Take-home message
Glia-enriched cortical organoids with mature astrocytes offer a powerful platform to study astrocyte diversity, immune responses, and neurological disorders. This model paves the way for deeper insights into glial biology and disease mechanisms.
Background
Brain organoids are 3D models created from human pluripotent stem cells, designed to imitate key aspects of the developing human brain. Despite significant advancements, the field continues to encounter significant challenges, particularly concerning the limited inclusion of functional glial cells in cortical organoids. These challenges impact the models’ structure, maturation, and overall function.
Astrocytes, a key type of glial cell, typically form during the later stages of pregnancy and continue to develop after birth. This delayed progression of astrocyte development is mirrored in cortical organoid models, limiting their effectiveness in studying neuron-astrocyte interactions and understanding astrocyte dysfunction in disease scenarios. Therefore, creating cortical organoids with fully mature and functional astrocytes is essential to advance organoid-based research and therapeutic applications.
Summary of the findings
During cortical development, radial glial cells first produce neurons before transitioning to glial cells. To accelerate this shift in cortical organoids, Wang and colleagues introduced gliogenic factors early in development by adding PDGF-AA to patterning cocktails and culturing organoids in astrocyte-specific media. This approach triggered early gliogenesis, resulting in astrocytes comprising 20–23% of cells by 8–10 weeks, compared to the usual three months.
To provide these cultured organoids with a more physiological environment and enhance their maturation, they transplanted them into the brains of immunodeficient mice, promoting their survival and functional integration. After eight months, most cells reached postnatal maturity, and glial–vessel interactions facilitated the development of astrocyte subtypes similar to those in the human cortex. In addition, using the NanoString GeoMx Digital Spatial Profiler, a spatial genomics platform, they confirmed location-specific gene expression in astrocytes. Moreover, they exposed the in vivo organoid model to TNFα, and observed that astrocytes showed a diverse immune response, with one subcluster exhibiting enhanced activity via the CD38 pathway, which regulates metabolic and stress responses.
Novelty of the results in the field/ whether and how these results advance knowledge in the field
Wang and colleagues developed a method for generating glia-enriched cortical organoids and used transplantation to promote astrocyte diversification and maturation at molecular, morphological, and functional levels. This model has proven valuable in studying immune responses to inflammation, offering a promising avenue for neurological disorder research.
Adopting single-cell spatial transcriptomics could be useful to uncover the precise molecular mechanisms driving the development of distinct astrocyte subclasses within the organoids.
This in vivo organoid model could be applied to the study of astrocyte-related neurological disorders and could be expanded by incorporating other glial cells, such as microglia, to answer broader questions about glial biology.
By Maria Teresa Gallo, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan.
Link and doi of the publication:
https://www.nature.com/articles/s41587-024-02157-8 doi: 10.1038/s41587-024-02157-8.