Zhang Shuchen, Xiang Boyang, Zhao Yiheng, Wang Wenjing, Chen Lili, Zhou Xiang
Department of Cardiology, The Second Affiliated Hospital of Nanjing Medical University, No. 121 Jiangjiayuan, Nanjing 210011, P. R. China.
Intensive Care Unit, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Cardiovasc Res. 2025 Aug 14;121(9):1419-1432. doi: 10.1093/cvr/cvaf101.
A comprehensive understanding of the genome-wide regulatory landscape of the cardiac tissues post-myocardial infarction (MI) is still lacking. We therefore integrated single-cell RNA sequencing (scRNA-seq) and single-cell for transposase-accessible chromatin sequencing (scATAC-seq) to elucidate the epigenetic landscape of the heart post-MI.
We established MI mice through ligation of the left anterior descending coronary artery, and obtained cardiac tissues from mice at 1-, 3-, 7-, and 14-days post-MI. Integrative analyses of the scRNA-seq and scATAC-seq data revealed the presence of two novel fibroblast subpopulations in the cardiac tissues of MI mice, termed GATA-binding protein 5/ISL LIM Homeobox 1 (GATA5/ISL1)+ fibroblasts and GLI family zinc finger 3 (Gli3)high fibroblasts. The GATA5/ISL1+ fibroblasts were characterized by fibroblast and cardiomyocyte signatures and were found to play a crucial role in cardiac repair post-MI. Moreover, adenoviral-mediated overexpression of GATA5 and ISL1 ameliorated cardiac function and attenuated myocardial fibrosis in the MI mice. RNA sequencing confirmed that GATA5 and ISL1 co-regulate Wnt signalling pathway to promote the transformation of fibroblasts into functional cardiomyocytes. Furthermore, analysis of the human cardiac tissues of MI patients also revealed the presence of GATA5/ISL1+ fibroblasts in the scar tissues, suggesting their crucial role in cardiac tissue repair post-MI. In addition, proteomic analyses revealed enhanced cardiac repair and development signalling in the GATA5/ISL1-overexpressing human cardiac fibroblasts.
The study provides novel perspectives on the mechanisms of myocardial injury and repair at the single-cell level and indicates the potential role of GATA5 and ISL1 as therapeutic targets for MI treatment.
目前仍缺乏对心肌梗死后心脏组织全基因组调控格局的全面了解。因此，我们整合了单细胞RNA测序（scRNA-seq）和单细胞转座酶可及染色质测序（scATAC-seq），以阐明心肌梗死后心脏的表观遗传格局。
我们通过结扎左冠状动脉前降支建立心肌梗死小鼠模型，并在心肌梗死后1天、3天、7天和14天从小鼠获取心脏组织。对scRNA-seq和scATAC-seq数据的综合分析揭示，在心肌梗死小鼠的心脏组织中存在两种新的成纤维细胞亚群，即GATA结合蛋白5/ISL LIM同源盒1（GATA5/ISL1）+成纤维细胞和GLI家族锌指3（Gli3）高表达成纤维细胞。GATA5/ISL1+成纤维细胞具有成纤维细胞和心肌细胞特征，并且发现在心肌梗死后的心脏修复中起关键作用。此外，腺病毒介导的GATA5和ISL1过表达改善了心肌梗死小鼠的心脏功能并减轻了心肌纤维化。RNA测序证实，GATA5和ISL1共同调节Wnt信号通路，以促进成纤维细胞向功能性心肌细胞的转化。此外，对心肌梗死患者的人类心脏组织分析还显示，瘢痕组织中存在GATA5/ISL1+成纤维细胞，表明它们在心肌梗死后心脏组织修复中起关键作用。此外，蛋白质组学分析显示，在过表达GATA5/ISL1的人类心脏成纤维细胞中，心脏修复和发育信号增强。
该研究在单细胞水平上为心肌损伤和修复机制提供了新的视角，并表明GATA5和ISL1作为心肌梗死治疗靶点的潜在作用。
