A novel mechanoeffector role of fibroblast S100A4 in myofibroblast transdifferentiation and fibrosis.
A novel mechanoeffector role of fibroblast S100A4 in myofibroblast transdifferentiation and fibrosis.
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DOI：
10.1016/j.jbc.2023.105530
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发表时间：
2024-01
影响因子：
4.8
通讯作者：
Olman, Mitchell A
中科院分区：
文献类型：
--
作者：
Southern, Brian D;Li, Haiyan;Mao, Hongxia;Crish, James F;Grove, Lisa M;Scheraga, Rachel G;Mansoor, Sanaa;Reinhardt, Amanda;Abraham, Susamma;Deshpande, Gauravi;Loui, Alicia;Ivanov, Andrei I;Rosenfeld, Steven S;Bresnick, Anne R;Olman, Mitchell A
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 the 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.
