Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing

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.

Piezo1 ion channels inherently function as independent mechanotransducers

“…STORM imaging of HEK293 cells stably expressing GFP-tagged Piezo1 also suggested a non-homogenous spatial distribution, but at channel densities that are likely not physiological ( Ridone et al, 2020 ). Additional studies have proposed the existence of clusters with varying numbers of channels ( Jiang et al, 2021 ), and that Piezo1 may be concentrated at focal adhesions ( Mingxi Yao et al, 2020 ) and at wound edges in keratinocytes ( Holt et al, 2021 ).…”

Nobel somatosensations and pain

“…The transducers and transmitter of the Schwann cells have not yet been identified, but the findings remind of the above-mentioned TRPV3 and TRPA1 expression in keratinocytes that confers the same sensory capacities on cells that are also in close contact with nociceptive nerve endings in the skin [147]; as a possible transmitter, ATP had previously been proposed [103]. In addition, PIEZO1 and PIEZO2 have recently been found in keratinocytes and in Schwann cells, respectively [76,153].…”

Store-Operated Ca2+ Entry Contributes to Piezo1-Induced Ca2+ Increase in Human Endometrial Stem Cells

“…Particularly, the increase of migration of mesenchymal stem cells in response to Yoda1 was reported, and the effect was mediated via the release of ATP and the activation of P2 receptor signaling [ 30 ]. In contrast, the decrease of migration of keratinocytes in response to Yoda1 was observed, and the specific mechanism which is the localized increase of the retraction of the rear end of the cells induced by Yoda1 was proposed [ 55 ]. Another mechanism of Piezo-controlled cell motility was reported in Dictyostelium where Piezo channels were shown to control whether cells migrate with blebs or pseudopods [ 56 ].…”