Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Invest Dermatol. 2021 Apr;141(4):894-902.e9. doi: 10.1016/j.jid.2020.09.007. Epub 2020 Oct 16.
It has been widely recognized that mechanical stretch can regulate the fate of stem cells (SCs). Previous research has shown that short-term mechanical stretch induces SC proliferation by activating the predominant transcription factor YAP, and YAP is a critical modulator in controlling epidermal proliferation. However, our study finds that after this phase, cell growth arrest appears, which is induced by long-term mechanical stretch. In the interfollicular epidermal SCs undergoing long-term mechanical stretch in vivo and in vitro, the level of H3K27me3 and its histone methyltransferase EZH2 are significantly elevated with suppressed expression of the target genes of YAP. EZH2 forms repressive H3K27me3 that suppresses gene transcription. Small-molecule inhibitor of EZH2 rescues significantly the cell growth arrest in interfollicular epidermal SCs induced by long-term mechanical stretch, thus promoting epidermal proliferation in vivo again. These findings reveal that there is an unexpected correlation between SC proliferation and the duration of mechanical stretch regulated by EZH2. This study of long-term mechanical stretch that induces cell growth arrest provides a strategy for clinical translation to promote skin regeneration.
人们普遍认识到，机械拉伸可以调节干细胞（SCs）的命运。先前的研究表明，短期机械拉伸通过激活主要转录因子 YAP 诱导 SC 增殖，而 YAP 是控制表皮增殖的关键调节剂。然而，我们的研究发现，在此阶段之后，会出现细胞生长停滞，这是由长期机械拉伸引起的。在体内和体外经历长期机械拉伸的毛囊间表皮SCs 中，H3K27me3 及其组蛋白甲基转移酶 EZH2 的水平显著升高，YAP 的靶基因表达受到抑制。EZH2 形成抑制性 H3K27me3，抑制基因转录。EZH2 的小分子抑制剂显著挽救了长期机械拉伸诱导的毛囊间表皮SCs 的细胞生长停滞，从而再次促进体内表皮增殖。这些发现揭示了 SC 增殖与 EZH2 调节的机械拉伸持续时间之间存在意外关联。这项关于诱导细胞生长停滞的长期机械拉伸的研究为促进皮肤再生的临床转化提供了一种策略。
