Wang Meiyan, Zhang Lei, Novak Sammy Weiser, Yu Jingting, Gallina Iryna S, Xu Lynne L, Lim Christina K, Fernandes Sarah, Shokhirev Maxim N, Williams April E, Saxena Monisha D, Coorapati Shashank, Parylak Sarah L, Quintero Cristian, Molina Elsa, Andrade Leonardo R, Manor Uri, Gage Fred H
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
Waitt Advanced Biophotonics Core, The Salk Institute for Biological Studies, La Jolla, CA, USA.
Nat Biotechnol. 2025 Jan;43(1):52-62. doi: 10.1038/s41587-024-02157-8. Epub 2024 Feb 28.
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，但由于皮质神经胶质细胞生成的延迟，在传统的皮质类器官模型中其代表性不足。在此，我们引入了一种新的富含神经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，在一部分祖细胞中诱导神经胶质细胞生成开关能够快速产生星形胶质细胞，这些细胞在分化8 - 10周内占细胞总数的25 - 31%。将这些类器官进行脑内移植能够可靠地产生多种皮质神经元以及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内不同亚类星形胶质细胞之间的层特异性表达模式。使用体内急性神经炎症模型，我们鉴定出了一个星形胶质细胞亚群，该亚群在细胞因子刺激下会迅速激活促炎途径。此外，我们证明CD38信号在介导反应性星形胶质细胞的代谢和线粒体应激中起关键作用。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。
