Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing

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 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.