Single-cell RNA sequencing analysis identified GARP-expressing myeloid cells that deteriorate postinfarct myocardial remodeling.

Abstract

Postinfarct myocardial remodeling is modulated by myeloid-derived cells; however, the precise mechanism remains to be fully elucidated. Here, by the targeted single-cell RNA sequence (scRNA-Seq) analysis, we newly identified a myeloid cell population that specifically expresses glycoprotein A repetition-predominant (GARP), a docking receptor and activator of latent transforming growth factor βs (TGF-βs). GARP-expressing myeloid (GEM) cells exhibited the gene expression profile characteristic of fibrocytes, fibroblast-like myeloid cells. Myeloid cell-specific-null mice (GARP-CKO mice) showed ameliorated cardiac fibrosis and improved cardiac function after myocardial infarction (MI). Myeloid-specificgene ablation resulted in the suppression of TGF-β signaling in cardiomyocytes and reduced the neutrophil infiltration into infarct myocardium, accompanied by decreased neutrophil chemotaxis cytokine production. In addition, cardiomyocyte apoptosis decreased in GARP-CKO mice, proposing that myeloid GARP/TGF-β axis is involved in cardiomyocyte loss. Comprehensive scRNA-Seq data, combined with the published dataset of healthy heart cells, revealed that GEM cells were derived from heart-resident fibrocytes. Finally, the Visium data of patients with MI suggested the existence of GARPCD11bcells in postinfarct myocardium. Collectively, GARP-expressing fibrocytes deteriorate cardiac remodeling by regulating neutrophil infiltration and cardiomyocyte apoptosis. The blockade of the transition from fibrocytes to GEM cells could be a therapeutic strategy against postinfarct heart failure.Myeloid cells are known to contribute to the progression of myocardial infarction. However, the precise roles of these cells have not been fully elucidated. Single-cell RNA sequencing analysis demonstrated a population of glycoprotein A repetition-predominant (GARP)-expressing myeloid cells (GEM cells) that were derived from heart-resident fibrocytes. GEM cells were found to regulate neutrophil infiltration and cardiomyocyte apoptosis, resulting in detrimental cardiac remodeling. Spatial transcriptomics suggests that GEM cells are also present in human infarcted myocardium.