The challenges of generating microglia from iPSCs are due to their unique developmental origin. Elegant lineage tracing studies show that microglia originate from yolk sac erythromyeloid progenitors (EMP) generated during primitive hematopoiesis (Ginhoux et al., 2010; Kierdorf et al., 2013; Schulz et al., 2012). EMPs further develop to early primitive macrophages that migrate into the developing neural tube, and become microglial progenitors (Kierdorf et al., 2013; Prinz and Priller, 2014). Microglia progenitors then mature and develop ramified processes used to survey their environment, facilitate CNS development, modulate synaptic plasticity, and respond to CNS injury and pathology. Recently, murine studies identified key cytokines, cell receptors, and transcription factors required for microglia development and survival in vivo. These factors include IL-34 and TGFβ-1 (Butovsky et al., 2014; Greter et al., 2012; Wang et al., 2012; Yamasaki et al., 2014). We hypothesized that iPSCs could be differentiated to human microglia in vitro by providing cues that mimic the environment present in the developing embryo.
