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.
Reviewing Editor
- David D Ginty, Harvard Medical School, United States
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.
Version history
- Received: December 3, 2020
- Accepted: September 24, 2021
- Accepted Manuscript published: September 27, 2021 (version 1)
- Version of Record published: November 9, 2021 (version 2)
- Version of Record updated: November 10, 2021 (version 3)
- 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.
Metrics
-
- 5,805
- views
-
- 955
- downloads
-
- 60
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing
eLife 10:e65415.
https://doi.org/10.7554/eLife.65415
Further reading
-
- Cell Biology
- Chromosomes and Gene Expression
Heat stress is a major threat to global crop production, and understanding its impact on plant fertility is crucial for developing climate-resilient crops. Despite the known negative effects of heat stress on plant reproduction, the underlying molecular mechanisms remain poorly understood. Here, we investigated the impact of elevated temperature on centromere structure and chromosome segregation during meiosis in Arabidopsis thaliana. Consistent with previous studies, heat stress leads to a decline in fertility and micronuclei formation in pollen mother cells. Our results reveal that elevated temperature causes a decrease in the amount of centromeric histone and the kinetochore protein BMF1 at meiotic centromeres with increasing temperature. Furthermore, we show that heat stress increases the duration of meiotic divisions and prolongs the activity of the spindle assembly checkpoint during meiosis I, indicating an impaired efficiency of the kinetochore attachments to spindle microtubules. Our analysis of mutants with reduced levels of centromeric histone suggests that weakened centromeres sensitize plants to elevated temperature, resulting in meiotic defects and reduced fertility even at moderate temperatures. These results indicate that the structure and functionality of meiotic centromeres in Arabidopsis are highly sensitive to heat stress, and suggest that centromeres and kinetochores may represent a critical bottleneck in plant adaptation to increasing temperatures.
