium supplemented with 10% FBS
HaCaT cells at passages 4-10 were used for further experiments
Mouse epidermal keratinocytes were isolated as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 63" title="Morris RJ, Readio N, Boland K, Johnson K, Lad S, Singh A, et al. Isolation of mouse epidermal keratinocytes and their in vitro clonogenic culture. J Vis Exp. 2019;10:150." href="/articles/s41419-024-07121-7#ref-CR63" id="ref-link-section-d150766397e1342">63</a>]
the keratinocytes were cultured in KGM Gold Keratinocyte Growth Basal Medium with supplements and growth factors from the Lonza™ KGM™ Gold Keratinocyte Growth Medium SingleQuots™ set according to the manufacturer’s instructions
we used recombinant TGF-β and EGF (both from PeproTech
These proteins were dissolved according to the manufacturer’s instructions
the culture medium was changed to serum-free (0% FBS) medium
after which the culture medium was changed every two days
The control group was treated with serum-free culture medium
cells were washed with PBS before changing to the same medium but without the two factors
All cells were maintained at 37 °C in a humidified incubator with 5% CO2
Cycle threshold (ΔΔCt) values were calculated by normalization to GAPDH
and the gene expression levels were compared using the 2-ΔΔCt method
Total protein of cells or animal tissues was extracted using Lysis Buffer for WB/IP Assays (Yeasen Biotechnology)
Protein concentrations were determined using the BCA protein assay (Yeasen
China) according to the manufacturer’s instructions
An equivalent amount of total protein (20 μg) was subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE) on a 10% acrylamide gel and transferred to a PVDF membrane (0.45μm
The membranes were blocked for 30 min with 5% skimmed milk powder in T-BST at room temperature
The blocked membranes were individually incubated overnight at 4 °C with rabbit or mouse primary antibodies against fibronectin (1:1000
the membranes were washed and incubated with secondary anti-rabbit antibodies (1:5000
The chemiluminescence signal was detected using Enlight buffer (Engreen
The optical densities of the bands were quantified using Image Lab software (Bio-Rad
USA) and normalized to GAPDH or β-actin as internal control
The densitometry of western blots was performed with ImageJ
Brightfield images were recoded using an AMG EVOS Microscope at room temperature
Following culture for varying durations (12 h and 72 h)
the cells were treated with 10 μL/well of the CCK-8 solution (Cell Counting Kit 8
Absorbance at 450 nm was determined using a conventional microplate reader
The lentiviral expressing vector carrying the shRNA targeting GRHL2 was obtained from the shRNA library of Tsinghua University (ID: TRCN0000015810)
The sequence for shRNA was: CCGGGCTGAAGATTTCACACCAGTTCTCGAGAACTGGTGTGAAATCTTCAGCTTTTT
The control vector was the MISSIONO shRNA Plasmid DNA Control Vector (Catalog Number SHC002)
HEK293T cells were transfected with the lentivirus expression plasmid
lentivirus packing plasmid PSPAX2 and lentivirus envelope expression plasmid PMD2.G at a mass ration of 2:3:1
The supernatant containing the lentivirus particles was harvested at 48 hours post transfection
filtered through 0.45μm pore-size membrane and used to infect 20% confluent HaCaT cells together with 10 mg/L polybrene (Beyotime
The culture medium was changed 12-16 hours after transfection
selection for positive cells was conducted with puromycin (2 mg/L
Solarbio) in the regular growth medium for 3 days
A monoclonal cell line was generated by limiting dilution
RT-qPCR was used to measure the knockdown efficiency
The RNA samples for RNA-seq were extracted using TRIzol reagent (Invitrogen
USA) according to manufacturer’s instructions
The sequencing and analysis were conducted by GENEWIZ Inc
The miRNAs were purchased from GenePharma Corporation (Shanghai
The sequences were as follows: siNC: 5’-UUCUCCGAACGUGUCACGUTT-3’; miR-200b analog: 5’-UAAUACUGCCUGGUAAUGAUGA3’
Cells were seeded into 12-well-plates at a density of 1.5 × 105/cm2
the cells were transfected with the negative control RNA molecule (siNC) or miR-200b analog using Lipofectamine 3000 (Thermo Fisher
USA) according to the manufacturer’s instructions
The final concentration of the siRNA solution was 50 nM
The research complied with the Declaration of Helsinki and it was approved by the ethics committee of Beijing Tsinghua Changgung Hospital
Total of three keloid tissue specimens were obtained from patients undergoing scar excision therapy at Beijing Tsinghua Changgung Hospital in 2023
All participants provided written informed consent
The sample size was determined according to the typical sample size used in the corresponding experimental method
The results are shown as means ± standard errors of the mean
GraphPad Prism 9.5 (GraphPad Software Inc.
