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Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection.

Abstract

The human cerebral cortex possesses distinct structural and functional features that are not found in the lower species traditionally used to model brain development and disease. Accordingly, considerable attention has been placed on the development of methods to direct pluripotent stem cells to form human brain-like structures termed organoids. However, many organoid differentiation protocols are inefficient and display marked variability in their ability to recapitulate the three-dimensional architecture and course of neurogenesis in the developing human brain. Here, we describe optimized organoid culture methods that efficiently and reliably produce cortical and basal ganglia structures similar to those in the human fetal brain in vivo. Neurons within the organoids are functional and exhibit network-like activities. We further demonstrate the utility of this organoid system for modeling the teratogenic effects of Zika virus on the developing brain and identifying more susceptibility receptors and therapeutic compounds that can mitigate its destructive actions.

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    Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment and Program in Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Physiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment and Program in Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.

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    Department of Cardiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Department of Cell and Tissue Engineering, Fraunhofer Institute for Interfacial Engineering and Biotechnology, 70569 Stuttgart, Germany.

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    Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.

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    Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment and Program in Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment and Program in Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

    Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: bnovitch@ucla.edu.

    Source

    Cell reports 21:2 2017 Oct 10 pg 517-532

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    29020636