心脏成纤维细胞是心肌梗死后瘢痕形成和心脏修复的关键。含有胶原三股螺旋重复区1(CTHRC1)的细胞外基质蛋白参与了血管重塑、骨形成和肿瘤进展的病理生理过程。然而，CTHRC1在心肌梗死后创面修复中的作用和作用机制还不完全清楚。生物信息学分析显示，在缺血性心脏损伤后，心脏成纤维细胞中CTHRC1的上调。MI小鼠血清中CTHRC1水平升高，MI后心脏成纤维细胞中CTHRC1表达上调。体外结果显示，心脏成纤维细胞中CTHRC1表达的诱导是通过经典TGFβ1-Smad2/3信号通路介导的。此外，CTHRC1能够促进创面愈合和增强体外心脏成纤维细胞的激活。缺乏Cthrc1会使心脏功能恶化，并减少胶原沉积，增加心脏破裂导致的死亡率。与上述表型一致，观察到心肌CD31、α-平滑肌肌动蛋白、胶原I和胶原III水平降低，而基质金属蛋白酶2和基质金属蛋白酶9的心肌表达在Cthrc1基因敲除小鼠MI后增加。上述作用可以部分通过rCTHRC1蛋白或rWNT5A蛋白逆转。我们的研究表明，心脏成纤维细胞来源的经典TGFβ1-Smad2/3介导的CTHRC1可以通过非经典WNT5A-PCP信号通路选择性活化，从而改善创面修复和预防心脏破裂。 ©作者。

Cardiac fibroblasts are crucial for scar formation and cardiac repair after myocardial infarction (MI). Collagen triple helix repeat containing 1 (CTHRC1), an extracellular matrix protein, is involved in the pathogenesis of vascular remodeling, bone formation, and tumor progression. However, the role and underlying mechanism of CTHRC1 in post-MI wound repair are not fully clear. Bioinformatics analysis demonstrated CTHRC1 up-regulation in cardiac fibroblasts after ischemic cardiac injury. Serum levels of CTHRC1 were increased in MI mice and CTHRC1 expression was up-regulated in cardiac fibroblasts after MI. In vitro results showed that the induction of CTHRC1 expression in cardiac fibroblasts was mediated by canonical TGFβ1-Smad2/3 signaling axis. Moreover, CTHRC1 improved wound healing and boosted cardiac fibroblast activation in vitro. Cthrc1 deficiency aggravated cardiac function and reduced collagen deposition as well as increased mortality attributable to cardiac rupture after MI. Consistent with above phenotypes, reduced the levels of myocardial CD31, α-smooth muscle actin, collagen I, and collagen III was observed, whereas myocardial expression of matrix metalloproteinase 2 and matrix metalloproteinase 9 were increased in Cthrc1 knockout mice post-MI. Above effects could be partly reversed by rCTHRC1 protein or rWNT5A protein. Our study indicates that cardiac fibroblast-derived, canonical TGFβ1-Smad2/3-dependent CTHRC1 could improve wound repair and prevent cardiac rupture after MI via selectively activating non-canonical WNT5A-PCP signaling pathway.© The author(s).