Journal Article

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

Brumwell, Alexis N., Kremp, Madison M., Cardenas-Diaz, Fabian L., Zhou, Su, Slovik, Katherine J., Basil, Maria C., Katzen, Jeremy, Hussain, Shah S., Diamond, Joshua M., Li, Shanru, Kotton, Darrell N., McCauley, Katherine B., Oyster, Michelle, Morley, Michael P., Liu, Xiaoming, Stewart, Kathleen M., Ying, Yun, Babu, Apoorva, Engelhardt, John F., Planer, Joseph D., Christie, Jason D., Kathiriya, Jaymin J., Windmueller, Rebecca, Carl, Justine, Morrisey, Edward E., Chapman, Harold A., Cantu, Edward, Rowe, Steven M.

2022

Overview

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. Human respiratory bronchioles contain a unique population of secretory cells called respiratory airway secretory cells that are distinct from the cells in the larger proximal airways, and act as unidirectional progenitors for alveolar type 2 cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/100 / 13/106 / 13/31 / 13/51 / 14 / 14/63 / 38/91 / 45 / 45/91 / 631/136/532/489 / 631/80/304 / Alveoli / Animals / Bronchioles - cytology / Cell differentiation / Cell Lineage / Chronic obstructive pulmonary disease / Ferrets / Gene expression / Humanities and Social Sciences / Humans / Lung - pathology / Lung diseases / Mice / Molecular modelling / multidisciplinary / Multipotent Stem Cells - cytology / Obstructive lung disease / Organoids / Population / Progenitor cells / Pulmonary Alveoli - cytology / Pulmonary Disease, Chronic Obstructive / Respiratory tract / Respiratory tract diseases / Science / Science (multidisciplinary) / Stem cells / Transcription / Wnt protein