Single-cell epigenomic and transcriptomic analysis unveils the pivotal role of GATA5/ISL1+ fibroblasts in cardiac repair post-myocardial infarction

作者：Shuchen Zhang, Boyang Xiang, Yiheng Zhao, Wenjing Wang, Lili Chen, Xiang Zhou · 发表于：Cardiovascular Research · 年份：2025 · DOI：10.1093/cvr/cvaf101 · 被引用次数：6 · 研究领域：Cardiac Fibrosis and Remodeling、Congenital heart defects research、Tissue Engineering and Regenerative Medicine

AIMS: 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. METHODS AND RESULTS: 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 a...