The Evolving Roles of Cardiac Macrophages in Homeostasis, Regeneration, and Repair

Abstract

Macrophages were first described as phagocytic immune cells responsible for maintaining tissue homeostasis by the removal of pathogens that disturb normal function. Historically, macrophages have been viewed as terminally differentiated monocyte-derived cells that originated through hematopoiesis and infiltrated multiple tissues in the presence of inflammation or during turnover in normal homeostasis. However, improved cell detection and fate-mapping strategies have elucidated the various lineages of tissue-resident macrophages, which can derive from embryonic origins independent of hematopoiesis and monocyte infiltration. The role of resident macrophages in organs such as the skin, liver, and the lungs have been well characterized, revealing functions well beyond a pure phagocytic and immunological role. In the heart, recent research has begun to decipher the functional roles of various tissue-resident macrophage populations through fate mapping and genetic depletion studies. Several of these studies have elucidated the novel and unexpected roles of cardiac-resident macrophages in homeostasis, including maintaining mitochondrial function, facilitating cardiac conduction, coronary development, and lymphangiogenesis, among others. Additionally, following cardiac injury, cardiac-resident macrophages adopt diverse functions such as the clearance of necrotic and apoptotic cells and debris, a reduction in the inflammatory monocyte infiltration, promotion of angiogenesis, amelioration of inflammation, and hypertrophy in the remaining myocardium, overall limiting damage extension. The present review discusses the origin, development, characterization, and function of cardiac macrophages in homeostasis, cardiac regeneration, and after cardiac injury or stress.

Keywords: cardiac homeostasis; inflammation; macrophages; monocytes; myocardial infarction; regeneration.

Figure 1

Derivation of cardiac-resident macrophages during embryonic and postnatal development. During embryonic development, cardiac-resident macrophages are derived from either yolk-sac macrophage-derived or fetal liver monocyte-derived cardiac-resident macrophages. The former develop, starting around embryonic day 7.0 (E7.0), and migrate to the heart at E7.5. The latter are derived from the erythroid myeloid progenitors from the hemogenic endothelium of the yolk sac (E8.0–8.5) and from the hemogenic endothelium of the aorto-gonad and mesonephros (AGM) region (E10.5). Fetal liver monocyte production starts at E12.5. Embryonic-derived cardiac-resident macrophages endure in the heart primarily by proliferation in situ. Bone marrow monocyte-derived cardiac-resident macrophages appear in the heart starting around postnatal day 14 (P14) and endure in the heart by continuous monocyte seeding from the circulation.