1. Human distal airways contain a multipotent secretory cell that can regenerate alveoli
- Author
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Basil, Maria C, Cardenas-Diaz, Fabian L, Kathiriya, Jaymin J, Morley, Michael P, Carl, Justine, Brumwell, Alexis N, Katzen, Jeremy, Slovik, Katherine J, Babu, Apoorva, Zhou, Su, Kremp, Madison M, McCauley, Katherine B, Li, Shanru, Planer, Joseph D, Hussain, Shah S, Liu, Xiaoming, Windmueller, Rebecca, Ying, Yun, Stewart, Kathleen M, Oyster, Michelle, Christie, Jason D, Diamond, Joshua M, Engelhardt, John F, Cantu, Edward, Rowe, Steven M, Kotton, Darrell N, Chapman, Harold A, and Morrisey, Edward E
- Subjects
Lung ,Stem Cell Research ,Stem Cell Research - Embryonic - Non-Human ,Aetiology ,2.1 Biological and endogenous factors ,Respiratory ,Animals ,Bronchioles ,Cell Lineage ,Ferrets ,Humans ,Mice ,Multipotent Stem Cells ,Pulmonary Alveoli ,Pulmonary Disease ,Chronic Obstructive ,General Science & Technology - Abstract
The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease.
- Published
- 2022