肌成纤维细胞
转分化
成纤维细胞
细胞生物学
细胞外基质
纤维化
特发性肺纤维化
生物
肺纤维化
癌症研究
病理
肺
医学
内科学
体外
干细胞
生物化学
作者
Brian D. Southern,Haiyan Li,Hua Mao,James F. Crish,L. Grove,Rachel G. Scheraga,Samina Mansoor,A. Reinhardt,Susamma Abraham,Gauravi Deshpande,Alicia Loui,Andrei I. Ivanov,Steven S. Rosenfeld,Anne R. Bresnick,Mitchell A. Olman
标识
DOI:10.1016/j.jbc.2023.105530
摘要
Fibroblast to myofibroblast transdifferentiation mediates numerous fibrotic disorders, such as idiopathic pulmonary fibrosis (IPF). We have previously demonstrated that non-muscle myosin II (NMII) is activated in response to fibrotic lung extracellular matrix, thereby mediating myofibroblast transdifferentiation. NMII-A is known to interact with the calcium-binding protein S100A4, but the mechanism by which S100A4 regulates fibrotic disorders is unclear. In this study, we show that fibroblast S100A4 is a calcium-dependent, mechanoeffector protein that is uniquely sensitive to pathophysiologic-range lung stiffness (8 – 25 kPa), and thereby mediates myofibroblast transdifferentiation. Re-expression of endogenous fibroblast S100A4 rescues the myofibroblastic phenotype in S100A4 KO fibroblasts. Analysis of NMII-A/actin dynamics reveals that S100A4 mediates unraveling and redistribution of peripheral actomyosin to a central location, resulting in a contractile myofibroblast. Furthermore, S100A4 loss protects against murine in vivo pulmonary fibrosis, and S100A4 expression is dysregulated in IPF. Our data reveal a novel mechanosensor/effector role for endogenous fibroblast S100A4 in inducing cytoskeletal redistribution in fibrotic disorders such as IPF.
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