Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
Department of Mathematics, University of California, Irvine, CA, USA.
EMBO Rep. 2019 Jan;20(1). doi: 10.15252/embr.201846273. Epub 2018 Nov 9.
Directional migration is inherently important for epithelial tissue regeneration and repair, but how it is precisely controlled and coordinated with cell proliferation is unclear. Here, we report that Ovol2, a transcriptional repressor that inhibits epithelial-to-mesenchymal transition (EMT), plays a crucial role in adult skin epithelial regeneration and repair. -deficient mice show compromised wound healing characterized by aberrant epidermal cell migration and proliferation, as well as delayed anagen progression characterized by defects in hair follicle matrix cell proliferation and subsequent differentiation. Epidermal keratinocytes and bulge hair follicle stem cells (Bu-HFSCs) lacking Ovol2 fail to expand in culture and display molecular alterations consistent with enhanced EMT and reduced proliferation. Live imaging of wound explants and Bu-HFSCs reveals increased migration speed but reduced directionality, and post-mitotic cell cycle arrest. Remarkably, simultaneous deletion of encoding an EMT-promoting factor restores directional migration to -deficient Bu-HFSCs. Taken together, our findings highlight the important function of an Ovol2-Zeb1 EMT-regulatory circuit in controlling the directional migration of epithelial stem and progenitor cells to facilitate adult skin epithelial regeneration and repair.
定向迁移对于上皮组织的再生和修复至关重要，但它如何与细胞增殖精确地进行控制和协调尚不清楚。在这里，我们报告转录抑制因子 Ovol2 抑制上皮-间充质转化（EMT），在成年皮肤上皮再生和修复中发挥关键作用。Ovol2 缺陷小鼠表现出受损的伤口愈合，其特征是表皮细胞迁移和增殖异常，以及毛发生长周期的延迟进展，其特征是毛囊基质细胞增殖和随后的分化缺陷。缺乏 Ovol2 的表皮角质形成细胞和隆起毛囊干细胞（Bu-HFSCs）在培养中无法扩增，并表现出与 EMT 增强和增殖减少一致的分子改变。伤口外植体和 Bu-HFSCs 的活体成像显示迁移速度增加但方向性降低，有丝分裂后细胞周期停滞。值得注意的是，同时删除编码 EMT 促进因子的 基因可恢复 -缺陷 Bu-HFSCs 的定向迁移。总之，我们的发现强调了 Ovol2-Zeb1 EMT 调节回路在控制上皮干细胞和祖细胞的定向迁移以促进成年皮肤上皮再生和修复中的重要功能。
