Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis

• 成果类型: Article
• 署名作者: Cho, Sangkyun; Rhee, Siyeon; Madl, Christopher M.; Caudal, Arianne; Thomas, Dilip; Kim, Hyeonyu; Kojic, Ana; Shin, Hye Sook; Mahajan, Abhay; Jahng, James W.; Wang, Xi; Thai, Phung N.; Paik, David T.; Wang, Mingqiang; Mullen, Mckay; Baker, Natalie M.; Leitz, Jeremy; Mukherjee, Souhrid; Winn, Virginia D.; Woo, Y. Joseph; Blau, Helen M.; Wu, Joseph C.
• 署名单位: Stanford University; Stanford University; Stanford University; University of Pennsylvania; University System of Ohio; Ohio State University; University of California System; University of California Davis; Stanford University; Stanford University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2263
• DOI: 10.1038/s41586-025-08945-9
• 发表日期: 2025-06-19
• 关键词: heart; differentiation; myofibroblasts; generation; stiffness; matrix; cells

摘要

Matrix-derived biophysical cues are known to regulate the activation of fibroblasts and their subsequent transdifferentiation into myofibroblasts(1, 2, 3, 4, 5-6), but whether modulation of these signals can suppress fibrosis in intact tissues remains unclear, particularly in the cardiovascular system(7, 8, 9-10). Here we demonstrate across multiple scales that inhibition of matrix mechanosensing in persistently activated cardiac fibroblasts potentiates-in concert with soluble regulators of the TGF beta pathway-a robust transcriptomic, morphological and metabolic shift towards quiescence. By conducting a meta-analysis of public human and mouse single-cell sequencing datasets, we identify the focal-adhesion-associated tyrosine kinase SRC as a fibroblast-enriched mechanosensor that can be targeted selectively in stromal cells to mimic the effects of matrix softening in vivo. Pharmacological inhibition of SRC by saracatinib, coupled with TGF beta suppression, induces synergistic repression of key profibrotic gene programs in fibroblasts, characterized by a marked inhibition of the MRTF-SRF pathway, which is not seen after treatment with either drug alone. Importantly, the dual treatment alleviates contractile dysfunction in fibrotic engineered heart tissues and in a mouse model of heart failure. Our findings point to joint inhibition of SRC-mediated stromal mechanosensing and TGF beta signalling as a potential mechanotherapeutic strategy for treating cardiovascular fibrosis.