Generation and characterization of iPSC derived microglia from blood derived PBMCs for in vitro modeling of stimuli-specific neuroimmune responses

Microglia are highly specialized brain immune cells which express several genes known to influence the risk of developing Alzheimer’s disease. While interest in harnessing the potential neuroprotective functions of microglia using targeted therapeutics is high, it remains challenging to test emerging tool molecules for their potential biological effects in physiologically relevant model systems. Here we describe the generation of iPS cell lines from donor somatic cells (PBMCs) using non-integrating episomal reprogramming vectors for the downstream stepwise differentiation of iPSC-derived microglia (iMG). We find that our stepwise differentiation protocol reproducibly generates iMG expressing several microglia signature genes. Moreover, these iMG are highly morphologically and transcriptionally dynamic. We challenge iMG with diverse stimuli and find that iMG respond to myelin debris by robustly changing lipid metabolism and upregulating several chemokines including CXCL10. While iMG express both TREM2 and DAP12, neither Interleukin 4 mediated upregulation of TREM2 or TREM2 binding by an antibody tool molecule caused an increase in the phagocytosis of myelin debris. Interestingly, we find the TREM2 binding antibody induces a consistent transcriptional response resulting in the upregulation of several chemokines. We conclude iMG are a flexible model system which can be used to explore the biological response of human microglia-like cells to specific physiological stimuli and to test emerging tool molecules for their transcriptional and functional impacts.