Research Article

Airway stem cells sense hypoxia and differentiate into protective solitary neuroendocrine cells

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Science  01 Jan 2021:
Vol. 371, Issue 6524, pp. 52-57
DOI: 10.1126/science.aba0629

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Protecting the lung from hypoxic stress

The lung experiences constantly changing oxygen concentrations and must recognize and respond to a low-oxygen environment. Shivaraju et al. reveal that airway stem cells directly sense hypoxia and respond by differentiating into protective neuroendocrine (NE) cells that secrete a peptide that mitigates tissue damage (see the Perspective by Zacharias). This work suggests that the observed NE cell hyperplasia that accompanies lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease represents a compensatory physiologic response. More broadly, it raises the possibility that stem cells throughout the body sense hypoxia and differentiate into organ-specific NE cells.

Science, this issue p. 52; see also p. 32


Neuroendocrine (NE) cells are epithelial cells that possess many of the characteristics of neurons, including the presence of secretory vesicles and the ability to sense environmental stimuli. The normal physiologic functions of solitary airway NE cells remain a mystery. We show that mouse and human airway basal stem cells sense hypoxia. Hypoxia triggers the direct differentiation of these stem cells into solitary NE cells. Ablation of these solitary NE cells during hypoxia results in increased epithelial injury, whereas the administration of the NE cell peptide CGRP rescues this excess damage. Thus, we identify stem cells that directly sense hypoxia and respond by differentiating into solitary NE cells that secrete a protective peptide that mitigates hypoxic injury.

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