Abstract 4362436: GARP deletion in myeloid cells ameliorated cardiac remodeling following myocardial infarction

Cardiac remodeling involves diverse types of myeloid-derived cells, including macrophages and neutrophils. While the general significance of myeloid cells is recognized, precise roles of these cells remain to be fully elucidated due to their heterogeneity. Characterization of myeloid cells based on gene expression profile is crucial for uncovering how myeloid cells regulate cardiac remodeling. We performed single cell RNA sequencing (scRNA-seq) analysis to characterize CD11b+ myeloid cell populations in infarcted hearts. To investigate the importance of unique population that specifically express GARP, we generated myeloid cell-specific GARP knockout (CKO) mice and subjected them to myocardial infarction (MI). Cardiac remodeling, function and cellular events were assessed using histological analysis, echocardiography, flow cytometry and immuno-staining. We also re-analyzed published spatial transcriptome data to characterize this unique cell population in human hearts. ScRNA-seq analysis revealed a distinct myeloid cell population that was separate from macrophages and neutrophils. This population specifically expressed 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. CKO mice showed significantly ameliorated cardiac fibrosis (fibrotic area (%): fl/flcontrol 45.5±14.8 vs. CKO 26.7±4.9, P<0.05) and improved cardiac function (Ejection Fraction (%): fl/flcontrol 22.4±11.7 vs. CKO 36.6±7.0, P<0.05) 14 days after MI. Mechanistically, GARP gene deletion resulted in the suppression of TGF-β signaling in cardiomyocytes and reduced neutrophil infiltration into myocardium, accompanied by decreased chemokine production. Additionally, cardiomyocyte apoptosis decreased in CKO mice (TUNEL+ cardiomyocytes (%): fl/flcontrol 1.66±0.32 vs. CKO 0.78±0.38, P<0.01), proposing the importance of myeloid GARP in cardiomyocyte death. Pseudotime analysis of scRNA-seq revealed that GEM cells were derived from heart-resident fibrocytes. Finally, a spatial transcriptome data from MI patients suggested the presence of CD11b+GARP+ cells in post-infarcted human hearts. These findings newly unveil GARP-expressing myeloid cells, differentiated from resident fibrocytes, exhibited a significant pathophysiologyical role in cardiac remodeling. This suggests that GEM cells could be a promising therapeutic target against post-infarct heart failure.