Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Although previous studies have demonstrated that certain embryonic developmental programs are reactivated aberrantly in adult organs to drive repair and regeneration1,2,3, it is not well understood how quiescence is maintained in organs such as the lung, which displays a remarkably low level of cellular turnover4,5. Here we demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signalling. Epithelial-specific deletion of sonic hedgehog (Shh) during postnatal homeostasis in the murine lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signalling is initially downregulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signalling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial–mesenchymal interactions coordinated by hedgehog actively maintain postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.
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Gene Expression Omnibus
The Gene Expression Omnibus accession number for the microarray data produced in these studies is GSE68201.
The authors appreciate the input of M. Kahn, M. Beers and R. Shah in these studies. The authors are grateful to A. Stout and the Department of Cell and Developmental Biology Microscopy Core for help with imaging. These studies were supported by funds from the National Institutes of Health (HL110942, HL100405, HL087825 to E.E.M). T.P. is supported by the American Heart Association Fellow-to-Faculty Transition Award, Actelion ENTELLIGENCE Award, and K08-HL121146.
Extended data figures
This table shows GO enrichment analysis for microarray analysis in Extended Data Figure 4. GO analysis was performed on the microarray data obtained from activation of Smo in isolated lung mesenchymal cells. The top 10 (by P value significance) categories identified are shown.
This table contains a list of differentially expressed genes found in the GO category of mitotic nuclear division obtained from activation of Smo in lung mesenchymal cells.
About this article
Alveolar Differentiation Potency of Human Distal Airway Stem Cells Is Associated with Pulmonary Pathological Conditions
Stem Cells International (2019)