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J Vis Exp. 2017 Apr 14;(122). doi: 10.3791/55372.

Generation of iPSC-derived Human Brain Organoids to Model Early Neurodevelopmental Disorders.

Author information

1
Center for Molecular Medicine Cologne, University of Cologne.
2
Center for Molecular Medicine Cologne, University of Cologne; Institute for Biochemistry I, Medical School of University of Cologne; jay.gopalakrishnan@uni-koeln.de.

Abstract

The restricted availability of suitable in vitro models that can reliably represent complex human brain development is a significant bottleneck that limits the translation of basic brain research into clinical application. While induced pluripotent stem cells (iPSCs) have replaced the ethically questionable human embryonic stem cells, iPSC-based neuronal differentiation studies remain descriptive at the cellular level but fail to adequately provide the details that could be derived from a complex, 3D human brain tissue. This gap is now filled through the application of iPSC-derived, 3D brain organoids, "Brains in a dish," that model many features of complex human brain development. Here, a method for generating iPSC-derived, 3D brain organoids is described. The organoids can help with modeling autosomal recessive primary microcephaly (MCPH), a rare human neurodevelopmental disorder. A widely accepted explanation for the brain malformation in MCPH is a depletion of the neural stem cell pool during the early stages of human brain development, a developmental defect that is difficult to recreate or prove in vitro. To study MCPH, we generated iPSCs from patient-derived fibroblasts carrying a mutation in the centrosomal protein CPAP. By analyzing the ventricular zone of microcephaly 3D brain organoids, we showed the premature differentiation of neural progenitors. These 3D brain organoids are a powerful in vitro system that will be instrumental in modeling congenital brain disorders induced by neurotoxic chemicals, neurotrophic viral infections, or inherited genetic mutations.

PMID:
28448044
PMCID:
PMC5564693
DOI:
10.3791/55372
[Indexed for MEDLINE]
Free PMC Article

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