Abstract
The efficiency of the repair process following ischemic cardiac injury is a crucial determinant for the progression into heart failure and is controlled by both intra- and intercellular signaling within the heart. An enhanced understanding of this complex interplay will enable better exploitation of these mechanisms for therapeutic use. We used single-cell transcriptomics to collect gene expression data of all main cardiac cell types at different time-points after ischemic injury. These data unveiled cellular and transcriptional heterogeneity and changes in cellular function during cardiac remodeling. Furthermore, we established potential intercellular communication networks after ischemic injury. Follow up experiments confirmed that cardiomyocytes express and secrete elevated levels of beta-2 microglobulin in response to ischemic damage, which can activate fibroblasts in a paracrine manner. Collectively, our data indicate phase-specific changes in cellular heterogeneity during different stages of cardiac remodeling and allow for the identification of therapeutic targets relevant for cardiac repair.
Highlights
The efficiency of the repair process following ischemic cardiac injury is a crucial determinant for the progression into heart failure and is controlled by both intra- and intercellular signaling within the heart
We found that natriuretic peptide A (Nppa) and natriuretic peptide B (Nppb), two well-established factors secreted by cardiomyocytes, were the only factors secreted by cardiomyocytes[30]
We used a fluorescence-activated cell sorting (FACS)-based scRNA-seq method on the adult, injured heart to detail the dynamics in cellular distribution, function and communication at different time points after ischemic damage
Summary
The efficiency of the repair process following ischemic cardiac injury is a crucial determinant for the progression into heart failure and is controlled by both intra- and intercellular signaling within the heart. We used single-cell transcriptomics to collect gene expression data of all main cardiac cell types at different time-points after ischemic injury. These data unveiled cellular and transcriptional heterogeneity and changes in cellular function during cardiac remodeling. High-throughput, unbiased gene expression studies of the infarcted heart were limited in resolution as they had to be performed on cardiac tissue or on populations of cells isolated by fluorescence-activated cell sorting (FACS) based on expression of a gene marker These types of studies failed to determine cell-specific gene expression, thereby preventing examination of transcription heterogeneity within cell populations or intercellular communication between cell types within the same tissue. Subsequent in vitro experiments suggested that one of these factors, beta-2 microglobulin (B2M), is able to stimulate the wound healing response via the activation of fibroblasts
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