Lee Yaelim, Shen Xingyu, Dreesen Oliver, Zhu Jin, Li Rong
Mechanobiology Institute, National University of Singapore, Singapore 117411.
A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research (A*STAR), Singapore 138648.
Mol Biol Cell. 2025 Aug 1;36(8):ar99. doi: 10.1091/mbc.E25-02-0074. Epub 2025 Jun 25.
Dermal aging is a complex process characterized by structural and functional changes in the extracellular matrix (ECM) and the resident cells, such as dermal fibroblasts. Fibronectin (FN) ECM is a crucial component of the dermis, yet its role in natural aging remains poorly understood. Here, we demonstrate a significant reduction in FN ECM in aged, otherwise healthy, mouse dermis. To explore whether aging dermal fibroblasts contribute to this decline in FN levels, we examined human dermal fibroblasts (HDF) from aged skin and observed that they produce lower extracellular FN densities in vitro than young HDFs. This age-associated deficiency correlates with reduced level of α5-integrin, a cell-surface FN receptor essential for extracellular FN assembly. Knockdown of α5-integrin (α5KD) in young HDFs impairs FN ECM formation and induces phenotypes characteristic of cellular senescence. Interestingly, the proliferation defect in α5KD fibroblasts is largely restored by cell-derived matrices (CDMs) in vitro, highlighting the importance of ECM organization. These findings underscore the essential role of α5-integrin in maintaining proper ECM formation, which in turn protects against fibroblast senescence during dermal aging.
皮肤老化是一个复杂的过程，其特征是细胞外基质（ECM）和驻留细胞（如真皮成纤维细胞）发生结构和功能变化。纤连蛋白（FN）ECM是真皮的关键组成部分，但其在自然老化中的作用仍知之甚少。在这里，我们证明了在老年但其他方面健康的小鼠真皮中，FN ECM显著减少。为了探究老化的真皮成纤维细胞是否导致了FN水平的下降，我们检测了来自老年皮肤的人真皮成纤维细胞（HDF），并观察到它们在体外产生的细胞外FN密度低于年轻的HDF。这种与年龄相关的缺陷与α5整合素水平降低有关，α5整合素是细胞表面FN受体，对细胞外FN组装至关重要。在年轻的HDF中敲低α5整合素（α5KD）会损害FN ECM的形成，并诱导细胞衰老的特征性表型。有趣的是，α5KD成纤维细胞的增殖缺陷在体外很大程度上通过细胞衍生基质（CDM）得以恢复，这突出了ECM组织的重要性。这些发现强调了α5整合素在维持适当的ECM形成中的重要作用，而这反过来又能在皮肤老化过程中防止成纤维细胞衰老。
