Assembly of functionally integrated human forebrain spheroids

作者：Birey, Fikri; Andersen, Jimena; Makinson, Christopher D.; Islam, Saiful; Wei, Wu; Huber, Nina; Fan, H. Christina; Metzler, Kimberly R. Cordes; Panagiotakos, Georgia; Thom, Nicholas; O'Rourke, Nancy A.; Steinmetz, Lars M.; Bernstein, Jonathan A.; Hallmayer, Joachim; Huguenard, John R.; Pasca, Sergiu P.^*

来源：Nature, 2017, 545(7652): 54-+.

DOI：10.1038/nature22330

• PLURIPOTENT STEM-CELLS
• INTERNEURON MIGRATION
• GENE-EXPRESSION
• IN-VITRO
• NEURONS
• DYSFUNCTION
• PROGENITOR
• INHIBITION
• ASTROCYTES
• MATURATION

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.

• 出版日期2017-5-4