USA) was used for data processing and graphing
The statistical significance of differences was assessed using two-tailed Student’s t-test
Differences with P &lt; 0.05 were considered statistically significant (*P &lt; 0.05
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request
Towards a Molecular Definition of Keratinocyte Activation after Acute Injury to Stratified Epithelia - ScienceDirect
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Defining stem cell dynamics and migration during wound healing in mouse skin epidermis
Morphological evidence for the role of suprabasal keratinocytes in wound reepithelialization
Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes
Erk5 Controls Slug Expression and Keratinocyte Activation during Wound Healing
Slug regulates integrin expression and cell proliferation in human epidermal keratinocytes
Cutaneous wound reepithelialization is compromised in mice lacking functional Slug (Snai2)
E-cadherin expression in wound healing of mouse skin
Epithelial-to-mesenchymal transition in cutaneous wound healing: where we are and where we are heading
Epithelial to Mesenchymal Transition in Human Skin Wound Healing Is Induced by Tumor Necrosis Factor-α through Bone Morphogenic Protein-2
Examination of epithelial mesenchymal transition in keloid tissues and possibility of keloid therapy target
Epithelial–mesenchymal transition in keloid tissues and TGF-•β1–induced hair follicle outer root sheath keratinocytes
Keloid‐derived keratinocytes exhibit an abnormal gene expression profile consistent with a distinct causal role in keloid pathology
Clinical and pathological diagnosis of scars
Total Scar Management: From Lasers to Surgery for Scars
Understanding keloid pathobiology from a quasi-neoplastic perspective: less of a scar and more of a chronic inflammatory disease with cancer-like tendencies
The transcription factor grainyhead-like 2 regulates the molecular composition of the epithelial apical junctional complex
Cell biology: master regulators of sealing and healing
Grainyhead-like 2 enhances the human telomerase reverse transcriptase gene expression by inhibiting DNA methylation at the 5′-CpG island in normal human keratinocytes
Grainyhead-like 2 (GRHL2) inhibits keratinocyte differentiation through epigenetic mechanism
Suppression of the Epithelial–Mesenchymal Transition by Grainyhead-like-2
Grhl2 Determines the Epithelial Phenotype of Breast Cancers and Promotes Tumor Progression
GRHL2-controlled gene expression networks in luminal breast cancer
The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells
Grhl2 reduces invasion and migration through inhibition of TGFβ-induced EMT in gastric cancer
The unique and cooperative roles of the Grainy head-like transcription factors in epidermal development reflect unexpected target gene specificity
16 and 17—Critical Barrier Alarmin Molecules in Skin Wounds and Psoriasis
Keratin 6 regulates collective keratinocyte migration by altering cell–cell and cell–matrix adhesion
Nrf2 Promotes Keratinocyte Proliferation in Psoriasis through Up-Regulation of Keratin 6
Impact of MMP-2 and MMP-9 enzyme activity on wound healing
The αvβ6 integrin plays a role in compromised epidermal wound healing
Functional Implications of the IL-6 Signaling Pathway in Keloid Pathogenesis
The Role of IL-6 in Skin Fibrosis and Cutaneous Wound Healing
Cytokine gene expression in a murine wound healing model
Endothelial to Mesenchymal Transition in Pulmonary Vascular Diseases
Epithelial-mesenchymal Transition and Cell Invasion
EMT Transition States during Tumor Progression and Metastasis
A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer
Keloid tissue analysis discredits a role for myofibroblasts in disease pathogenesis
Fibronectin (FN) in hypertrophic scars and keloids
GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification
The GRHL2/ZEB feedback loop—a key axis in the regulation of EMT in breast cancer
Mesenchymal-epithelial transition in sarcomas is controlled by the combinatorial expression of microRNA 200s and GRHL2
Grainyhead-like 2 regulates epithelial plasticity and stemness in oral cancer cells
A reciprocal repression between ZEB1 and members of the miR‐200 family promotes EMT and invasion in cancer cells
The miR-200 Family Inhibits Epithelial-Mesenchymal Transition and Cancer Cell Migration by Direct Targeting of E-cadherin Transcriptional Repressors ZEB1 and ZEB2
The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2
Transforming growth factor beta (TGFβ) and keloid disease
Mechanisms of TGFβ-Induced Epithelial–Mesenchymal Transition
Analysis of epithelial–mesenchymal transition markers in psoriatic epidermal keratinocytes
Single-cell RNA-seq reveals keratinocytes and fibroblasts heterogeneity and their crosstalk via epithelial-mesenchymal transition in psoriasis
and Morphological Changes in Psoriasis-like Keratinocytes: “Insights into Similarity with Psoriatic Lesional Epidermis”
IL-17 induces autophagy dysfunction to promote inflammatory cell death and fibrosis in keloid fibroblasts via the STAT3 and HIF-1α dependent signaling pathways
Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17/IL-6 axis
Correlation between serum IL 37 levels with keloid severity
Grainyhead-like 2 (GRHL2) knockout abolishes oral cancer development through reciprocal regulation of the MAP kinase and TGF-β signaling pathways
MMP-9 secretion and MMP-2 activation distinguish invasive and metastatic sublines of a mouse mammary carcinoma system showing epithelial-mesenchymal transition traits
Isolation of mouse epidermal keratinocytes and their in vitro clonogenic culture
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This study was financially supported by a grant from the Ministry of Science and Technology of the People’s Republic of China (Grant No
