Abstract
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-epithelialization 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 at some regions of the wound edge induces a localized cellular retraction that slows keratinocyte collective migration. In migrating single keratinocytes, PIEZO1 is enriched at the rear of the cell, where maximal retraction occurs, and we find that chemical activation of PIEZO1 enhances retraction during single as well as collective migration. Our findings uncover novel molecular mechanisms underlying single and collective keratinocyte migration that may 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.
Highlights
The skin, the largest organ of the body, serves as a barrier against a myriad of external insults while performing important sensory and homeostatic functions
During the repair of wounded skin, the migration of keratinocytes from the wound edge into the wound bed plays an essential step in re-establishing the epithelial barrier and restoring its protective functions has shown that mechanical cues and cell-generated traction forces in keratinocytes play an important role in regulating the healing process and wound closure mechanotransducers that control re-epithelialization remains unknown
Our results demonstrate that PIEZO1 induces cellular retraction to slow single and collective cell migration and causes delayed wound healing
Summary
The skin, the largest organ of the body, serves as a barrier against a myriad of external insults while performing important sensory and homeostatic functions. During the repair of wounded skin, the migration of keratinocytes from the wound edge into the wound bed plays an essential step in re-establishing the epithelial barrier and restoring its protective functions has shown that mechanical cues and cell-generated traction forces in keratinocytes play an important role in regulating the healing process and wound closure mechanotransducers that control re-epithelialization remains unknown. The Piezo[1] ion channel has been shown to play an important role in a variety of cell types, and it regulates several key biological processes including vascular and lymphatic development, red blood cell volume regulation, stem cell fate, the baroreceptor response, cardiovascular homeostasis, cartilage mechanics, and others importance of the channel in homeostatic regulation of epithelial cell numbers 20,21. We asked whether Piezo[1] may function as a mechanosensor regulating keratinocyte re-epithelialization during the wound healing process. The channel exhibits dynamic changes in its subcellular localization, concentrating at areas of the wound edge and causing local retraction at these regions
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