Spatiotemporal transcriptome analysis reveals critical roles for mechano-sensing genes at the border zone in remodeling after myocardial infarction

Abstract

The underlying mechanisms of ventricular remodeling after myocardial infarction (MI) remain largely unknown. In this study, we performed an integrative analysis of spatial transcriptomics and single-nucleus RNA sequencing (snRNA-seq) in a 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. An integrative analysis of snRNA-seq and spatial transcriptome of the heart tissue after MI identified the unique cluster that appeared at the border zone in an early stage, highly expressing mechano-sensing genes, such as Csrp3. AAV9-mediated gene silencing and overexpression of Csrp3 demonstrated that upregulation of Csrp3 plays critical roles in preventing cardiac remodeling after MI by regulation of genes associated with mechano-sensing. Overall, our study not only provides an insight into spatiotemporal molecular changes after MI but also highlights that the mechano-sensing genes at the border zone act as adaptive regulators of left ventricular remodeling.

Multiomic Spatial Mapping of Myocardial Infarction and Implications for Personalized Therapy

“…Interestingly, the loss of neighboring cardiomyocytes in vitro (scratch assay) increased the expression of the same mechano-sensing genes in cardiomyocytes, supporting the loss of neighbor hypothesis. 52 In accordance with these findings, Yamada et al 51 observed increased gene expression of mechano-sensing genes in the border zone. They identified the mechano-sensing gene cysteine and glycine-rich protein 3 ( Csrp3 ) as a regulator of post-MI remodeling in the border zone after MI.…”

“…Concerning cardiovascular research, only studies using sequencing-based spatial transcriptomics investigating MI have been published yet. [46][47][48][49][50][51][52]…”

“…Recently, 2 studies integrated scRNA-seq and spatial transcriptomics of various time points after MI to dissect the cellular and molecular mechanisms driving remodeling in the border zone after MI. 51,52,54 Both studies highlighted the critical role of mechano-sensing genes for the remodeling in the border zone early after MI. Calcagno et al 52 discovered two layers of cardiomyocytes with distinct gene expression and specific spatial localization (border zone 1 is adjacent to the remote zone, whereas border zone 2 is adjacent to the ischemic zone).…”

Circuit to target approach defines an autocrine myofibroblast loop that drives cardiac fibrosis

“…1I, methods ). The spatial position of these clusters indicates that they correspond to the infarct zone (with scar components such as: Col1a1 , Col3a1, Fn1 ), remote zone (with functional cardiomyocyte marker genes such as: Myh6, Myl2 ) and a defined border zone population between them (with marker genes such as Nppa , Ankrd1 and Clu) (Calcagno et al, 2022; Duijvenboden et al, 2019; Yamada et al, 2022) ( fig. S1D-E, Table S1 ).…”

Transcriptome Profile Reveals Differences between Remote and Ischemic Myocardium after Acute Myocardial Infarction in a Swine Model

“…These techniques are on the rise due to the large amount of information provided. Recently, two studies have been published where spatial multiomics data reveal the molecular differences in myocardium after MI in human and mouse [ 7 , 8 ]. However, in the field of cardiology, although the porcine model is an excellent tool to evaluate the efficacy of different therapies, its use in “omics” studies has been limited by an incomplete annotation of the pig genome.…”