Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing
- University of California, Irvine, United States
- The Scripps Research Institute, United States
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.
Data availability
The datasets for graphs included in each figure have been made available as source data files.
Article and author information
Author details
Funding
National Institutes of Health (DP2AT010376)
- Medha M Pathak
National Institutes of Health (R01NS109810)
- Medha M Pathak
National Institutes of Health (R01HL143297)
- Ardem Patapoutian
Howard Hughes Medical Institute (GT11549)
- Jesse R Holt
- Medha M Pathak
George Hewitt Foundation for Medical Research
- Wei-Zheng Zeng
National Science Foundation (DMS1763272)
- Jesse R Holt
- Wei-Zheng Zeng
Simons Foundation (594598)
- Jesse R Holt
- Wei-Zheng Zeng
Howard Hughes Medical Institute
- Ardem Patapoutian
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All studies were approved by the Institutional Animal Care and Use Committee of Uni-versity of California at Irvine (protocol number AUP-19-184) and The Scripps Research Institute (protocol number 08-0136-4), as appropriate, and performed in accordance with their guidelines.
Copyright
© 2021, Holt et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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- Cell Biology
Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify 14 EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic, and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.
