Single-cell RNA sequencing analysis identified GARP-expressing myeloid cells that deteriorate post-infarct myocardial remodeling

Post-infarct 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 TGF-βs. GARP-expressing myeloid cells (GEM cells) exhibited the gene expression profile characteristic of fibrocytes, fibroblast-like myeloid cells. Myeloid cell-specific GARP-null mice (GARP-CKO mice) showed ameliorated cardiac fibrosis and improved cardiac function after myocardial infarction (MI). Myeloid-specific GARP gene 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. Additionally, 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 MI patients suggested the existence of GARP + CD11b + cells in post-infarct 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 post-infarct heart failure.