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Single-cell transcriptomics defines heterogeneity of epicardial cells and fibroblasts within the infarcted murine heart.

ABSTRACT: In the adult heart, the epicardium becomes activated after injury, contributing to cardiac healing by secretion of paracrine factors. Here, we analyzed by single-cell RNA sequencing combined with RNA in situ hybridization and lineage tracing of Wilms tumor protein 1-positive (WT1⁺) cells, the cellular composition, location, and hierarchy of epicardial stromal cells (EpiSC) in comparison to activated myocardial fibroblasts/stromal cells in infarcted mouse hearts. We identified 11 transcriptionally distinct EpiSC populations, which can be classified into three groups, each containing a cluster of proliferating cells. Two groups expressed cardiac specification markers and sarcomeric proteins suggestive of cardiomyogenic potential. Transcripts of hypoxia-inducible factor (HIF)-1α and HIF-responsive genes were enriched in EpiSC consistent with an epicardial hypoxic niche. Expression of paracrine factors was not limited to WT1⁺ cells but was a general feature of activated cardiac stromal cells. Our findings provide the cellular framework by which myocardial ischemia may trigger in EpiSC the formation of cardioprotective/regenerative responses.

SUBMITTER: Hesse J

PROVIDER: S-EPMC8216715 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The metabolic status of surviving cardiomyocytes (CM) in the myocardial tissues of patients who sustained myocardial infarction (MI) is largely unknown. Spatial single-cell RNA-sequencing (scRNA-seq) is a novel tool that enables the unbiased analysis of RNA signatures within intact tissues. We employed this tool to assess the metabolic profiles of surviving CM in the myocardial tissues of patients post-MI.MethodsA spatial scRNA-seq dataset was used to compare the genetic profiles of CM from patients with MI and control patients; we analyzed the metabolic adaptations of surviving CM within the ischemic niche. A standard pipeline in Seurat was used for data analysis, including normalization, feature selection, and identification of highly variable genes using principal component analysis (PCA). Harmony was used to remove batch effects and integrate the CM samples based on annotations. Uniform manifold approximation and projection (UMAP) was used for dimensional reduction. The Seurat "FindMarkers" function was used to identify differentially expressed genes (DEGs), which were analyzed by the Gene Ontology (GO) enrichment pathway. Finally, the scMetabolism R tool pipeline with parameters method = VISION (Vision is a flexible system that utilizes a high-throughput pipeline and an interactive web-based report to annotate and explore scRNA-seq datasets in a dynamic manner) and metabolism.type = Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to quantify the metabolic activity of each CM.ResultsAnalysis of spatial scRNA-seq data showed fewer surviving CM in infarcted hearts than in control hearts. GO analysis revealed repressed pathways in oxidative phosphorylation, cardiac cell development, and activated pathways in response to stimuli and macromolecular metabolic processes. Metabolic analysis showed downregulated energy and amino acid pathways and increased purine, pyrimidine, and one-carbon pool by folate pathways in surviving CM.ConclusionsSurviving CM within the infarcted myocardium exhibited metabolic adaptations, as evidenced by the downregulation of most pathways linked to oxidative phosphorylation, glucose, fatty acid, and amino acid metabolism. In contrast, pathways linked to purine and pyrimidine metabolism, fatty acid biosynthesis, and one-carbon metabolism were upregulated in surviving CM. These novel findings have implications for the development of effective strategies to improve the survival of hibernating CM within the infarcted heart.

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Single-cell transcriptomics defines heterogeneity of epicardial cells and fibroblasts within the infarcted murine heart.

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