BACKGROUND Myocardial fibrosis, a pathological hallmark of adverse cardiac remodeling and heart failure, has been conventionally attributed to the activation of resident fibroblasts. Although recent studies suggest contributions from non-fibroblast lineages, direct in vivo genetic evidence that cardiomyocytes can undergo a mesenchymal-like fate transition during myocardial fibrosis remains absent. This study aims to investigate whether such a transition occurs and to elucidate the underlying regulatory mechanisms. METHODS Human myocardial infarction (MI) tissues were analyzed by immunohistochemistry and integrated with public single nucleus RNA sequencing (snRNA seq) data to detect mesenchymal like signatures in cardiomyocytes. Genetic lineage-tracing was performed in MI mice, and in cardiomyocyte-specific Hgs (hepatocyte growth factor-regulated tyrosine kinase substrate) gene knockout mice, to map the fate of cardiomyocyte-derived cells. Mechanistic insights were obtained through proteomic and snRNA-seq analysis of Hgs knockout hearts and validated through gain- and loss-of-function experiments targeting Aldh1a2 (aldehyde dehydrogenase 1 family member A2). RESULTS In human MI samples, a subset of cardiomyocytes showed reduced expression of cardiomyocyte markers concurrent with acquisition of mesenchymal-associated markers. Genetic lineage tracing demonstrated that adult cardiomyocytes can adopt a mesenchymal-like cell fate during post MI remodeling. We identify HGS as a factor constraining this transition. Hgs knockout in adult cardiomyocytes upregulated Aldh1a2, triggered the mesenchymal-like fate transition, and gave rise to cells expressing markers of activated fibroblasts or osteoblasts, accompanied by pronounced myocardial fibrosis and calcification. Forced Aldh1a2 overexpression in cardiomyocytes drove the mesenchymal-like fate transition in vitro and in vivo, whereas Aldh1a2 deletion in cardiomyocytes mitigated MI-induced myocardial fibrosis. CONCLUSIONS This study provides in vivo genetic evidence that adult cardiomyocytes possess the capacity to undergo a mesenchymal-like fate transition under pathological conditions. Our data suggest that HGS and ALDH1A2 serve as regulators of the transition, offering a new basis for understanding cellular and molecular mechanisms of myocardial fibrosis.
Wang, T., Zhou, C., Liu, M., Xing, Y., Han, C., Li, R., Huang, Y., Li, Z., Teng, Y., Yang, G., Liu, W., Xu, P., Wang, S.-Q., Zhou, B., Han, J.-D. J., Wang, J., Yang, X.
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