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
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Nature. 2025 Apr 30. doi: 10.1038/s41586-025-08945-9.
Matrix-derived biophysical cues are known to regulate the activation of fibroblasts and their subsequent transdifferentiation into myofibroblasts, but whether modulation of these signals can suppress fibrosis in intact tissues remains unclear, particularly in the cardiovascular system. Here we demonstrate across multiple scales that inhibition of matrix mechanosensing in persistently activated cardiac fibroblasts potentiates-in concert with soluble regulators of the TGFβ 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 TGFβ 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 TGFβ signalling as a potential mechanotherapeutic strategy for treating cardiovascular fibrosis.
已知基质衍生的生物物理信号可调节成纤维细胞的激活及其随后向肌成纤维细胞的转分化，但这些信号的调节是否能抑制完整组织中的纤维化仍不清楚，尤其是在心血管系统中。在这里，我们在多个尺度上证明，在持续激活的心脏成纤维细胞中抑制基质机械传感，与TGFβ途径的可溶性调节因子协同作用，可促使转录组、形态和代谢向静止状态发生强大转变。通过对公开的人类和小鼠单细胞测序数据集进行荟萃分析，我们确定粘着斑相关酪氨酸激酶SRC是一种在成纤维细胞中富集的机械传感器，可在基质细胞中选择性靶向，以模拟体内基质软化的效果。用萨拉卡替尼对SRC进行药理学抑制，再加上抑制TGFβ，可诱导成纤维细胞中关键促纤维化基因程序的协同抑制，其特征是对MRTF-SRF途径有明显抑制，单独使用任何一种药物治疗后均未观察到这种情况。重要的是，双重治疗可减轻纤维化工程心脏组织和心力衰竭小鼠模型中的收缩功能障碍。我们的研究结果表明，联合抑制SRC介导的基质机械传感和TGFβ信号传导是治疗心血管纤维化的一种潜在机械治疗策略。
