Mechanical Stretch-Induced Interlayer Coordination between MMP2 and COL17A1 Exacerbates Regenerative Exhaustion in Skin.

IF 14.1 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Yidan Sun, Qili Qian, Luwen Xu, Bowen Gao, Ting Li, Yin Li, Jiayi Zheng, Qiaoyu Fu, Xi Cheng, Nuo Chen, Sijia Wang, Liang Zhang, Caiyue Liu, Qingfeng Li
{"title":"Mechanical Stretch-Induced Interlayer Coordination between MMP2 and COL17A1 Exacerbates Regenerative Exhaustion in Skin.","authors":"Yidan Sun, Qili Qian, Luwen Xu, Bowen Gao, Ting Li, Yin Li, Jiayi Zheng, Qiaoyu Fu, Xi Cheng, Nuo Chen, Sijia Wang, Liang Zhang, Caiyue Liu, Qingfeng Li","doi":"10.1002/advs.202511474","DOIUrl":null,"url":null,"abstract":"<p><p>The layered structure of skin necessitates highly sophisticated tissue coordination during regeneration. The unmet clinical need of long-term skin expansion therapy stems from limited regenerative capacity, yet the underlying mechanism remains enigmatic due to the lack of appropriate animal model. A mouse scalp-based mechanical stretch model is established that mimics clinical long-term skin expansion. Prolonged skin expansion progressively drives interfollicular epidermal stem cells towards a state of irreversible regenerative exhaustion, marked by impaired proliferation, differentiation, adhesion, and activity. Mechanistically, mechano-stress-induced accumulation of MMP2 in the dermis mediates a shift in extracellular matrix turnover from deposition to degradation, impairing stem cell activity, disrupting niche integrity, and simultaneously triggering proteolysis of COL17A1 at the interlayer. Restoring COL17A1, either through genetic overexpression or administration of Marimastat, a protease inhibitor, is sufficient to mitigate regenerative exhaustion. Consistently, in patient-derived skin samples, COL17A1 levels correlate with ECM integrity and regenerative potential. Combined, a new stretch-induced skin expansion model is established, revealing hidden components underlying regenerative exhaustion, and proposing Marimastat for drug repurposing. Restoration of COL17A1 is proposed to provide clinical benefits for skin expansion therapy.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":" ","pages":"e11474"},"PeriodicalIF":14.1000,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Advanced Science","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1002/advs.202511474","RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0

Abstract

The layered structure of skin necessitates highly sophisticated tissue coordination during regeneration. The unmet clinical need of long-term skin expansion therapy stems from limited regenerative capacity, yet the underlying mechanism remains enigmatic due to the lack of appropriate animal model. A mouse scalp-based mechanical stretch model is established that mimics clinical long-term skin expansion. Prolonged skin expansion progressively drives interfollicular epidermal stem cells towards a state of irreversible regenerative exhaustion, marked by impaired proliferation, differentiation, adhesion, and activity. Mechanistically, mechano-stress-induced accumulation of MMP2 in the dermis mediates a shift in extracellular matrix turnover from deposition to degradation, impairing stem cell activity, disrupting niche integrity, and simultaneously triggering proteolysis of COL17A1 at the interlayer. Restoring COL17A1, either through genetic overexpression or administration of Marimastat, a protease inhibitor, is sufficient to mitigate regenerative exhaustion. Consistently, in patient-derived skin samples, COL17A1 levels correlate with ECM integrity and regenerative potential. Combined, a new stretch-induced skin expansion model is established, revealing hidden components underlying regenerative exhaustion, and proposing Marimastat for drug repurposing. Restoration of COL17A1 is proposed to provide clinical benefits for skin expansion therapy.

机械拉伸诱导的MMP2和COL17A1之间的层间协调加剧了皮肤再生衰竭。
皮肤的分层结构需要在再生过程中高度复杂的组织协调。由于再生能力有限,长期皮肤扩张治疗的临床需求未得到满足,但由于缺乏适当的动物模型,其潜在机制仍然是谜。建立了模拟临床长期皮肤扩张的小鼠头皮机械拉伸模型。长时间的皮肤扩张逐渐将滤泡间表皮干细胞推向不可逆转的再生衰竭状态,其特征是增殖、分化、粘附和活性受损。从机制上讲,机械应力诱导的MMP2在真皮中的积累介导了细胞外基质转换从沉积到降解的转变,损害了干细胞活性,破坏了生态位的完整性,同时引发了COL17A1在中间层的蛋白水解。通过基因过表达或给药Marimastat(一种蛋白酶抑制剂)来恢复COL17A1足以减轻再生衰竭。一致地,在患者来源的皮肤样本中,COL17A1水平与ECM完整性和再生潜力相关。本文建立了一种新的拉伸诱导皮肤扩张模型,揭示了再生衰竭背后的隐藏成分,并提出了Marimastat的药物再利用。COL17A1的修复可为皮肤扩张治疗提供临床益处。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Advanced Science
Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
18.90
自引率
2.60%
发文量
1602
审稿时长
1.9 months
期刊介绍: Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信