Contribution of Trp63CreERT2 labeled cells to alveolar regeneration is independent of tuft cells
- Columbia University Medical Center, United States
- Zhejiang University, China
- Massachusetts General Hospital, United States
- Stanford University, United States
- Wuhan Institute of Virology, China
- Huazhong University of Science and Technology, China
- University of Virginia, United States
- Monell Chemical Senses Center, United States
- 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)
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Alveolar regeneration following viral infection is independent of tuft cellsDryad Digital Repository, doi:10.5061/dryad.0vt4b8h1w.
Article and author information
Author details
Wellington V Cardoso
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).
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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