Origin and differentiation of microglia

Abstract

Microglia are the resident macrophage population of the central nervous system (CNS). Adequate microglial function is crucial for a healthy CNS. Microglia are not only the first immune sentinels of infection, contributing to both innate and adaptive immune responses locally, but are also involved in the maintenance of brain homeostasis. Emerging data are showing new and fundamental roles for microglia in the control of neuronal proliferation and differentiation, as well as in the formation of synaptic connections. While microglia have been studied for decades, a long history of experimental misinterpretation meant that their true origins remained debated. However, recent studies on microglial origin indicate that these cells in fact arise early during development from progenitors in the embryonic yolk sac (YS) that seed the brain rudiment and, remarkably, appear to persist there into adulthood. Here, we review the history of microglial cells and discuss the latest advances in our understanding of their origin, differentiation, and homeostasis, which provides new insights into their roles in health and disease.

Keywords: central nervous system; macrophage; microglia; origin; yolk sac.

Figure 1

Brain development and microglial homeostasis. Primitive macrophages exit the yolk sac blood islands at the onset of circulation and colonize the neuroepithelium from E9.5 to give rise to microglia. The blood brain barrier starts to form from E13.5 and may isolate the developing brain from the contribution of fetal liver hematopoiesis. Embryonic microglia expand and colonize the whole CNS until adulthood. Importantly, in steady state conditions, embryonically-derived microglia will maintain themselves until adulthood, via local proliferation during late gestation and post-natal development as well as in the injured adult brain in reaction to inflammation. Nevertheless, during certain inflammatory conditions found for example after bone marrow transplantation, the recruitment of monocytes or other bone marrow-derived progenitors can supplement the microglial population to some extent. However, we do not understand yet whether these cells persist and become integrated in the microglial network, or are a temporary addition to the endogenous population.

Figure 2

Strategy for directed differentiation of microglial precursors from pluripotent stem cells. Microglial differentiation in vitro can be achieved by recapitulating the steps of yolk sac hematopoiesis. Hemangioblast cells arise in the posterior primitive streak and migrate into the yolk sac, giving rise to the blood islands. Primitive erythroblasts are observed from E7.0–7.5, followed by definitive erythroblasts and primitive macrophages at E8.5. At the onset of circulation, primitive macrophages exit the yolk sac and seed the developing brain, forming microglia. Likewise, pluripotent stem cells can be differentiated into Bry⁺Flk⁺ cells with hemangioblast properties; these cells are then further differentiated into both primitive and definitive eryothroblasts and primitive macrophages. In vitro-derived primitive macrophages may be the functional equivalent to primitive microglia in the embryo.