Spatiotemporal single-cell analysis reveals critical roles of mechano-sensing genes at the border zone in remodeling after myocardial infarction

Abstract The left ventricular remodeling after myocardial infarction (MI) causes heart failure, but its underlying mechanisms remain largely unknown. Here, we performed an integrative analysis of spatial transcriptomics and single cell RNA-seq in murine MI model and found that mechanical stress-response genes are expressed at the border zone and play a critical role in left ventricular remodeling after MI. Single-cardiomyocyte RNA-seq of the heart after MI divided cardiomyocytes into 8 clusters. We identified the cell cluster which was specifically derived from the ischemic area in an early stage after MI and expressed mechano-sensing genes such as Csrp3, Ankrd1 and Ankrd2. Spatial transcriptomic analysis demonstrated that cardiomyocytes with this gene expression profile were specifically localized at the border zone in post-MI day 1. AAV9-mediated gene silencing of Csrp3 exacerbated cardiac dilatation and dysfunction after MI. Collectively, our datasets and findings not only provide an insight into spatiotemporal molecular pathogenesis of myocardial infarction but also highlight mechano-sensing genes at the border zone as an adaptive regulator of left ventricular remodeling.