Fetal heart as a new local site for hematopoiesis and macrophage formation

Cardiac tissue macrophages are crucial components of the immune system and tissue homeostasis. Traditionally, these macrophages have been classified into three primary lineages: yolk sac blood island-derived erythromyeloid progenitor (EMP), yolk sac hemogenic endothelial-derived late-EMP, and hematopoietic stem cell (HSC)-derived macrophages. These classifications have shaped our understanding of the developmental origin of macrophages in the heart. However, recent studies have significantly shifted this perspective by revealing that the heart itself possesses an intrinsic source of macrophages, independent of the traditionally recognized hematopoietic sources. This discovery has added a new dimension to our understanding of macrophage biology in the context of cardiac development. Our recent work has provided compelling evidence that endocardial cells exhibit hematopoietic potential during embryonic days (E) 8.5 to E10. This discovery challenges the previously held belief that macrophages in the heart are exclusively derived from EMP or HSC. Endocardial cells give rise to a distinct population of cardiac tissue macrophages that play vital roles in heart morphogenesis. These findings open up new avenues for understanding how macrophages contribute to heart formation, homeostasis, and their disruption. This review summarized the latest findings on the role of endocardium-derived macrophages, along with other macrophage lineages, in contributing to heart development and the maintenance of cardiac homeostasis.