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.