Primary lung fibroblasts activated with constitutively active Smo

Postnatal tissue quiescence is generally thought to be a default state in the absence of a proliferative stimulus such as injury. We now demonstrate that in the lung, quiescence in the adult is an actively maintained state and is regulated by paracrine hedgehog signaling. Epithelial-specific deletion of Sonic Hedgehog during normal homeostasis results in a proliferative expansion of the adjacent lung mesenchyme. Injury to the lung epithelium results in decreased hedgehog activation, accompanied by proliferative expansion of the adjacent mesenchyme. Moreover, reconstitution of Hedgehog signaling during epithelial injury attenuated the proliferative expansion of the adjacent mesenchyme. Hedgehog signaling maintains lung quiescence by attenuating PDGF induced activation. These results indicate that in postnatal tissues, epithelial cells can actively maintains mesenchymal quiescence via paracrine hedgehog activation, and that imbalances in this pathway could lead to aberrant mesenchymal expansion and postnatal disease. Fibroblasts were isolated from lungs of adult UBCCreERT2:R26RSmoM2 mice and incubated with or without 4-hydroxytamoxifen to activate the SmoM2 allele for 48 hours before RNA was isolated for microarray.