Contribution of Trp63CreERT2 labeled cells to alveolar regeneration is independent of tuft cells

  1. Huachao Huang
  2. Yinshan Fang
  3. Ming Jiang
  4. Yihan Zhang
  5. Jana Biermann
  6. Johannes C Melms
  7. Jennifer A Danielsson
  8. Ying Yang
  9. Li Qiang
  10. Jia Liu
  11. Yiwu Zhou
  12. Manli Wang
  13. Zhihong Hu
  14. Timothy C Wang
  15. Anjali Saqi
  16. Jie Sun
  17. Ichiro Matsumoto
  18. Wellington V Cardoso
  19. Charles W Emala
  20. Jian Zhu
  21. Benjamin Izar
  22. Hongmei Mou  Is a corresponding author
  23. Jianwen Que  Is a corresponding author
  1. Columbia University Medical Center, United States
  2. Zhejiang University, China
  3. Massachusetts General Hospital, United States
  4. Stanford University, United States
  5. Wuhan Institute of Virology, China
  6. Huazhong University of Science and Technology, China
  7. University of Virginia, United States
  8. Monell Chemical Senses Center, United States
  9. The Ohio State University, United States

Abstract

Viral infection often causes severe damage to the lungs, leading to the appearance of ectopic basal cells (EBCs) and tuft cells in the lung parenchyma. Thus far the roles of these ectopic epithelial cells in alveolar regeneration remain controversial. Here, we confirm that the ectopic tuft cells are originated from EBCs in mouse models and COVID-19 lungs. The differentiation of tuft cells from EBCs is promoted by Wnt inhibition while suppressed by Notch inhibition. Although progenitor functions have been suggested in other organs, pulmonary tuft cells don't proliferate or give rise to other cell lineages. Consistent with previous reports, Trp63CreERT2 and KRT5-CreERT2 labeled ectopic EBCs do not exhibit alveolar regeneration potential. Intriguingly, when tamoxifen was administrated post viral infection, Trp63CreERT2 but not KRT5-CreERT2 labels islands of alveolar epithelial cells that are negative for EBC biomarkers. Furthermore, germline deletion of Trpm5 significantly increases the contribution of Trp63CreERT2 labeled cells to the alveolar epithelium. Although Trpm5 is known to regulate tuft cell development, complete ablation of tuft cell production fails to improve alveolar regeneration in Pou2f3-/- mice, implying that Trpm5 promotes alveolar epithelial regeneration through a mechanism independent of tuft cells.

Data availability

Data Availability: All data are available in the main text or the supplementary materials and deposited toDryad (doi:10.5061/dryad.0vt4b8h1w)

The following data sets were generated

Article and author information

Author details

  1. Huachao Huang

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yinshan Fang

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ming Jiang

    Institute of Genetics, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yihan Zhang

    Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jana Biermann

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8907-4633
  6. Johannes C Melms

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5410-6586
  7. Jennifer A Danielsson

    Department of Anesthesiology, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. 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
  9. Li Qiang

    Department of Pathology and Cell Biology, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8322-1797
  10. Jia Liu

    State Key Laboratory of Virology, Wuhan Institute of Virology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Yiwu Zhou

    Department of Forensic Medicine, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Manli Wang

    State Key Laboratory of Virology, Wuhan Institute of Virology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Zhihong Hu

    State Key Laboratory of Virology, Wuhan Institute of Virology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1560-0928
  14. Timothy C Wang

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Anjali Saqi

    Department of Pathology and Cell Biology, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Jie Sun

    Carter Immunology Center, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Ichiro Matsumoto

    Monell Chemical Senses Center, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Wellington V Cardoso

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8868-9716
  19. Charles W Emala

    Department of Anesthesiology, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Jian Zhu

    Department of Pathology, The Ohio State University, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Benjamin Izar

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2379-6702
  22. Hongmei Mou

    Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, United States
    For correspondence
    HMOU@mgh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
  23. Jianwen Que

    Department of Medicine, Columbia University Medical Center, New York, United States
    For correspondence
    jq2240@columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6540-6701

Funding

National Heart, Lung, and Blood Institute (R01HL152293)

  • Jianwen Que

National Heart, Lung, and Blood Institute (R01HL159675)

  • Jianwen Que

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120650)

  • Jianwen Que

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100342)

  • Jianwen Que

Cystic Fibrosis Foundation (MOU19G0)

  • Hongmei Mou

Harvard Stem Cell Institute (SG-0120-19-00)

  • Hongmei Mou

Charles H. Hood Foundation

  • Hongmei Mou

U.S. Department of Defense (W81XWH-21-1-0196)

  • Huachao Huang

National Institute of Allergy and Infectious Diseases (R21AI163753)

  • Huachao Huang

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 animal studies used a minimum of three mice per group. Mouse studies were approved by Columbia University Medical Center Institutional Animal Care and Use Committees (Approval protocol number AC-AABM6565).

Reviewing Editor

  1. Paul W Noble, Cedars-Sinai Medical Centre, United States

Publication history

  1. Received: February 27, 2022
  2. Accepted: September 18, 2022
  3. Accepted Manuscript published: September 21, 2022 (version 1)

Copyright

© 2022, Huang 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. Huachao Huang
  2. Yinshan Fang
  3. Ming Jiang
  4. Yihan Zhang
  5. Jana Biermann
  6. Johannes C Melms
  7. Jennifer A Danielsson
  8. Ying Yang
  9. Li Qiang
  10. Jia Liu
  11. Yiwu Zhou
  12. Manli Wang
  13. Zhihong Hu
  14. Timothy C Wang
  15. Anjali Saqi
  16. Jie Sun
  17. Ichiro Matsumoto
  18. Wellington V Cardoso
  19. Charles W Emala
  20. Jian Zhu
  21. Benjamin Izar
  22. Hongmei Mou
  23. Jianwen Que
(2022)
Contribution of Trp63CreERT2 labeled cells to alveolar regeneration is independent of tuft cells
eLife 11:e78217.
https://doi.org/10.7554/eLife.78217

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