Editors' ChoiceTissue Regeneration

Actively quiescent

Sci. Signal.  27 Oct 2015:
Vol. 8, Issue 400, pp. ec309
DOI: 10.1126/scisignal.aad7088

Unless injured, many tissues are quiescent, which has been considered a default state that occurs in the absence of proliferative signals. Peng et al. examined tissue homeostasis and injury response in the adult mouse lung and determined that Hedgehog signaling was necessary to maintain the mesenchyme in the quiescent state. Using genetically encoded reporters showed that Sonic hedgehog (Shh) was expressed in a subset of epithelial cells in the airway and the gene encoding the Shh effector protein Gli was expressed in the adjacent mesenchymal cells. Lineage tracing combined with marker analysis to identify dividing cells indicated that the Gli-positive cells were not proliferating in the uninjured lung. Knockout of Shh in the adult lung epithelial cells or knockout of Smo, which encodes the Shh-activated protein Smoothened, in the Gli-positive mesenchymal cells resulted in proliferation and increased numbers of mesenchymal cells in the absence of injury. In two chemically-induced lung injury models, reporter analysis indicated that Shh and Gli expression were reduced in the injured epithelium and mesenchyme, respectively. Introduction of a constitutively active form of Smo blocked injury-induced proliferation of Gli-positive cells, which were identified by lineage tracing. Several months after injury when the tissue had been repaired, the epithelium was reconstituted, and the tissue was quiescent, Shh and Gli expression returned to amounts similar to those in uninjured lung. Knockout of Smo in the Gli-positive cells prevented the return to quiescence after injury and resulted in excessive proliferation of both the mesenchymal cells and the Shh-producing epithelial cells, suggesting a feedback circuit between these cells that involves Hedgehog signaling actively controls lung tissue homeostasis.

T. Peng, D. B. Frank, R. S. Kadzik, M. P. Morley, K. S. Rathi, T. Wang, S. Zhou, L. Cheng, M. M. Lu, E. E. Morrisey, Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration. Nature 526, 578–582 (2015). [PubMed]