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.

Spatiotemporal transcriptomics reveals pathogenesis of viral myocarditis

“…Upregulation of Ankrd1 , a myocyte survival factor, occurs during late-stage heart disease in patients with idiopathic dilated cardiomyopathy 29 . A recent study shows that cardiomyocytes expressing Ankrd1 are localized in the border zone on day 1 post-myocardial infarction 30 . Together, our analysis reveals that tissue injury is localized to myocarditic regions with remodeling programs being active in the border zone and demonstrates the importance of spatially resolved molecular measurements to study viral myocarditis.…”

“…Upregulation of Ankrd1 , a myocyte survival factor, occurs during late-stage heart disease in patients with idiopathic dilated cardiomyopathy 29 . A recent study shows that cardiomyocytes expressing Ankrd1 are localized in the border zone on day 1 post-myocardial infarction 30 .…”

“…Integrated high-throughput scRNA-seq and spatial transcriptomics was recently used to study heart development 32,33 and heart disease 30,34 , but these methods have not been used to study viral myocarditis prior to our work. Bulk RNA-seq has been used previously to profile transcriptomic signatures of infection, inflammation, and tissue injury associated with viral myocarditis 9,[35][36][37][38] .…”

Spatiotemporal transcriptomics reveals pathogenesis of viral myocarditis

“…Integrated high-throughput scRNA-seq and spatial transcriptomics was recently used to study heart development 37,38 and heart disease 30,39 , but, to our knowledge, these methods have not been used Resource https://doi.org/10.1038/s44161-022-00138-1…”

“…Upregulation of Ankrd1, a myocyte survival factor, occurs during late-stage heart disease in patients with idiopathic dilated cardiomyopathy 29 . A recent study shows that cardiomyocytes expressing Ankrd1 are localized in the border zone on day 1 after myocardial infarction 30 .…”