2021YFC2101700) and grants from the National Natural Science Foundation of China (Grant Nos
MIX-UP has received funding from the European Union’s Horizon 2020 research and innovation program under grant Agreement No
This study is also sponsored by the Ministry of Science and Technology of China (Grant No
2018YFA0900100) as well as the Vanke Special Fund for Public Health and Health Discipline Development of Tsinghua University (NO.20221080049)
Tsinghua University) for technical support with flow cytometry analysis
These authors contributed equally: Tianying Chen
TC and QW conceived a designed the study; TC
and performed statistical analysis; CH provided technical and material support
All authors read and approved the final manuscript
Experiments using mice were approved by the laboratory animal facility which has been accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC)
as well as the institutional animal care and use committee of Tsinghua University (Approval No
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DOI: https://doi.org/10.1038/s41419-024-07121-7
image:&nbsp;Disruptions during wound healing phases (inflammation
and remodeling) can result in scar formation
Higher levels of inflammatory markers (TGF-&beta;1
VEGF) and type 1 collagen are present in scars
Current treatments for scars include pressure garments
Current research explores Yes-associated protein and harnesses TGF-&beta; inhibition to reduce scaring
Dagum and Gurtej Singh*/ Stony Brook University
In a study published in the journal Biofunctional Materials
researchers review different types of scars along with their various aspects and existing treatment options
New therapies that have the potential to reduce scar formation through skin regeneration were explored
in an effort to prevent scarring in the future
Scars can present as functional concerns for patients
They can also affect patients negatively by becoming aesthetic and psychological concerns
There are different types of scars including immature
Hypertrophic scars are raised but do not extend beyond the injury site
There are three phases of wound healing: the inflammatory phase
growth factors are secreted to allow for cell proliferation and angiogenesis
which is the formation of blood vessels from vessels that already exist
angiogenesis and the depositing of collagen occur
an excess of a growth factor called VEGF (vascular endothelial growth factor) leads to more collagen being produced
hypertrophic scars respond better to treatment
It is important to moisturize and maintain a clean environment for preventing both types of scars
The most common treatments for hypertrophic scars are compression therapy
and corticosteroids applied topically or directly into the skin lesion
laser therapy or surgical intervention can be used
Some of the most common treatments for keloids include surgical excision and steroids applied directly into the skin lesion
New therapeutic targets for treating scars were explored
By balancing the usage of VEGF inhibitors and administration of a growth factor called TGF-&beta;3
it is possible to improve scarring and promote skin regeneration
This paper&ldquo; Erase the trace: new frontiers in scar prevention and skin repair&rdquo;was published in Biofunctional Materials
Singh DK,&nbsp;et al.&nbsp;Erase the trace: new frontiers in scar prevention and skin repair.&nbsp;Biofunct
https://doi.org/10.55092/bm20240009.&nbsp;
<a href="http://dx.doi.org/10.55092/bm20240009" target="_blank">10.55092/bm20240009 </a>
Erase the trace: new frontiers in scar prevention and skin repair
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
Copyright © 2025 by the American Association for the Advancement of Science (AAAS)
I thought I was going for a relaxing acupuncture facial
What I actually got was an opportunity to treat facial scarring that I’ve had since I was a toddler
I’ve been a longtime fan of the ancient Chinese practice and have gone for a myriad of different reasons: seasonal allergies
I’ve traveled all the way to Como Shambhala in Bali
to try acupuncture for period cramps and then to the Six Senses in Ibiza
for an acupuncture facial and Reiki healing
a routine acupuncture-goer and beauty writer
hadn’t heard of acupuncture as a treatment for scars
“It’s not as widely talked about as the other benefits,” says New York–based acupuncturist <a data-offer-url="https://www.adelereising.com/" class="external-link" data-event-click="{&quot;element&quot;:&quot;ExternalLink&quot;,&quot;outgoingURL&quot;:&quot;https://www.adelereising.com/&quot;}" href="https://www.adelereising.com/" rel="nofollow noopener" target="_blank">Adele Reising</a>
who has been practicing Chinese medicine for decades
“People see the phrase cosmetic acupuncture and often assume that it’s only a superfluous beauty treatment with no long-term benefits.” According to the National Library of Medicine
some initial studies have reported positive outcomes with the use of acupuncture for scar symptoms
London-based cosmetic acupuncturist <a data-offer-url="https://www.sarahbradden.com/" class="external-link" data-event-click="{&quot;element&quot;:&quot;ExternalLink&quot;,&quot;outgoingURL&quot;:&quot;https://www.sarahbradden.com/&quot;}" href="https://www.sarahbradden.com/" rel="nofollow noopener" target="_blank">Sarah Bradden</a> started offering this specialty treatment in her signature Bradden Method after experiencing her own scar and skin issues
“I fully understand how my clients feel about scarring because I’ve experienced it firsthand,” she says
“If I can change how the skin on my face looks and feels
then I want to bring those results to my clients.”
