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 NauenCheng Ying Ho, Zhexing Wen, Kimberly M. Christian, Pei Yong Shi, Brady J. Maher, Hao Wu, Peng Jin, Hengli Tang, Hongjun Song*, Guo Li Ming

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1440 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1238-1254
Number of pages17
JournalCell
Volume165
Issue number5
Early online date22 Apr 2016
DOIs
Publication statusPublished - 19 May 2016
Externally publishedYes

Bibliographical note

Author Contributions: X.Q., H.N.N., H.S., and G.-l.M. conceived of the research, designed the study, and wrote the manuscript. M.M.S., C. Hadiono, and W.J. designed SpinΩ. X.Q., S.C.O., C. Hammack, and H.T. performed ZIKV experiments. P.-Y.S. provided ZIKVC clone. B.Y., L.L., Y.L., H.W., and P.J. performed RNA-seq analyses. G.H. and B.J.M. performed electrophysiology analysis. C.-Y.H. and D.N. contributed human tissue samples. F.J., C.Z., J.T., K.-j.Y., D.B., C.Z., E.K., M.C., Z.W., and K.M.C. contributed to additional data collection and writing.

Acknowledgments: We thank Hopkins WSE machine shop and Nathaniel Leon for help of 3D printing and members of the Ming and Song laboratories for discussion; L. Liu and Y. Cai for technical support; and Robert B. Tesh at UTMB and the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA) for the Cambodian strain ZIKVC. 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.; and MH104593 to B.J.M.), MSCRF (to H.S.), and SFARI (308988 to H.S.).

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