Airway-derived emphysema-specific alveolar type II cells exhibit impaired regenerative potential in COPD
Emphysema, the progressive destruction of gas exchange surfaces in the lungs, is a hallmark of COPD that is presently incurable. This therapeutic gap is largely due to a poor understanding of potential drivers of impaired tissue regeneration, such as abnormal lung epithelial progenitor cells, including alveolar type II (ATII) and airway club cells. We discovered an emphysema-specific subpopulation of ATII cells located in enlarged distal alveolar sacs, termed asATII cells. Single-cell RNA sequencing and <i>in situ</i> localisation revealed that asATII cells co-express the alveolar marker surfactant protein C and the club cell marker secretaglobin-3A2 (SCGB3A2). A similar ATII subpopulation derived from club cells was also identified in mouse COPD models using lineage labelling. Human and mouse ATII subpopulations formed 80-90% fewer alveolar organoids than healthy controls, indicating reduced progenitor function. Targeting asATII cells or their progenitor club cells could reveal novel COPD treatment strategies.
Authors
- Herbert B. Schiller (ORCID: https://orcid.org/0000-0001-9498-7034)
- Kent Riemondy
- Christopher M. Evans (ORCID: https://orcid.org/0000-0001-5600-7314)
- Mareike Lehmann (ORCID: https://orcid.org/0000-0002-8601-8206)
- Yan Hu (ORCID: https://orcid.org/0000-0003-0586-6527)
- Kenny Ngo
- Qianjiang Hu (ORCID: https://orcid.org/0000-0003-1069-3181)
- John Sembrat (ORCID: https://orcid.org/0000-0003-4108-803X)
- Maria C. Basil (ORCID: https://orcid.org/0000-0003-4716-1285)
- Edward E. Morrisey (ORCID: https://orcid.org/0000-0001-5785-1939)
- William J. Janssen (ORCID: https://orcid.org/0000-0002-6397-3454)
- Kellie Ha
- Adriana S. Leme (ORCID: https://orcid.org/0000-0003-3608-5766)
- Mélanie Königshoff (ORCID: https://orcid.org/0000-0001-9414-5128)
- Corrine R. Kliment (ORCID: https://orcid.org/0000-0002-3815-9370)
- Meshal Ansari (ORCID: https://orcid.org/0000-0002-8819-7965)
- Ricardo Pineda (ORCID: https://orcid.org/0000-0001-8768-4801)
- Olivia Morgenthaler
- Bifeng Gao
Institutions
- University of Pittsburgh (US)
- Helmholtz Zentrum München (DE)
- National Jewish Health (US)
- Geriatric Research Education and Clinical Center (US)
- Penn Center for AIDS Research (US)
- German Center for Lung Research (DE)
- VA Pittsburgh Healthcare System (US)
- University of Pittsburgh Medical Center (US)
- Dermatology Research Center (US)
- University of Pennsylvania (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- European Respiratory Journal
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1183/13993003.02071-2023
- Citations
- 23
- Primary Topic
- Neonatal Respiratory Health Research
- Type
- article
- Field-Weighted Citation Impact
- 9.64
Funders
- U.S. Department of Defense
- U.S. Department of Veterans Affairs
- Burroughs Wellcome Fund
- University of Pittsburgh
- Chan Zuckerberg Initiative
- European Commission
- Deutsche Forschungsgemeinschaft
- Deutsches Zentrum für Lungenforschung
- Lung Foundation Netherlands
- National Institutes of Health
- Cancer Center, University of Colorado
- Anschutz Medical Campus, University of Colorado
- Bundesinstitut für Risikobewertung
- National Heart, Lung, and Blood Institute
- National Institute of Allergy and Infectious Diseases
- University of Colorado School of Medicine, Anschutz Medical Campus
- Common Fund