Microglia, the brain-resident macrophages, exhibit highly dynamic functions in neurodevelopment and neurodegeneration. Human microglia possess unique features as compared to mouse microglia, but our understanding of human microglial functions is largely limited by an inability to obtain human microglia under homeostatic states. Here, we develop a human pluripotent stem cell (hPSC)-based microglial chimeric mouse brain model by transplanting hPSC-derived primitive macrophage progenitors into neonatal mouse brains. Single-cell RNA-sequencing of the microglial chimeric mouse brains reveals that xenografted hPSC-derived microglia largely retain human microglial identity, as they exhibit signature gene expression patterns consistent with physiological human microglia and recapitulate heterogeneity of adult human microglia. Importantly, the engrafted hPSC-derived microglia exhibit dynamic response to cuprizone-induced demyelination and species-specific transcriptomic differences in the expression of neurological disease-risk genes in microglia. This model will serve as a tool to study the role of human microglia in brain development and degeneration.

小胶质细胞是常驻在大脑的巨噬细胞，在神经发育和神经变性中表现出高度动态的功能。与小鼠小胶质细胞相比，人小胶质细胞具有独特的功能，但是我们对人小胶质细胞功能的了解在很大程度上受到无法在稳态下获得人小胶质细胞的限制。在这里，我们通过将hPSC衍生的原始巨噬细胞祖细胞移植到新生小鼠大脑中，开发了基于人类多能干细胞（hPSC）的小胶质细胞嵌合小鼠大脑模型。小胶质细胞嵌合小鼠大脑的单细胞RNA测序表明，异种移植的hPSC衍生的小胶质细胞在很大程度上保留了人类小胶质细胞的身份，因为它们表现出与生理性人类小胶质细胞一致的签名基因表达模式，并概括了成年人类小胶质细胞的异质性。重要的，嫁接的hPSC衍生的小胶质细胞对铜质酮诱导的脱髓鞘表现出动态响应，并且在小胶质细胞中表达神经系统疾病风险基因时存在种特异性转录组差异。该模型将作为研究人类小胶质细胞在大脑发育和变性中的作用的工具。