Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoid transplanted in mouse brain.
Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoid transplanted in mouse brain.
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DOI：
10.1038/s41587-024-02157-8
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发表时间：
2024-02
影响因子：
46.9
通讯作者：
Meiyan Wang;Lei Zhang;S. Novak;Jingting Yu;Iryna S. Gallina;Lynne L Xu;Christina K Lim;Sarah Fern
中科院分区：
文献类型：
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作者：
Meiyan Wang;Lei Zhang;S. Novak;Jingting Yu;Iryna S. Gallina;Lynne L Xu;Christina K Lim;Sarah Fern
星形胶质细胞是大脑中最丰富的胶质细胞类型，由于皮质胶质细胞发生的延迟，在传统的皮质类器官模型中代表性不足。在这里，我们介绍了一个新的胶质细胞丰富的皮质类器官模型，表现出加速星形胶质细胞。我们证明了在祖细胞亚群中诱导胶质细胞生成开关能够快速衍生星形胶质细胞，其在分化的8-10周内占细胞群的25-31%。这些类器官的脑内移植可靠地产生了皮质神经元和人类星形胶质细胞的解剖学亚类的各种库。空间转录组分析确定了类器官移植中星形胶质细胞不同亚类之间的层特异性表达模式。使用体内急性神经炎症模型，我们鉴定了一个星形胶质细胞亚群，其在细胞因子刺激后迅速激活促炎通路。此外，我们证明了CD 38信号传导在介导反应性星形胶质细胞的代谢和线粒体应激中起着至关重要的作用。该模型为研究人类星形胶质细胞功能提供了一个强大的平台。
Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here we introduce a new glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled the rapid derivation of astroglial cells, which account for 25–31% of the cell population within 8–10 weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates pro-inflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling has a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function.