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

• Type of Material: Article
• Authors: Xuyu Qian, Johns Hopkins University; Ha Nam Nguyen, Johns Hopkins University; Mingxi M. Song, Johns Hopkins University; Christopher Hadiono, Johns Hopkins University; Sarah C. Ogden, Florida State University; Christy Hammack, Florida State University; Bing Yao, Emory University; Gregory Hamersky, Johns Hopkins University; Fadi Jacob, Johns Hopkins University; Chun Zhong, Johns Hopkins University; Ki-Joon Yoon, Johns Hopkins University; William Jeang, Johns Hopkins University; Li Lin, Emory University; Yujing Li, Emory University; Jai Thakor, Johns Hopkins University; Daniel Berg, Johns Hopkins University; Ce Zhang, Johns Hopkins University; Eunchai Kang, Johns Hopkins University; Michael Chickering, Johns Hopkins University; David Nauen, Johns Hopkins University; Cheng-Ying Ho, George Washington University; Zhexing Wen, Emory University; Kimberly M Christian, Johns Hopkins University; Pei-Yong Shi, University of Texas Medical Branch; Brady J. Maher, Johns Hopkins University; Hao Wu, Emory University; Peng Jin, Emory University; Hao Tang, Florida State University; Hongjun Song, Johns Hopkins University; Guo-li Ming, Johns Hopkins University
• Language: English
• Date: 2016-05-19
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2016.04.032
• Title of Journal or Parent Work: Cell
• ISSN: 0092-8674
• Volume: 165
• Issue: 5
• Start Page: 1238
• End Page: 1254
• Grant/Funding Information: This work was supported by grants from NIH (NS048271, MH105128, and NS095348 to G.L.M., NS047344 and ES021957 to H.S., AI119530 and AI111250 to H.T, NS051630, NS079625, and MH102690 to P.J., MH104593 to B.J.M.), MSCRF (to H.S.), and SFARI (308988 to H.S.).
• Keywords: SELF-ORGANIZATION; SCHIZOPHRENIA; Cell Biology; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; DIFFERENTIATION; DYSREGULATION; STEM-CELLS; HUMAN NEOCORTEX; Science & Technology; NEURONS; HYPOTHALAMUS; MICROGRAVITY; TISSUE
• Research Categories: Biology, Genetics; Biology, Neuroscience; Biology, Cell

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.