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

• Published in: Cell Vol. 165; no. 5; pp. 1238 - 1254
• Main Authors: Qian, Xuyu, Nguyen, Ha Nam, Song, Mingxi M., Hadiono, Christopher, Ogden, Sarah C., Hammack, Christy, Yao, Bing, Hamersky, Gregory R., Jacob, Fadi, Zhong, Chun, Yoon, Ki-jun, Jeang, William, Lin, Li, Li, Yujing, Thakor, Jai, Berg, Daniel A., Zhang, Ce, Kang, Eunchai, Chickering, Michael, Nauen, David, Ho, Cheng-Ying, Wen, Zhexing, Christian, Kimberly M., Shi, Pei-Yong, Maher, Brady J., Wu, Hao, Jin, Peng, Tang, Hengli, Song, Hongjun, Ming, Guo-li
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.05.2016
• Subjects: antiviral agents; Bioreactors; brain; Brain - cytology; Cell Culture Techniques - economics; cell death; Embryo, Mammalian; Embryonic Development; gene expression; Humans; Induced Pluripotent Stem Cells; Models, Biological; Neurogenesis; neurons; Neurons - cytology; Organoids - virology; quantitative analysis; spinning; Zika virus; Zika Virus - physiology; Zika Virus Infection - physiopathology; Zika Virus Infection - virology
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2016.04.032

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. [Display omitted] •A miniaturized spinning bioreactor for cost-effective culturing of organoids•Generation of brain-region-specific organoids from human iPSCs•ZIKV causes decrease of neuronal cell-layer volume resembling microcephaly•Both African and Asian ZIKV infect neural progenitors in organoids Zika virus preferentially infects neural progenitors in early stage cortical organoids generated using cost-effective miniaturized spinning bioreactors, resulting in suppressed proliferation, increased cell death, and macroscopic features resembling microcephaly.