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

Momoko Watanabe; Jessie E Buth; Neda Vishlaghi; Luis de la Torre-Ubieta; Jiannis Taxidis; Baljit S Khakh; Giovanni Coppola; Caroline A Pearson; Ken Yamauchi; Danyang Gong; Xinghong Dai; Robert Damoiseaux; Roghiyh Aliyari; Simone Liebscher; Katja Schenke-Layland; Christine Caneda; Eric J Huang; Ye Zhang; Genhong Cheng; Daniel H Geschwind; Peyman Golshani; Ren Sun; Bennett G Novitch

doi:10.1016/j.celrep.2017.09.047

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

Cell Rep. 2017 Oct 10;21(2):517-532. doi: 10.1016/j.celrep.2017.09.047.

Authors

Momoko Watanabe¹, Jessie E Buth¹, Neda Vishlaghi¹, Luis de la Torre-Ubieta², Jiannis Taxidis³, Baljit S Khakh⁴, Giovanni Coppola², Caroline A Pearson¹, Ken Yamauchi¹, Danyang Gong⁵, Xinghong Dai⁵, Robert Damoiseaux⁵, Roghiyh Aliyari⁶, Simone Liebscher⁷, Katja Schenke-Layland⁸, Christine Caneda⁹, Eric J Huang¹⁰, Ye Zhang⁹, Genhong Cheng⁶, Daniel H Geschwind¹¹, Peyman Golshani², Ren Sun⁵, Bennett G Novitch¹²

Affiliations

¹ 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.
² 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.
³ Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ 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.
⁵ 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.
⁶ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
⁸ 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.
⁹ 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.
¹⁰ Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.
¹¹ 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.
¹² 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.

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.

Keywords: Zika virus; cerebral cortex; differentiation; embryonic stem cell; human brain; neural development; neural stem cell; neurogenesis; organoid.

MeSH terms

Anti-Retroviral Agents / pharmacology*
Cell Line
Cerebral Cortex / cytology*
Cerebral Cortex / virology
Drug Evaluation, Preclinical / methods*
Embryonic Stem Cells / cytology
Embryonic Stem Cells / metabolism
Embryonic Stem Cells / virology
Humans
Neurons / cytology
Neurons / metabolism
Neurons / virology
Organoids / cytology
Organoids / metabolism
Organoids / virology*
Primary Cell Culture / methods*
Receptor Protein-Tyrosine Kinases / metabolism
STAT3 Transcription Factor / metabolism
Zika Virus / drug effects*
c-Mer Tyrosine Kinase / metabolism

Substances

Anti-Retroviral Agents
STAT3 Transcription Factor
STAT3 protein, human
Receptor Protein-Tyrosine Kinases
TYRO3 protein, human
c-Mer Tyrosine Kinase

Abstract

MeSH terms

Substances

Grants and funding