Fibrotic extracellular matrix microenvironment induces alveolar type II epithelial cell senescence via integrin-β1/FAK/YAP signaling pathway

Abstract

Senescent alveolar epithelial cells (AEC) play a pivotal role in the progression of idiopathic pulmonary fibrosis (IPF), attracting increasing attention from researchers. Central to the pathogenesis of pulmonary fibrosis (PF) is the excessive deposition of extracellular matrix (ECM). However, there remains a significant gap in understanding how the ECM microenvironment influences senescence in type II alveolar epithelial cells (AEC II). This study investigates the activation of the integrin-β₁/FAK/YAP signaling pathway and its role in inducing cellular senescence in both in vivo and in vitro models of bleomycin (BLM)-induced PF. We employed decellularized lung scaffolds (DLS) to replicate the natural ECM microenvironment, aiming to elucidate whether the fibrotic ECM promotes AEC II senescence through the integrin-β₁/FAK/YAP pathway. Notably, our findings indicate that exogenous integrin-β₁ does not induce AEC II senescence. This suggests that the fibrotic ECM microenvironment regulates AEC II senescence via the integrin-β₁/FAK/YAP pathway independently of exogenous integrin-β₁. Therefore, targeting alterations in the fibrotic ECM microenvironment may represent a promising therapeutic strategy for IPF by modulating AEC II senescence.