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.

星形胶质细胞是大脑中最丰富的神经胶质细胞类型，由于皮质胶质生成延迟，在传统皮质类器官模型中代表性不足。在这里，我们介绍了一种新的富含胶质细胞的皮质类器官模型，该模型表现出加速的星形胶质细胞生成。我们证明，在祖细胞亚群中诱导胶质生成开关能够快速衍生出星形胶质细胞，在分化的 8-10 周内，星形胶质细胞占细胞群的 25-31%。这些类器官的脑内移植可靠地产生了多种皮质神经元和人类星形胶质细胞的解剖亚类。空间转录组分析确定了类器官移植物中不同星形胶质细胞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，我们鉴定了星形胶质细胞亚群，该亚群在细胞因子刺激后迅速激活促炎途径。此外，我们证明 CD38 信号传导在调节反应性星形胶质细胞的代谢和线粒体应激中具有至关重要的作用。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。