Mesothelial plasticity regulates lung mechanical homeostasis in regeneration and fibrosis

Here we show that mesothelial cells are key regulators of lung mechanical adaptation. Following pneumonectomy, elevated stretch activates YAP and induces a transient fibroblast-like mesothelial cell state (F-LMC) characterized by reduced mesothelial identity, increased fibroblast feature, and extracellular-matrix remodeling at the pleural surface.

Yap deletion suppresses F-LMC formation, resulting in lung overinflation and defective regeneration following pneumonectomy. By contrast, in fibrotic lungs, this mesothelial remodeling program is aberrantly activated and restricts lung inflation. Inhibition of this maladaptive response prevents the decline in lung capacity following bleomycin-induced pulmonary fibrosis.