Primitive Embryonic Macrophages are Required for Coronary Development and Maturation
Rationale: It is now recognized that macrophages residing within developing and adult tissues are derived from diverse progenitors including those of embryonic origin. While the functions of macrophages in adult organisms are well studied, the functions of macrophages during organ development remain largely undefined. Moreover, it is unclear whether distinct macrophage lineages have differing functions.
Objective: To address these issues, we investigated the functions of macrophage subsets resident within the developing heart, an organ replete with embryonic-derived macrophages.
Methods and Results: Using a combination of flow cytometry, immunostaining, and genetic lineage tracing, we demonstrate that the developing heart contains a complex array of embryonic macrophage subsets that can be divided into CCR2- and CCR2+ macrophages derived from primitive yolk sac, Rag1+ lymphomyeloid, and Flt3+ fetal monocyte lineages. Functionally, yolk sac-derived CCR2- macrophages are instrumental in coronary development where they are required for remodeling of the primitive coronary plexus. Mechanistically, CCR2- macrophages are recruited to coronary blood vessels at the onset of coronary perfusion where they mediate coronary plexus remodeling through selective expansion of perfused vasculature. We further demonstrate that IGF signaling may mediate the pro-angiogenic properties of embryonic-derived macrophages.
Conclusions: Together, these findings demonstrate that the embryonic heart contains distinct lineages of embryonic macrophages with unique functions and reveal a novel mechanism that governs coronary development.
- Received December 30, 2015.
- Revision received March 21, 2016.
- Accepted March 23, 2016.