Assembly of functionally integrated human forebrain spheroids

Fikri Birey, Jimena Andersen, Christopher D. Makinson, Saiful Islam, Wu Wei, Nina Huber, H. Christina Fan, Kimberly R. Cordes Metzler, Georgia Panagiotakos, Nicholas Thom, Nancy A. O’Rourke, Lars M. Steinmetz, Jonathan A. Bernstein, Joachim Hallmayer, John R. Huguenard and Sergiu P. Paşca ()
Additional contact information
Fikri Birey: Center for Sleep Sciences and Medicine, Stanford University School of Medicine
Jimena Andersen: Center for Sleep Sciences and Medicine, Stanford University School of Medicine
Christopher D. Makinson: Stanford University School of Medicine
Saiful Islam: Stanford University School of Medicine
Wu Wei: Stanford University School of Medicine
Nina Huber: Center for Sleep Sciences and Medicine, Stanford University School of Medicine
H. Christina Fan: BD Genomics
Kimberly R. Cordes Metzler: BD Genomics
Georgia Panagiotakos: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California
Nicholas Thom: Center for Sleep Sciences and Medicine, Stanford University School of Medicine
Nancy A. O’Rourke: Center for Sleep Sciences and Medicine, Stanford University School of Medicine
Lars M. Steinmetz: Stanford University School of Medicine
Jonathan A. Bernstein: Stanford University School of Medicine
Joachim Hallmayer: Center for Sleep Sciences and Medicine, Stanford University School of Medicine
John R. Huguenard: Stanford University School of Medicine
Sergiu P. Paşca: Center for Sleep Sciences and Medicine, Stanford University School of Medicine

Nature, 2017, vol. 545, issue 7652, 54-59

Abstract: Abstract The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-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 CaV1.2 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.

Date: 2017
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DOI: 10.1038/nature22330

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