Qin Zhaoping, He Tianyuan, Guo Chunfang, Quan Taihao
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
JID Innov. 2022 Feb 22;2(3):100111. doi: 10.1016/j.xjidi.2022.100111. eCollection 2022 May.
CCN2, a member of the CCN family of matricellular proteins, is a key mediator and biomarker of tissue fibrosis. We previously reported that CCN2 is significantly reduced in aged human dermis, which contributes to dermal aging through the downregulation of collagen production, the major structural protein in the skin. In this study, we investigated the underlying mechanisms of the age-related downregulation of CCN2 in human skin dermal fibroblasts. Dermal fibroblasts isolation and laser-capture microdissection‒coupled RT-PCR from human skin confirmed that age-related reduction of CCN2 expression is regulated by epigenetics. Mechanistic investigation revealed that age-related reduction of CCN2 is regulated by impaired dermal fibroblast spreading/cell size, which is a prominent feature of aged dermal fibroblasts in vivo. Gain-of-function and loss-of-function analysis confirmed that age-related downregulation of CCN2 is regulated by YAP/TAZ in response to reduced cell size. We further confirmed that restoration of dermal fibroblast size rapidly reversed the downregulation of CCN2 in a YAP/TAZ-dependent manner. Finally, we confirmed that reduced YAP/TAZ nuclear staining is accompanied by loss of CCN2 in aged human skin in vivo. Our data reveal a mechanism by which age-related reduction in fibroblast spreading/size drives YAP/TAZ-dependent downregulation of CCN2 expression, which in turn contributes to loss of collagen in aged human skin.
CCN2是基质细胞蛋白CCN家族的成员之一，是组织纤维化的关键介质和生物标志物。我们之前报道过，CCN2在老年人真皮中显著减少，它通过下调胶原蛋白的产生（皮肤中的主要结构蛋白）导致皮肤老化。在本研究中，我们调查了人皮肤真皮成纤维细胞中CCN2与年龄相关下调的潜在机制。从人皮肤中分离真皮成纤维细胞并进行激光捕获显微切割结合逆转录聚合酶链反应，证实CCN2表达与年龄相关的降低受表观遗传学调控。机制研究表明，CCN2与年龄相关的降低受真皮成纤维细胞铺展/细胞大小受损的调节，这是体内老化真皮成纤维细胞的一个显著特征。功能获得和功能丧失分析证实，CCN2与年龄相关的下调受YAP/TAZ调控，以应对细胞大小的减小。我们进一步证实，恢复真皮成纤维细胞大小以YAP/TAZ依赖的方式迅速逆转了CCN2的下调。最后，我们证实在体内老年人皮肤中，YAP/TAZ核染色减少伴随着CCN2的缺失。我们的数据揭示了一种机制，即与年龄相关的成纤维细胞铺展/大小减少驱动YAP/TAZ依赖的CCN2表达下调，这反过来又导致老年人皮肤中胶原蛋白的流失。
