Tissue-Resident Macrophage Development and Function

Abstract

Tissue-resident macrophages have been associated with important and diverse biological processes such as native immunity, tissue homeostasis and angiogenesis during development and postnatally. Thus, it is critical to understand the origins and functions of tissue-resident macrophages, as well as mechanisms underlying their regulation. It is now well accepted that murine macrophages are produced during three consecutive waves of hematopoietic development. The first wave of macrophage formation takes place during primitive hematopoiesis, which occurs in the yolk sac, and gives rise to primitive erythroid, megakaryocyte and macrophage progenitors. These "primitive" macrophage progenitors ultimately give rise to microglia in the adult brain. The second wave, which also occurs in the yolk sac, generates multipotent erythro-myeloid progenitors (EMP), which give rise to tissue-resident macrophages. Tissue-resident macrophages derived from EMP reside in diverse niches of different tissues except the brain, and demonstrate tissue-specific functions therein. The third wave of macrophages derives from hematopoietic stem cells (HSC) that are formed in the aorta-gonad-mesonephros (AGM) region of the embryo and migrate to, and colonize, the fetal liver. These HSC-derived macrophages are a long-lived pool that will last throughout adulthood. In this review, we discuss the developmental origins of tissue-resident macrophages, their molecular regulation in specific tissues, and their impact on embryonic development and postnatal homeostasis.

Keywords: definitive hematopoiesis; erythro-myeloid progenitors; hemogenic endothelial cells; primitive hematopoiesis; tissue-resident macrophages.

FIGURE 1

Fetal Macrophage Development. Murine macrophages originate from three successive waves of hematopoiesis. The first wave, termed primitive hematopoiesis, occurs in the blood islands of the extra-embryonic yolk sac at E7.5. It produces primitive erythroblasts and megakaryocytes, as well as CSF-1R⁺ c-Myb^- progenitors, which give rise to adult microglia in the brain. The second wave arises from the hemogenic endothelium formed at E8.5 in the yolk sac. Because the second wave generates the c-Myb⁺ hematopoietic progenitors named eythro-myeloid precursors (EMP), thus it is termed the EMP wave. The EMP either give rise to yolk sac macrophages locally or migrate into the fetal liver through the blood circulation, where they expand and differentiate into tissue-resident macrophages, which then migrate to, and colonize, different tissues. The third wave arises from the hemogenic endothelium in the aorta-gonad-mesonephros (AGM) region, which gives rise to fetal hematopoietic stem and progenitor cells beginning at E9.5. Subsequently, these precursors colonize the fetal liver where they establish definitive hematopoiesis and will eventually seed the bone marrow and lead to the generation of adult hematopoietic stem and progenitor cells.