PIEZO1 mediates periostin+ myofibroblast activation and pulmonary fibrosis in mice

作者：Liran Xu, Ting Li, Yapeng Cao, Yu He, Zehua Shao, Siyu Liu, Bianbian Wang, Ailing Su, Huijing Tian, Yongxin Li, Guozheng Liang, Changhe Wang, John Shyy, Ying Xiong, Fangyuan Chen, Jason X.‐J. Yuan, Junjun Liu, Bin Zhou, Nina Wettschureck, Stefan Offermanns, Yan Yang, Zuyi Yuan, Shengpeng Wang · 发表于：Journal of Clinical Investigation · 年份：2025 · DOI：10.1172/jci184158 · 被引用次数：52 · 研究领域：Erythrocyte Function and Pathophysiology、Blood properties and coagulation、Cell death mechanisms and regulation

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the excessive accumulation of activated myofibroblasts that deposit extracellular matrix (ECM) protein, leading to progressive scar formation and mechanical stress. However, the cellular origin and fate of myofibroblasts remain controversial, and the mechanisms by which myofibroblasts sense mechanical cues in the lung are unclear. Here, we report that periostin (Postn) is a reliable and distinctive marker for pulmonary myofibroblasts, while ablation of Postn+ myofibroblasts after injury ameliorated lung fibrosis. PIEZO1 was highly expressed in Postn+ myofibroblast and played a vital role in mechanoactivation of Postn+ myofibroblast and development of lung fibrosis. Conditional deletion of Piezo1 in Postn+ myofibroblasts significantly inhibited lung fibrosis by suppressing myofibroblast activation and proliferation. Loss of Piezo1 led to disruption of actin organization and prevention of Yap/Taz nuclear localization, thus shifting the myofibroblasts from a proliferative state into a stressed and apoptotic state. Furthermore, myofibroblast-specific Yap/Taz deletion fully recapitulated the protective phenotypes of myofibroblast-Piezo1-KO mice. These findings show that periostin marks pulmonary myofibroblasts, and that PIEZO1-mediated mechanosensation is essential for myofibroblast activation in the lung. Targeting PIEZO1 in the periostin-expressing cells is a novel therapeutic option ...