Airway-derived emphysema-specific alveolar type II cells exhibit impaired regenerative potential in COPD
Yan Hu, Qianjiang Hu, Meshal Ansari, Kent Riemondy, Ricardo Pineda, John Sembrat, Adriana S. Leme, Kenny Ngo, Olivia Morgenthaler, Kellie Ha, Bifeng Gao, William J. Janssen, Maria C. Basil, Corrine R. Kliment, Edward E. Morrisey, Mareike Lehmann, Christopher M. Evans, Herbert B. Schiller, Mélanie Königshoff
Abstract
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 in situ 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.