Human distal airways contain a multipotent secretory cell that can regenerate alveoli

Maria C. Basil, Fabian L. Cardenas-Diaz, Jaymin J. Kathiriya, Michael P. Morley, Justine Carl, Alexis N. Brumwell, Jeremy Katzen, Katherine J. Slovik, Apoorva Babu, Su Zhou, Madison M. Kremp, Katherine B. McCauley, Shanru Li, Joseph D. Planer, Shah S. Hussain, Xiaoming Liu, Rebecca Windmueller, Yun Ying, Kathleen M. Stewart, Michelle Oyster, Jason D. Christie, Joshua M. Diamond, John F. Engelhardt, Edward Cantu, Steven M. Rowe, Darrell N. Kotton, Harold A. Chapman and Edward E. Morrisey ()
Additional contact information
Maria C. Basil: University of Pennsylvania
Fabian L. Cardenas-Diaz: University of Pennsylvania
Jaymin J. Kathiriya: University of California, San Francisco
Michael P. Morley: University of Pennsylvania
Justine Carl: University of Pennsylvania
Alexis N. Brumwell: University of California, San Francisco
Jeremy Katzen: University of Pennsylvania
Katherine J. Slovik: University of Pennsylvania
Apoorva Babu: University of Pennsylvania
Su Zhou: University of Pennsylvania
Madison M. Kremp: University of Pennsylvania
Katherine B. McCauley: Boston University and Boston Medical Center
Shanru Li: University of Pennsylvania
Joseph D. Planer: University of Pennsylvania
Shah S. Hussain: University of Alabama at Birmingham
Xiaoming Liu: University of Iowa
Rebecca Windmueller: University of Pennsylvania
Yun Ying: University of Pennsylvania
Kathleen M. Stewart: University of Pennsylvania
Michelle Oyster: University of Pennsylvania
Jason D. Christie: University of Pennsylvania
Joshua M. Diamond: University of Pennsylvania
John F. Engelhardt: University of Iowa
Edward Cantu: University of Pennsylvania
Steven M. Rowe: University of Alabama at Birmingham
Darrell N. Kotton: Boston University and Boston Medical Center
Harold A. Chapman: University of California, San Francisco
Edward E. Morrisey: University of Pennsylvania

Nature, 2022, vol. 604, issue 7904, 120-126

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04552-0

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