Keratinocytes, the predominant cell type of the epidermis, migrate to reinstate the epithelial barrier during wound healing . Mechanical cues are known to regulate keratinocyte re-epithelization and wound healing however, the underlying molecular transducers and biophysical mechanisms remain elusive. Here, we show through molecular, cellular and organismal studies that the mechanically-activated ion channel PIEZO1 regulates keratinocyte migration and wound healing. Epidermal-specific Piezo1 knockout mice exhibited faster wound closure while gain-of-function mice displayed slower wound closure compared to littermate controls. By imaging the spatiotemporal localization dynamics of endogenous PIEZO1 channels we find that channel enrichment in sub-cellular regions induces a localized cellular retraction that slows keratinocyte migration. Our findings suggest a potential pharmacological target for wound treatment. More broadly, we show that nanoscale spatiotemporal dynamics of Piezo1 channels can control tissue-scale events, a finding with implications beyond wound healing to processes as diverse as development, homeostasis, disease and repair.

中文翻译：

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PIEZO1诱导的细胞收缩控制伤口愈合中的角质形成细胞迁移

角质形成细胞是表皮的主要细胞类型，并形成对外部环境的重要保护性屏障。在伤口皮肤愈合期间，角质形成细胞从伤口边缘迁移，以恢复上皮屏障。机械提示是此过程中细胞迁移的重要调节剂。然而，这种机械调节的分子换能器和生物物理机制仍然难以捉摸。在这里，我们通过分子，细胞和有机体研究表明，机械激活的离子通道PIEZO1通过动态细胞定位（指示收缩事件）调节角质形成细胞迁移。从表皮特异的_Piezo1_基因敲除小鼠中分离出的单个角质形成细胞比同窝仔对照组更快地移动并且迁移得更远。为了确定PIEZO1如何促进细胞迁移，我们在几个小时内成像了迁移角质形成细胞中内源性通道的定位。我们发现，PIEZO1通道点的富集与迁移单个细胞和集体迁移单层细胞的收缩有关。令人惊讶的是，用Yoda1激活PIEZO1会导致单细胞以及单层角质形成细胞的回缩事件增加。在体外刮擦试验中，由于伤口回缩事件增加，Yoda1诱导的PIEZO1激活导致伤口闭合较慢。相反，通道缺失导致更快的划痕伤口闭合。该结果在体内得到反映，其中与同窝仔对照相比，表皮特异性PIEZO1敲除小鼠表现出更快的伤口闭合，而表皮特异性PIEZO1功能获得小鼠表现出较慢的伤口闭合。总体，我们的发现表明，降低Piezo1活性可以加速伤口愈合，表明伤口治疗的潜在药理学目标。更广泛地说，我们表明Piezo1通道的分子尺度时空动力学控制组织尺度的细胞迁移，这是在发育，体内平衡和修复中至关重要的细胞过程。