State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China.
Cell Stem Cell. 2022 Apr 7;29(4):620-634.e6. doi: 10.1016/j.stem.2022.02.004. Epub 2022 Mar 3.
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.
区域相关的小胶质细胞异质性和状态转变对于大脑发育和神经发病机制很重要。然而，在人类中枢神经系统早期发育过程中小胶质细胞的区域特化和状态转变仍不清楚。在这里，我们对来自发育中人类大脑不同区域的小胶质细胞进行了单细胞转录组分析，并结合实验验证，定义和描述了与区域特化和状态转变相关的早期小胶质细胞命运决定。我们鉴定了几个具有区域特异性的富含神经元基因的小胶质细胞亚类，这些亚类在早期脑区形成时动态且短暂地出现。相比之下，免疫相关的小胶质细胞在中枢神经系统发育的后期具有区域特异性。令人惊讶的是，我们发现，区域特化的免疫相关小胶质细胞从小胶质细胞的相对静止状态中退出，并转变为不同的激活状态。此外，我们还通过实验验证了小胶质细胞的状态转变。最后，我们表明该状态转变是保守的，但在人和小鼠发育中的小胶质细胞中存在分子差异。
