Vasculature atrophy causes a stiffened microenvironment that augments epidermal stem cell differentiation in aged skin
Vasculature atrophy causes a stiffened microenvironment that augments epidermal stem cell differentiation in aged skin
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DOI：
10.1038/s43587-022-00244-6
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发表时间：
2022-07-01
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影响因子：
--
通讯作者：
Toyoshima, Fumiko
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文献类型：
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作者：
Ichijo, Ryo;Maki, Koichiro;Toyoshima, Fumiko
干细胞的丢失会导致与衰老相关的组织退化。基因组和氧化应激诱导的DNA损伤的积累是干细胞损失的内在线索（1,2）；然而，是否有外部微环境提示触发干细胞丢失仍不清楚。在这里，我们报道皮肤血管的退化导致皮肤硬化，增强了老年小鼠皮肤中滤泡间表皮干细胞（IFESCs）的分化和半薄壁体的脆弱性。与衰老相关的IFESC失调发生在足底和尾部皮肤，并与钙内流延长有关，这是由机械反应性离子通道Piezo1造成的（参考文献(3)）。表皮中Piezo1的缺失改善了衰老皮肤中IFESC的失调，而在年轻小鼠中，Piezo1的激活增强了IFESC的分化和半粒酶的脆弱性。真皮随着年龄的增长而变硬，并伴有真皮血管萎缩。相反，真皮血管的诱导软化了真皮层，改善了衰老皮肤中IFESC的失调。真皮成纤维细胞的单细胞RNA测序发现了一种与衰老相关的抗血管生成分泌分子，penttraxin 3 (ref.(4))，它导致老化皮肤的真皮硬化和IFESC失调。我们的研究结果表明，血管软化了干细胞维持的微环境，并提供了一种潜在的基于机械生物学的治疗衰老皮肤疾病的策略。
Stem cell loss causes tissue deterioration associated with aging. The accumulation of genomic and oxidative stress-induced DNA damage is an intrinsic cue for stem cell loss(1,2); however, whether there is an external microenvironmental cue that triggers stem cell loss remains unclear. Here we report that the involution of skin vasculature causes dermal stiffening that augments the differentiation and hemidesmosome fragility of interfollicular epidermal stem cells (IFESCs) in aged mouse skin. Aging-related IFESC dysregulation occurs in plantar and tail skin, and is correlated with prolonged calcium influx, which is contributed by the mechanoresponsive ion channel Piezo1 (ref. (3)). Epidermal deletion of Piezo1 ameliorated IFESC dysregulation in aged skin, whereas Piezo1 activation augmented IFESC differentiation and hemidesmosome fragility in young mice. The dermis stiffened with age, which was accompanied by dermal vasculature atrophy. Conversely, induction of the dermal vasculature softened the dermis and ameliorated IFESC dysregulation in aged skin. Single-cell RNA sequencing of dermal fibroblasts identified an aging-associated anti-angiogenetic secretory molecule, pentraxin 3 (ref. (4)), which caused dermal sclerotization and IFESC dysregulation in aged skin. Our findings show that the vasculature softens the microenvironment for stem cell maintenance and provide a potential mechanobiology-based therapeutic strategy against skin disorders in aging.