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Lung epithelial tip progenitors integrate glucocorticoid- and STAT3-mediated signals to control progeny fate

U. Laresgoiti,M. Nikolić,Chandrika Rao,J. Brady,R. Richardson,Emma J. Batchen,K. Chapman,E. Rawlins

Published 2016 in Development

ABSTRACT

Insufficient alveolar gas exchange capacity is a major contributor to lung disease. During lung development, a population of distal epithelial progenitors first produce bronchiolar-fated and subsequently alveolar-fated progeny. The mechanisms controlling this bronchiolar-to-alveolar developmental transition remain largely unknown. We developed a novel grafting assay to test if lung epithelial progenitors are intrinsically programmed or if alveolar cell identity is determined by environmental factors. These experiments revealed that embryonic lung epithelial identity is extrinsically determined. We show that both glucocorticoid and STAT3 signalling can control the timing of alveolar initiation, but that neither pathway is absolutely required for alveolar fate specification; rather, glucocorticoid receptor and STAT3 work in parallel to promote alveolar differentiation. Thus, developmental acquisition of lung alveolar fate is a robust process controlled by at least two independent extrinsic signalling inputs. Further elucidation of these pathways might provide therapeutic opportunities for restoring alveolar capacity. Highlighted Article: Glucocorticoid receptor and STAT3 signalling act in parallel, but cross-regulated, pathways to control epithelial differentiation during lung alveolar development in mice.

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