Assembly of functionally integrated human forebrain spheroids

  • Nature. 2017 May 4;545(7652):54-59. doi: 10.1038/nature22330.
Fikri Birey  1 ,  Jimena Andersen  1 ,  Christopher D Makinson  2 ,  Saiful Islam  3 ,  Wu Wei  3  4 ,  Nina Huber  1 ,  H Christina Fan  5 ,  Kimberly R Cordes Metzler  5 ,  Georgia Panagiotakos  6 ,  Nicholas Thom  1 ,  Nancy A O'Rourke  1 ,  Lars M Steinmetz  3  4  7 ,  Jonathan A Bernstein  8 ,  Joachim Hallmayer  1 ,  John R Huguenard  2 ,  Sergiu P Paşca  1
Affiliations
  • 1. Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
  • 2. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
  • 3. Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
  • 4. Stanford Genome Technology Center, Stanford University, Palo Alto, California 94304, USA.
  • 5. BD Genomics, Menlo Park, California 94025, USA.
  • 6. Department of Biochemistry and Biophysics, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California 94143, USA.
  • 7. European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
  • 8. Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
PMID: 28445465 DOI: 10.1038/nature22330
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.