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

INTRODUCTION: Microglia are macrophage-like brain resident immune cells known to express numerous Alzheimer's disease risk genes. Here we generated a human induced pluripotent stem cell (iPSC) derived microglia cell culture model for use in neuroimmune modeling and therapeutic testing. METHODS: We generated iPSC lines using episomal reprogramming for subsequent stepwise differentiation of iPSC-derived microglia (iMG) without commercial kits. We characterized the responses of this model to immunogenic stimuli and recombinant TREM2 antibodies. RESULTS: The iMG expressed several key microglia signature genes and are morphologically and transcriptionally dynamic. iMG rapidly phagocytosed myelin debris and strongly changed expression of lipid homeostasis genes. iMG expressed TREM2 and increased TREM2 levels in response to IL-4. Recombinant TREM2 antibody treatment impaired iMG myelin phagocytosis and upregulated chemokines. DISCUSSION: We validated our iMG model system for the evaluation of biological responses of human microglia-like cells to stimuli and pharmacological agents for their transcriptional and functional impacts.