or topical can completely erase a scar—but there are things you can do to help improve their texture
thought the only treatment options were extensive dry microneedling
then read ahead: Acupuncture may be a great alternative option
The treatment for scars is essentially the same as regular acupuncture treatment
You’ll start with a consultation where the practitioner will review your medical history
Most acupuncturists offer a comprehensive treatment beyond just the scar work
total-body-and-mind rebalancing treatment too
“It’s never just about the scar,” says Bradden
and when we take a 360 approach to the treatments
the results are going to be so much better.”
but creating these microscopic abrasions on the skin with targeted needle stimulation can help encourage the body’s own healing process and boost cellular turnover around the scars
“Scars—especially on the face—are tricky in terms of healing because once the scar is formed
it can affect how the muscles in the face move
You can treat pretty much any scar with acupuncture
so there’s a risk of making it worse,” she says
“It can have the reverse effect and stimulate more growth so I would avoid treating it with acupuncture.” My scars
are on my face—from my right eyebrow to my cheekbone
and on the corner of my mouth—and are a result of the reconstructive plastic surgery I had when I was two years old from a dog bite
Reising used what’s called intradermal needles on my scars—teeny tiny versions of standard acupuncture needles placed with tweezers on either side of the scar to help break up the tissue
When she underwent a laparoscopy for endometriosis a year later
her acupuncturist suggested treating the five surgical scars on her stomach with acupuncture
“I work in aesthetics and didn’t know this type of treatment existed until my practitioner told me,” says Marty
I already had a great relationship with my acupuncturist
Marty started the treatment a week after her surgery
so I was relieved to have an option to kick-start the healing process,” she says
Both Bradden and Reising agree that unless your doctor specifies otherwise
you can seek scar treatment about a week after the scar forms
but it can make a huge difference in your overall results.” You can also use acupuncture to treat older
I started my own acupuncture treatment 31 years after my scars had healed
One of the best parts of acupuncture is that there’s minimal to no downtime after the session
and when you go to a certified practitioner
the latter of which I experienced after a particularly intense treatment with the intradermals next to my eye
The area was slightly purple and sensitive to the touch for about a week after my session
it depends on the person and their pain tolerance
I have a relatively high pain tolerance; some needles I didn’t feel at all
sharp flash of pain—especially in more sensitive areas like around the eyes or mouth
and sounds of the ocean played in the background
I felt so zoned out and relaxed that I didn’t feel them at all
it’s worth noting that you might experience a flood of emotions as well
“Scars are often associated with some sort of trauma whether it’s an accident
you wake up and your body is just different
It can be hard to process and cope with that.” Bradden says that because the fascia “holds emotional memory,” it’s not surprising that there can be an emotional release when the scar tissue is released
consistency is essential to see real results
The amount of sessions depends on your age
she recommends roughly 12 sessions for scar treatment and adds or subtracts sessions based on the individual
“Clients usually see a difference after five or six sessions,” says Bradden
noting that 12 sessions are a good starting point since it’s the length of a TCM season
consistent acupuncture treatments to align with the changing energies of the seasons
started to see results after only four sessions: “It’s amazing for me to visibly see the progression of healing,” she says
and what else is included in the appointments
Bradden’s 90-minute sessions start at $395
but the sessions typically include LED light therapy
the post-healing package includes six 60-minute treatments for $650 (which comes out to about $108 a treatment)
And at Reising’s private acupuncture studio
a single session can range from $200 to $350
The best part of acupuncture is that once the scar tissue has been separated from the fascia
Acupuncturists often combine the treatment with glow-ifying add-ons like LED light therapy
and jade rolling before we get into the body
the treatment finishes with a liquid egg mask to firm and soften
followed by a facial massage with hyaluronic acid and face oil
While I won’t go as far to say that I’ve seen drastic changes
