Airway basal cells show regionallydistinct potential to undergo metaplastic differentiation
Basal cells are multipotent stem cells of a variety of organs, including the respiratory tract, where they are major components of the airway epithelium. However, it remains unclear how diverse basal cells are, and how distinct subpopulations respond to airway challenges. Using single cell RNA-sequencing and functional approaches, we report a significant and previously underappreciated degree of heterogeneity in the basal cell pool, leading to identification of six subpopulations in the adult murine trachea. Among these, we found two major subpopulations collectively comprising the most uncommitted of all the pool, but with distinct gene expression signatures. Notably, these occupy distinct ventral and dorsal tracheal niches and differ in their ability to self-renew and initiate a program of differentiation in response to environmental perturbations in primary cultures and in mouse injury models in vivo. We found that such heterogeneity is acquired prenatally, when the basal cell pool and local niches are still being established, and depends on the integrity of these niches, as supported by the altered basal cell phenotype of tracheal cartilage-deficient mouse mutants. Lastly, we show that features that distinguish these progenitor subpopulations in murine airways are conserved in humans. Together, the data provide novel insights into the origin and impact of basal cell heterogeneity on the establishment of regionally distinct responses of the airway epithelium during injury-repair and in disease conditions.
scRNA-Seq data for mouse trachea BCs described in the manuscript have been deposited at the Gene Expression Omnibus (GEO) under accession number GSE134064. It can also be explored through MmTrBC data portal at http://visualify.pharmacy.arizona.edu/MmTrBC/
scRNA-Seq of Mouse Trachea Basal CellsNCBI Gene Expression Omnibus, GSE134064.
Article and author information
National Institutes of Health (R35-HL135834-01)
- Wellington V Cardoso
National Institutes of Health (RO1-144744)
- Debora Sinner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All studies were approved by the Columbia University Institutional Animal Care and Use committees (WVC IACUC #: AC-AABF2567,) and CCHMC Institutional Animal Care and Use Committee (DS IACUC #: 2021-0053).
- Edward E Morrisey, University of Pennsylvania, United States
- Preprint posted: May 5, 2022 (view preprint)
- Received: May 7, 2022
- Accepted: September 29, 2022
- Accepted Manuscript published: September 30, 2022 (version 1)
- Version of Record published: October 18, 2022 (version 2)
© 2022, Zhou 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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