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).

Reviewing Editor

  1. Edward E Morrisey, University of Pennsylvania, United States

Publication history

  1. Preprint posted: May 5, 2022 (view preprint)
  2. Received: May 7, 2022
  3. Accepted: September 29, 2022
  4. Accepted Manuscript published: September 30, 2022 (version 1)
  5. Version of Record published: October 18, 2022 (version 2)

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.

Metrics

  • 1,521
    Page views
  • 297
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

  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

Further reading

    1. Developmental Biology
    2. Genetics and Genomics
    Mahdi Moradi Marjaneh, Edwin P Kirk ... Richard P Harvey
    Research Article

    Unlike single-gene mutations leading to Mendelian conditions, common human diseases are likely to be emergent phenomena arising from multilayer, multiscale and highly interconnected interactions. Atrial and ventricular septal defects are the most common forms of cardiac congenital anomalies in humans. Atrial septal defects (ASD) show an open communication between left and right atria postnatally, potentially resulting in serious hemodynamic consequences if untreated. A milder form of atrial septal defect, patent foramen ovale (PFO), exists in about one quarter of the human population, strongly associated with ischaemic stroke and migraine. The anatomic liabilities and genetic and molecular basis of atrial septal defects remain unclear. Here, we advance our previous analysis of atrial septal variation through quantitative trait locus (QTL) mapping of an advanced intercross line (AIL) established between the inbred QSi5 and 129T2/SvEms mouse strains, that show extremes of septal phenotypes. Analysis resolved 37 unique septal QTL with high overlap between QTL for distinct septal traits and PFO as a binary trait. Whole genome sequencing of parental strains and filtering identified predicted functional variants, including in known human congenital heart disease genes. Transcriptome analysis of developing septa revealed downregulation of networks involving ribosome, nucleosome, mitochondrial and extracellular matrix biosynthesis in the 129T2/SvEms strain, potentially reflecting an essential role for growth and cellular maturation in septal development. Analysis of variant architecture across different gene features, including enhancers and promoters, provided evidence for involvement of non-coding as well as protein coding variants. Our study provides the first high resolution picture of genetic complexity and network liability underlying common congenital heart disease, with relevance to human ASD and PFO.

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine
    Virginia folgado-marco, Kristina Ames ... Nicholas E Baker
    Research Article

    Ribosomal protein (Rp) gene haploinsufficiency can result in Diamond-Blackfan Anemia (DBA), characterized by defective erythropoiesis and skeletal defects. Some mouse Rp mutations recapitulate DBA phenotypes, although others lack erythropoietic or skeletal defects. We generated a conditional knockout mouse to partially delete Rps12. Homozygous Rps12 deletion resulted in embryonic lethality. Mice inheriting the Rps12+/- genotype had growth and morphological defects, pancytopenia and impaired erythropoiesis. A striking reduction in hematopoietic stem cells (HSCs) and progenitors in the bone marrow (BM) was associated with decreased ability to repopulate the blood system after competitive and non-competitive BM transplantation. Rps12+/- mutants lost HSC quiescence, experienced ERK and MTOR activation and increased global translation in HSC and progenitors. Post-natal heterozygous deletion of Rps12 in hematopoietic cells using Tal1-Cre-ERT also resulted in pancytopenia with decreased HSC numbers. However, post-natal Cre-ERT induction led to reduced translation in HSCs and progenitors, suggesting that this is the most direct consequence of Rps12 haploinsufficiency in hematopoietic cells. Thus, RpS12 has a strong requirement in HSC function, in addition to erythropoiesis.