Primitive Macrophages Drive Coronary Development.

Abstract

Macrophages populate most tissues of the body. They perform many important functions that are required to maintain tissue homeostasis and fight infection, including the uptake and degradation of dead cells, debris, and foreign invaders. Macrophage ontogeny has been debated since the late 1960s when van Furth and Cohn1 postulated that macrophages are derived exclusively from bone marrow monocytes. However, the use of sophisticated in vivo fate-mapping approaches has recently shown that many tissue macrophages arise during embryogenesis in the yolk sac and fetal liver before the onset of definitive hematopoiesis.2–5 Two distinct developmental programs have been identified: early yolk sac–derived erythromyeloid progenitors that give rise to macrophages without monocyte intermediates and fetal liver monocytes that are derived from late c-Myb+ erythromyeloid progenitors generated in the yolk sac. In some circumstances, bone marrow–derived monocytes are also capable of colonizing developing tissues, especially during the perinatal period.6–9 The contributions of early and late erythromyeloid progenitors and hematopoietic stem cells to macrophage development vary considerably across different tissues.10 Article, see p 1498 In this issue of Circulation Research , Leid et al11 define macrophage ontogeny in the developing heart. At least 2 distinct populations of embryonic heart macrophages are identified based on the cell surface expression of the C-C chemokine receptor type 2 (CCR2), which encodes the receptor for monocyte chemoattractant protein-1. The authors previously demonstrated that CCR2 expression distinguished cardiac macrophages of adult monocyte versus embryonic origin.12 In the current study, genetic lineage tagging experiments using Csf1r MeriCreMer× Rosa26 Tomato mice administered tamoxifen at E7.5 (the approximate timing of yolk sac hematopoiesis) confirmed that primitive embryonic CCR2− heart macrophages are derived from the yolk sac. Complementary approaches using Rag1 Cre and Flt3 Cre mice further demonstrated that embryonic CCR2 …