I’ve done 10 sessions and I can see a visible difference
and the deepest scar (by my mouth) is smaller and no longer pulling downward
which softened some fine lines I was experiencing
“That’s the biggest benefit clients can notice right away,” says Bradden
“There’s a subtle lift and release around the scar.” And while I’ve mostly come to peace about my scars
even the smallest 10% improvement made it worth it and made me feel a million times better
Marty and I agreed that we love that the treatment forced us to take 90 minutes to do something inherently soothing—and we always get in a really good nap
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Lucy Notarantonio is Newsweek's Senior Lifestyle and Trends Reporter
Her focus is trending stories and human interest features ranging from health
Lucy joined Newsweek in August 2022 and previously worked at Mercury Press and Media and other&nbsp;UK national newspapers
the Australian Women Magazines and The New York Post
My focus is human-interest stories ranging from relationships to health
I am always on the lookout for relationships that go against the "norm" such as age-gap ones along with incredible weight loss stories aimed to inspire and motivate others
Languages: English She is a Derby University graduate You can get in touch with l.notarantonio@newsweek.com
either observed and verified firsthand by the reporter
or reported and verified from knowledgeable sources
Translations may contain inaccuracies—please refer to the original content
Living with a rare condition that causes visible symptoms can be mentally and physically challenging
but people are sometimes subjected to cruel comments about something beyond their control
Take Kate Bogner, 27, for example. She has a rare autoimmune disease called Linear Scleroderma, which affects about one in every 300,000 Americans, according to the<a rel="noopener nofollow" href="https://scleroderma.org/who-gets-scleroderma/" target="_blank" class="multivariate"> National Scleroderma Foundation.</a>
which causes superficial or deep lesions in a band-like pattern on the trunk
or face&mdash;sometimes appearing as a distinct line on the head known as "en coup de sabre," a French term meaning "strike of the sword."
While she went into "spontaneous remission" at 13
was bullied throughout school and has only begun to embrace her scar in recent years
In an interview with Newsweek, she shared the reason why she will never stop talking about it on <a href="https://www.newsweek.com/topic/instagram" data-sys="1" class="multivariate">Instagram</a> (@<a rel="noopener nofollow" href="https://www.instagram.com/reel/DHG2NuoxW9F/" target="_blank" class="multivariate">naturallyintoxikated</a>)
Bogner recently racked up 1.8 million views on just one clip where she shared cruel comments she's received from others about her scar
including "butthead," and hairstyle suggestions intended to cover it
adding that she advocated for herself from a young age and encourages others to do the same
She told Newsweek: "Being a teenager with a very unusual scar on my face, in high school wasn't easy&mdash;let alone in elementary school.<a href="https://www.newsweek.com/mom-emails-school-daughters-bully-then-realizes-whos-ccd-copied-2027073" target="_blank" rel="noopener" class="multivariate"> Kids can be nasty!"</a>
little did I know that all of this was building my confidence
allowing me to embrace and accept my scar more and more," she said
After living with the scar since she was five
she learned to embrace it in her early twenties
"I wasn't going to be ashamed or hide from it
I was going to accept it and choose to inspire other people to be authentically themselves," she shared
"I was inspired to make this video to show others that although I get bombarded with nasty comments daily, I don't let them affect me. I don't need <a href="https://www.newsweek.com/womans-boyfriend-hates-bangs-haircut-1952757" target="_blank" rel="noopener" class="multivariate">bangs to be beautiful.</a> I don't have to hide my scar
I am proud of my story and the battle I have overcome!"
and I am inspiring and teaching others to love theirs
and we must embrace this to be confident!" she added
her message has resonated loudly online&mdash;with hundreds of users commenting in support
"It's interesting how you don't learn or understand until you are older that people who make fun of others are just insecure with themselves," said one user
Another wrote: "Scars make us unique and tell a story of our strength
<a href="https://www.newsweek.com/influencers-five-top-tips-confidence-1893280" target="_blank" rel="noopener" class="multivariate">"So proud of your confidence.</a> I have linear morphea scleroderma of the forehead
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