Cell competition drives bronchiolization and pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory scarring disease arising from the maladaptive differentiation of lung stem cells into bronchial epithelial cells rather than into alveolar type 1 (AT1) cells, which are responsible for gas exchange. Here, we report that healthy lungs maintain their stem cells through tonic Hippo and β-catenin signaling, which promote Yap/Taz degradation and allow for low-level expression of the Wnt target gene Myc. Inactivation of upstream activators of the Hippo pathway in lung stem cells inhibits this tonic β-catenin signaling and Myc expression and promotes their Taz-mediated differentiation into AT1 cells.

Cell competition drives bronchiolization and pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease arising from the maladaptive differentiation of lung stem cells into bronchial epithelial cells rather than into alveolar type 1 (AT1) cells, which are responsible for gas exchange. Here, we report that healthy lungs maintain their stem cells through tonic Hippo and β-catenin signaling, which promote Yap/Taz degradation and allow for low level expression of the Wnt target gene . Inactivation of upstream activators of the Hippo pathway in lung stem cells inhibits this tonic β-catenin signaling and expression and promotes their Taz mediated differentiation into AT1 cells.

Protocol for the use of signal amplification by exchange reaction-fluorescence in situ hybridization on adult formalin-fixed paraffin-embedded mouse lung tissue.

Fluorescence in situ hybridization (FISH) is a useful tool for analyzing RNA expression, but difficulties arise with low-abundance RNA and in tissues that are formalin-fixed paraffin-embedded (FFPE) because reagents can be expensive. In this protocol, we adapt a previously designed FISH amplification protocol (SABER [signal amplification by exchange reaction]) for adult mouse FFPE lung sections by using probes that are extended and branched to amplify the signal. We combine FISH and immunostaining to identify cell-specific RNA.

Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicates that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveolar type 2 (AT2) stem cells or mutations that either impair their self-renewal and/or impair their differentiation into AT1 cells can serve as a trigger of pulmonary fibrosis.

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.