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

Xuyu Qian; Ha Nam Nguyen; Mingxi M Song; Christopher Hadiono; Sarah C Ogden; Christy Hammack; Bing Yao; Gregory R Hamersky; Fadi Jacob; Chun Zhong; Ki-Jun Yoon; William Jeang; Li Lin; Yujing Li; Jai Thakor; Daniel A Berg; Ce Zhang; Eunchai Kang; Michael Chickering; David Nauen; Cheng-Ying Ho; Zhexing Wen; Kimberly M Christian; Pei-Yong Shi; Brady J Maher; Hao Wu; Peng Jin; Hengli Tang; Hongjun Song; Guo-Li Ming

doi:10.1016/j.cell.2016.04.032

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

Cell. 2016 May 19;165(5):1238-1254. doi: 10.1016/j.cell.2016.04.032. Epub 2016 Apr 22.

Authors

Xuyu Qian¹, Ha Nam Nguyen², Mingxi M Song³, Christopher Hadiono⁴, Sarah C Ogden⁵, Christy Hammack⁵, Bing Yao⁶, Gregory R Hamersky⁷, Fadi Jacob⁸, Chun Zhong⁹, Ki-Jun Yoon⁹, William Jeang¹⁰, Li Lin⁶, Yujing Li⁶, Jai Thakor⁸, Daniel A Berg⁸, Ce Zhang⁹, Eunchai Kang⁹, Michael Chickering⁸, David Nauen¹¹, Cheng-Ying Ho¹², Zhexing Wen⁹, Kimberly M Christian⁹, Pei-Yong Shi¹³, Brady J Maher¹⁴, Hao Wu¹⁵, Peng Jin⁶, Hengli Tang⁵, Hongjun Song¹⁶, Guo-Li Ming¹⁷

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: [email protected].
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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Bioreactors
Brain / cytology*
Cell Culture Techniques* / economics
Embryo, Mammalian
Embryonic Development
Humans
Induced Pluripotent Stem Cells
Models, Biological*
Neurogenesis
Neurons / cytology
Organoids* / virology
Zika Virus / physiology*
Zika Virus Infection / physiopathology
Zika Virus Infection / virology

Abstract

Publication types

MeSH terms

Grants and funding