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      Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure.

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          Abstract

          Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability, and tissue heterogeneity limit their broad applications. Here, we developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and, notably, a distinct human-specific outer radial glia cell layer. We also developed protocols for midbrain and hypothalamic organoids. Finally, we employed the forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed preferential, productive infection of neural progenitors with either African or Asian ZIKV strains. ZIKV infection leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell-layer volume resembling microcephaly. Together, our brain-region-specific organoids and SpinΩ provide an accessible and versatile platform for modeling human brain development and disease and for compound testing, including potential ZIKV antiviral drugs.

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          Author and article information

          Journal
          Cell
          Cell
          0092-8674
          0092-8674
          May 19 2016
          : 165
          : 5
          Affiliations
          [1 ] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Biomedical Engineering Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
          [2 ] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
          [3 ] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Riverhill High School, Clarksville, MD 21029, USA.
          [4 ] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Byram Hills High School, Armonk, NY 10504, USA.
          [5 ] Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
          [6 ] Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
          [7 ] Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
          [8 ] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
          [9 ] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
          [10 ] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Clear Lake High School, Harris, TX 77058, USA.
          [11 ] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
          [12 ] Division of Pathology, Children's National Medical Center, George Washington University, Washington, DC 20010, USA; Pathology and Pediatrics, George Washington University, Washington, DC 20010, USA.
          [13 ] Department of Biochemistry and Molecular Biology, Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA.
          [14 ] Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
          [15 ] Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
          [16 ] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: shongju1@jhmi.edu.
          [17 ] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: gming1@jhmi.edu.
          Article
          S0092-8674(16)30467-6 NIHMS780987
          10.1016/j.cell.2016.04.032
          4900885
          27118425
          e62bfa19-1c30-4e60-ba24-899bea6375df
          Copyright © 2016 Elsevier Inc. All rights reserved.
          History

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