Microglia are hematopoietic-derived innate immune cells that constantly survey the environment and regulate the development of the central nervous system (CNS). These cells have dynamic cellular processes that make contact with synapses and engulf cellular debris from dying neurons. The origin of microglia has been a controversial topic for decades. Recently, it was demonstrated that microglia originate in the yolk sac (YS) from YS-derived macrophages during primitive hematopoiesis and subsequently populate the embryonic brain (Ginhoux et al., 2010). However, it remains unclear whether this cohort accounts for the total resident CNS microglia population following embryonic development because of the transient spatiotemporal nature of hematopoietic sites and circulation of microglial progenitors through the developing vasculature system. Furthermore, it is also not known whether progenitors from preceding hematopoietic sites are required to seed impending hematopoietic sites for the generation of hematopoietic stem cells (HSCs). In this review, we will provide a brief context on hematopoietic development at major hematopoietic sites followed by a discussion on the current evidence regarding the origin(s) of resident CNS microglia.
Hematopoiesis is the development of the blood system that is characterized by a spatiotemporal sequence of transient events. Each transient event is thought to follow the monophyletic theory of hematopoiesis whereby pluripotent stem cells undergo asymmetric division to either self-renew or generate lineage-restricted committed progenitor cells. These committed progenitors generate immature blood cells specific for the lymphoid, erythroid, and myeloid lineages (Chaplin et al., 2003, Laiosa et al., 2006). The lymphoid lineage generates T- and B-cells from a common lymphoid progenitor (CLP) that reside in the thymus. The erythroid and myeloid lineages generate red blood cells and platelets, mast cells, neutrophils, monocytes, macrophages, and dendritic cells, respectively, from a common myeloid progenitor (CMP). Progenitors fated to each hematopoietic lineage is generated at different times in different tissues, hence the spatiotemporal nature of hematopoiesis. Two caveats arise in studying hematopoiesis: 1) the primary site (e.g. yolk sac, aorta-gonad-mesenephros, fetal liver, bone marrow) to generate HSCs shifts during embryonic development and 2) the migration of HSCs through the developing vasculature following the onset of circulation.
Microglia, as well as CNS-associated macrophages, are tissue-resident macrophages in the CNS derived from mononuclear phagocytes. Mononuclear phagocytes originate from HSCs through differentiation pathways based on endogenous and environmental cues. These mononuclear cells were believed to be derived from leukocyte HSCs because bone marrow-derived monocytes (leukocytes) could differentiate into tissue-resident macrophages. Current evidence suggests that there is...