Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoid transplanted in mouse brain- Meiyan Wang,
- Lei Zhang,
- Sammy Weiser Novak,
- Jingting Yu,
- Iryna S. Gallina,
- Lynne L. Xu,
- Christina K. Lim,
- Sarah Fernandes,
- Maxim N. Shokhirev,
- April E. Williams,
- Monisha D. Saxena,
- Shashank Coorapati,
- Sarah L. Parylak,
- Cristian Quintero,
- Elsa Molina,
- Leonardo R. Andrade,
- Uri Manor &
- Fred H. Gage
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AbstractAstrocytes, 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.
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