The Microglia Forebrain Assembloid Model Recapitulates Human Brain Development and Neuroimmune Biology

ABSTRACT Microglia are innate immune cells of the CNS whose dysfunction contributes to inflammation and metabolic changes across neurodegenerative and CNS disorders. Across all stages of life, microglia are essential for immune surveillance, neural homeostasis, and synaptic pruning; however, their role in neurodevelopment is less understood. Microglia invade the brain during early neurogenesis, prior to neuronal/glial differentiation, but their potential role at this stage remains undescribed. To model neuroimmune interactions during human cortical development, we created an “assembloid” of human ESC–derived forebrain organoids combined with developmentally matched microglia during cortex formation. Functional contributions of microglia were compared to control organoids using histology and metabolomics. Competing Interest Statement The authors have declared no competing interest. Footnotes Publication statement: Declare any conflicts of interest: The authors have no competing financial interests. Include appropriate funding statements in the manuscript: All funding for this research was provided internally by Arizona State University. Data sharing policy: The raw that support the findings of this study are available from the corresponding author. Funding statement: BB: NIH Office of the Director DP2MH136493, NIBIB R21EB034970