Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration

Abstract

Summary Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Previous studies have demonstrated that certain embryonic development programs are reactivated aberrantly in adult organs to drive repair and regeneration1–3, 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. We now demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signaling. Epithelial-specific deletion of sonic hedgehog during postnatal homeostasis in the lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signaling is initially down-regulated 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 signaling 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 maintains postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.

Distinct Mesenchymal Lineages and Niches Promote Epithelial Self-Renewal and Myofibrogenesis in the Lung

“…Loss of Shh leads to increased aggressiveness of pancreatic tumors suggesting that during cancer development, mesenchyme can restrain tumor growth. In contrast, Shh signaling inhibits mesenchymal growth and proliferation in the adult lung during normal homeostasis (Peng et al, 2015). Loss of Shh or hedgehog signaling in general leads to increased proliferation in both hedgehog receptive mesenchyme as noted by Gli1 expression as well as in the adjoining airway epithelium.…”

“…Moreover, there are few cell specific marker genes that demarcate different mesenchymal lineages within the lung or most other adult tissues. Recent evidence has revealed a critical role for an epithelial derived hedgehog signal in regulation of airway-adjacent mesenchyme homeostasis and repair in the lung (Peng et al, 2015). However, there is little understanding or characterization of the different mesenchymal lineages and their respective abilities to promote homeostasis and regeneration in the lung alveolus or in most other tissue specific niches.…”

Hedgehog: the key to maintaining adult lung repair and regeneration

“…Deregulation of the hedgehog signaling pathway leads to abnormal repair and regeneration in the lung (Peng et al 2015). Moreover, these results demonstrate that the functions of various pathways may change at any given time.…”

“…Stochastic multicolor clonal analysis was utilized in Gli1 creERT2 :R26R confetti mice to show clonal expansion in Gli1 1 lung cells after injury (Peng et al 2015). To determine the role of Hh signaling in the restoration of quiescence, Peng et al measured Hh activation as well as Shh and Gli1 expression by qPCR, following naphthalene induced injury in Gli1 lacZ lungs.…”

The smoking gun: Genetics and genomics reveal causal pathways for COPD

“…Continued activation of the pathway maintains lung homeostasis and blockade is associated with an exaggerated mesenchymal proliferative response and aberrant repair of injured lungs. 20 The ligand for the pathway, Sonic Hedgehog is secreted by the airway epithelium and acts on its receptor PTCH1 expressed on mesenchymal cells to activate hedgehog signaling. HHIP is also expressed on these cells and it can block the pathway.…”