Cardiac Macrophages Across Space and Time: Roles in Homeostasis, Disease, and Remodeling

Cardiac macrophages are central regulators of heart homeostasis, injury response, and repair, exhibiting remarkable heterogeneity shaped by developmental origin, transcriptional state, and spatial localization. Recent advances in single-cell and spatial transcriptomics have revealed the complex organization of macrophage niches, raising a critical question: Could targeting macrophages in a zone- and context-specific manner unlock more effective therapies for cardiac injury and remodeling? Tissue-resident macrophages (TRMs), derived from embryonic progenitors, and recruited CCR2⁺ macrophages from hematopoietic sources occupy distinct niches within cardiac tissue, enabling precise crosstalk with cardiomyocytes, fibroblasts, endothelial cells, and pericytes. After myocardial infarction, ischemia-reperfusion injury, myocarditis, or pressure-overload stress, macrophage subsets dynamically redistribute, promoting inflammation, fibrosis, and vascular remodeling in a zone-specific manner. Early-phase TRMs clear apoptotic debris, secrete reparative cytokines, and stimulate angiogenesis, whereas recruited monocyte-derived macrophages mediate pro-inflammatory signaling and extracellular matrix deposition, contributing to adverse remodeling. Spatial proximity to fibroblasts and endothelial cells underlies paracrine interactions that drive myofibroblast differentiation, angiogenesis, and scar formation, whereas macrophage-cardiomyocyte coupling via connexin 43 and oncostatin M-gp130 signaling regulates electrical conduction and regenerative responses. Aging alters macrophage composition, density, and spatial organization, leading to profibrotic signaling and impaired repair. Understanding these spatially defined interactions provides a framework for precision immunomodulatory strategies, potentially improving cardiac repair while limiting pathologic remodeling.