Assembly of functionally integrated human forebrain spheroids

Article

关键词: PLURIPOTENT STEM-CELLS;    INTERNEURON MIGRATION;    GENE-EXPRESSION;    IN-VITRO;    NEURONS;    DYSFUNCTION;    PROGENITOR;    INHIBITION;    ASTROCYTES;    MATURATION;   

DOI  :  10.1038/nature22330

来源: SCIE

【 摘 要 】

The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (gamma-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca(V)1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.

【 授权许可】

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