Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing

  1. Jesse R Holt
  2. Wei-Zheng Zeng
  3. Elizabeth L Evans
  4. Seung-Hyun Woo
  5. Shang Ma
  6. Hamid Abuwarda
  7. Meaghan Loud
  8. Ardem Patapoutian  Is a corresponding author
  9. Medha M Pathak  Is a corresponding author
  1. University of California, Irvine, United States
  2. 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

  1. Jesse R Holt

    Physiology & Biophysics, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wei-Zheng Zeng

    Discipline of Neuroscience, Department of Anatomy, Histology and Embryology, Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Elizabeth L Evans

    Physiology & Biophysics, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Seung-Hyun Woo

    Howard Hughes Medical Institute, Department of Neuroscience, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Shang Ma

    Howard Hughes Medical Institute, Department of Neuroscience, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Hamid Abuwarda

    Physiology & Biophysics, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Meaghan Loud

    Howard Hughes Medical Institute, Department of Neuroscience, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ardem Patapoutian

    Department of Neuroscience, The Scripps Research Institute, La Jolla, United States
    For correspondence
    ardem@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0726-7034
  9. Medha M Pathak

    Physiology & Biophysics, University of California, Irvine, Irvine, United States
    For correspondence
    medhap@uci.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6518-3085

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.

Reviewing Editor

  1. David D Ginty, Harvard Medical School, United States

Publication history

  1. Received: December 3, 2020
  2. Accepted: September 24, 2021
  3. Accepted Manuscript published: September 27, 2021 (version 1)
  4. Version of Record published: November 9, 2021 (version 2)
  5. Version of Record updated: November 10, 2021 (version 3)
  6. Version of Record updated: April 1, 2022 (version 4)

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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  1. Jesse R Holt
  2. Wei-Zheng Zeng
  3. Elizabeth L Evans
  4. Seung-Hyun Woo
  5. Shang Ma
  6. Hamid Abuwarda
  7. Meaghan Loud
  8. Ardem Patapoutian
  9. Medha M Pathak
(2021)
Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing
eLife 10:e65415.
https://doi.org/10.7554/eLife.65415

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