Airway basal cells show regionallydistinct potential to undergo metaplastic differentiation

  1. Yizhuo Zhou
  2. Ying Yang
  3. Lihao Guo
  4. Jun Qian
  5. Jian Ge
  6. Debora Sinner
  7. Hongxu Ding  Is a corresponding author
  8. Andrea Califano  Is a corresponding author
  9. Wellington V Cardoso  Is a corresponding author
  1. Columbia University Medical Center, United States
  2. Stanford University, United States
  3. University of Arizona, United States
  4. Cincinnati Children's Hospital Medical Center, United States

Abstract

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.

Data availability

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/

The following data sets were generated

Article and author information

Author details

  1. Yizhuo Zhou

    Columbia Center for Human Development, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ying Yang

    Program in Epithelial Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4197-6216
  3. Lihao Guo

    Department of Pharmacy Practice and Science, University of Arizona, Tucson, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jun Qian

    Columbia Center for Human Development, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jian Ge

    Columbia Center for Human Development, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Debora Sinner

    Neonatology and Pulmonary Biology Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0704-5223
  7. Hongxu Ding

    Department of Pharmacy Practice and Science, University of Arizona, Tucson, United States
    For correspondence
    hongxuding@arizona.edu
    Competing interests
    The authors declare that no competing interests exist.
  8. Andrea Califano

    Department of Systems Biology, Columbia University Medical Center, New York, United States
    For correspondence
    ac2248@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
  9. Wellington V Cardoso

    Department of Medicine, Columbia University Medical Center, New York, United States
    For correspondence
    wvc2104@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8868-9716

Funding

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.

Ethics

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).

Copyright

© 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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  1. Yizhuo Zhou
  2. Ying Yang
  3. Lihao Guo
  4. Jun Qian
  5. Jian Ge
  6. Debora Sinner
  7. Hongxu Ding
  8. Andrea Califano
  9. Wellington V Cardoso
(2022)
Airway basal cells show regionallydistinct potential to undergo metaplastic differentiation
eLife 11:e80083.
https://doi.org/10.7554/eLife.80083

Share this article

https://doi.org/10.7554/eLife.80083

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