Region-related heterogeneity and state transitions of microglia are important for brain development and neurological pathogenesis. However, regional specialization and state transition in microglia during early human CNS development remain unclear. Here, we profile single-cell transcriptomes of microglia from distinct regions of the developing human brain, and combined with experimental verification, we define and characterize early microglial fate determinations related to regional specification and state transition. We identified several subclasses of neuronal gene-enriched microglia with regional specification that dynamically and transiently appeared as early brain regions formed. In contrast, immune-related microglia were regionally specialized at later stages of CNS development. Surprisingly, we discovered that region-specialized immune-related microglia exit from a relative resting state and transition into distinct active states. In addition, we experimentally verified the microglial state transition. Finally, we showed that the state transition is conserved but that there are molecular differences in developing microglia in humans and mice.

小胶质细胞的区域相关异质性和状态转换对于大脑发育和神经发病机制很重要。然而，人类中枢神经系统早期发育过程中小胶质细胞的区域专业化和状态转变仍不清楚。在这里，我们分析了来自发育中的人类大脑不同区域的小胶质细胞的单细胞转录组，并结合实验验证，我们定义和表征了与区域规范和状态转换相关的早期小胶质细胞命运决定。我们确定了几个神经元基因富集的小胶质细胞亚类，这些亚类具有在早期大脑区域形成时动态和瞬时出现的区域规范。相比之下，免疫相关的小胶质细胞在 CNS 发育的后期是区域特化的。出奇，我们发现区域特异性免疫相关小胶质细胞从相对静止状态退出并转变为不同的活跃状态。此外，我们通过实验验证了小胶质细胞的状态转变。最后，我们发现状态转换是保守的，但在人类和小鼠的小胶质细胞发育过程中存在分子差异。