Niche-mediated repair of airways is directed in an occupant-dependent manner

In injured airways of the adult lung, epithelial progenitors are called upon to repair by nearby mesenchymal cells via signals transmitted through the niche. Currently, it is unclear whether repair is coordinated by the mesenchymal cells that maintain the niche or by the airway epithelial cells that occupy it. Here, we show that the spatiotemporal expression of Fgf10 by the niche is primarily orchestrated by the niche's epithelial occupants—both those that reside prior to, and following, injury. During homeostasis, differentiated airway epithelial cells secrete Sonic hedgehog (Shh) to inhibit Fgf10 expression by Gli1⁺ peribronchial mesenchymal cells in the niche. After injury, remaining epithelial cells produce Wnt7b to induce Fgf10 expression in airway smooth muscle cells in the niche. We find that this reliance on a common activator of airway epithelial stem cells also allows for the recruitment of remote stem cell populations when local populations have been exhausted.