YAP Alleviates Pulmonary Fibrosis Through Promoting Alveolar Regeneration via Modulating the Stemness of Alveolar Type 2 Cells

作者：Jingyu Wang, Jingyu Wang, Fengqing Zhu, Fengqing Zhu, Renru Luo, Yingyin Cui, Ziyu Zhang, Mengling Xu, Yuanyuan Zhao, Yonghui He, Wenqing Yang, Nianle Li, Zhu Zhu, Yingshan Chen, Tao Wang, Xuan Jiang, Xuan Jiang, Chuwen Lin, Chuwen Lin · 发表于：Stem Cells and Development · 年份：2024 · DOI：10.1089/scd.2024.0101 · 被引用次数：6 · 研究领域：Hippo pathway signaling and YAP/TAZ、Wnt/β-catenin signaling in development and cancer、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no cure except transplantation. Abnormal alveolar epithelial regeneration is a key driver of IPF development. The function of Yes1 Associated Transcriptional Regulator (YAP) in alveolar regeneration and IPF pathogenesis remains elusive. Here, we first revealed the activation of YAP in alveolar epithelium 2 cells (AEC2s) from human IPF lungs and fibrotic mouse lungs. Notably, conditional deletion of YAP in mouse AEC2s exacerbated bleomycin-induced pulmonary fibrosis. Intriguingly, we showed in both conditional knockout mice and alveolar organoids that YAP deficiency impaired AEC2 proliferation and differentiation into alveolar epithelium 1 cells (AEC1s). Mechanistically, YAP regulated expression levels of genes associated with cell cycle progression and AEC1 differentiation. Furthermore, overexpression of YAP in vitro promoted cell proliferation. These results indicate the critical role of YAP in alveolar regeneration and IPF pathogenesis. Our findings provide new insights into the regulation of alveolar regeneration and IPF pathogenesis, paving the road for developing novel treatment strategies.