Fig 1: Human iPSC-microglia and blood-derived monocytes fully engraft within the brains of adult hFIRE mice but adopt differing morphologies.(a) Microglia arise from primitive hematopoietic stem cells within the yolk sac, whereas monocytes arise later in development from bone marrow derived definitive hematopoietic stem and progenitor cells. Lineage tracing studies have shown that very few monocytes infiltrate the healthy brain, but increased numbers migrate into the brain in response to injury, irradiation-induced loss of microglia, or neurodegeneration. (b) Schematic depicting transplantation paradigm of 2-month-old xenotolerant FIRE mice with iPSC-microglia (Mg) or human CD14+ monocytes (Mo) derived from 4 male subjects then sacrificed at 5.5-months of age. (c-d) Brain wide human (Ku80, human-specific nuclei, white) xenografted iMG (xMG) and monocytes (IBA1, green), scale bar: 500μm. (e-f) Quantification of xenografted microglia and monocytes in half brain coronal sections of xenotolerant hFIRE mice; p values from unpaired, two-sided t test. Half brain (Bregma AP −1.94): t(16)= 0.6068; ns=0.5525. Forebrain (Bregma AP +0.14): t(16)= 0.01849; ns=0.9855. (g-h) Representative confocal microscopy combined with IMARIS-based branching analysis of xenografted microglia and monocytes, scale bar: 20μm. (i-j) Quantification of xenografted microglia and monocytes branch complexity within the cortex and hippocamps; p values from unpaired, two-sided t test (Cortex: t(16)= 8.087; ****P<0.0001) (Hippocampus: t(16)=3.446; **P=0.0033). Data represented as average mean value ± SEM (Mg, n = 7; Mo, n = 11). ns, not significant; **p < 0.01, and ****p < 0.0001.