Cardiomyocyte proliferation: Advances and insights in macrophage-targeted therapy for myocardial injury

Figures

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  Figure 1. Developmental origin and subtype function of cardiac macrophages. Embryonic development (E7.5-E12.5) revolves around the hematopoietic endothelium (HE) of the yolk sac (YS), which undergoes three waves of hematopoiesis. A short period of deterministic hematopoietic cells migrates to the fetal liver after generating YS macrophages or multiple lineages, which subsequently develop into resident macrophages and eventually migrate to the embryonic heart. During the perinatal period, traditional bone marrow hematopoietic stem cells (HSCs) will become the primary site of hematopoiesis, differentiating into circulating monocytes and macrophages in the peripheral blood to produce a full immune lineage. In adult mice, resident cardiac macrophages are depleted after myocardial infarction and mononuclear-derived macrophages are recruited and enriched in large numbers and subsequently partially restored to the level of the uninjured state.

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  Figure 2. Schematic representation of cardiac macrophages initiating cardiomyocyte proliferation and repair. During the inflammatory response to myocardial injury, oncostatin M (OSM) secreted by cardiac infiltrating macrophages binds to the type II receptor Gp130 and stimulates Src-enhanced YAP phosphorylation to promote cardiomyocyte proliferation and myocardial repair. Meanwhile, the cardiac resident macrophage subpopulation MP1 (CX3CR1+CCR2−Ly6C−MHCII−) directly triggered cardiomyocyte proliferation via the Jagged-1-Notch1 axis, significantly ameliorating cardiac injury after myocardial infarction. The glycolytic metabolite lactate dehydrogenase A (LDHA) creates a beneficial cardiac regenerative microenvironment through the polarization of M2 macrophages. The iron-regulating hormone hepcidin and interleukin (IL)-4/6 enhance cellular plasticity and adaptation of the extracellular matrix microenvironment, facilitating cardiac regeneration and repair.