Emerging Role of Macrophage-Fibroblast Interactions in Cardiac Homeostasis and Remodeling

Figures

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  Figure 1. The Phenotypic and Functional Characteristics of Cardiac Macrophages and Fibroblasts (A) Current mainly investigated macrophage subtypes in cardiac homeostasis and remodeling. RCM (resident cardiac macrophage) refers to macrophage subsets that exist in the heart under steady state and are derived primarily from embryonic progenitors. During cardiac remodeling, peripheral monocyte-derived macrophage (moMφs) dominate the injured heart. (B) Fibroblast dynamics in cardiac homeostasis and remodeling. The steady-state heart is populated by resident mature fibroblasts. On cardiac injury, mature cardiac fibroblasts transform into activated fibroblasts and exhibit elevated proliferation and collagen production. A proportion of activated fibroblasts undergo transdifferentiation into myofibroblasts, a more profibrotic and contractile phenotype characterized by significantly increased synthesis of contractile proteins. CCR2 = C-C chemokine receptor 2; ECM = extracellular matrix; FAP = fibroblast activation protein; IGF = insulin-like growth factor; IL = interleukin; Ly6C = lymphocyte antigen 6C; LYVE1 = lymphatic vessel endothelial hyaluronan receptor 1; MHC-II = major compatibility complex…

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  Figure 2. Cardiac Macrophage and Fibroblast Dynamics in the Infarcted and the Pressure-Overloaded Myocardium (A) Acute ischemic injury results in a significant reduction of RCMs and recruitment of proinflammatory moMφs in the infarcted myocardium, and mature resident fibroblasts are activated into a proliferative and more collagen-producing phenotype. During the reparative phase, moMφs exhibit a proreparative and antiinflammatory phenotype, that supports myofibroblast differentiation and scar formation, and RCMs show slow recovery through local proliferation. During the scar maturation phase, the majority of cardiac macrophages gradually diminish. (B) In the pressure-overloaded myocardium induced via transverse aortic constriction surgery, RCMs proliferate significantly during adaptive remodeling, while they decrease during adverse remodeling and heart failure progression. Recruited moMφs continue to infiltrate and induce proinflammatory and profibrotic cascades. MHC-II = major compatibility complex II; moMφ = monocyte-derived macrophage; RCM = resident cardiac macrophage; TLF = expression of Timd4, Lyve1, and Folr2.

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  Central Illustration. The Integrated Landscape of Macrophage-Fibroblast Interactions in Cardiac Homeostasis and Remodeling (A) In the steady-state heart, intramyocardial spaces are predominantly occupied by embryonic RCMs and mature fibroblasts, both of which play organ-specific roles in maintaining cardiac homeostasis. (B) Acute ischemic injury results in extensive cell death, including cardiomyocytes and RCMs. The subsequent release of damage-associated molecular patterns leads to the recruitment of monocytes and differentiation into moMφs, exhibiting a proinflammatory phenotype and participating in efferocytosis to clear cellular debris. Simultaneously, environmental growth factors activate fibroblasts, promoting their transition into a proliferative and more collagen-producing phenotype. Once cellular debris is removed, environmental cues drive moMφ polarization, adopting a proreparative and antiinflammatory phenotype that supports cardiac repair and scar formation. Profibrotic signaling further induces transdifferentiation of activated fibroblasts into myofibroblasts, contributing to the maturation of cardiac scars. (C) During adaptive cardiac remodeling, embryonic RCMs proliferate and produce…