? Project 1 Despite the tremendous promise of cerebral organoid technology for studying human brain development, modeling brain diseases and testing drug efficacy, we are still at the beginning of an era to engineer mini- brains from human stem cells. For broad applications in basic and translational research, organoid development should be scalable, cost efficient and highly consistent. Previous methods are largely based on cell self-assembly with little external control, and organoids generated by this approach exhibit large variability from sample to sample. We recently developed a miniaturized bioreactor and a protocol to generate forebrain- specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, and gene expression. We employed the forebrain organoid platform to model Zika virus (ZIKV) exposure and showed that preferential, productive infection of neural progenitors by ZIKV leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell-layer volume resembling microcephaly. In this collaborative research Center, we will investigate the effects of ZIKV and West Nile virus infections at different time points of organoid development to evaluate our platform with two different neurotropic flaviviruses that may target different stages of neural development. Project 1 will focus on technology development to reduce organoid heterogeneity and allow for quantitative analyses of the effects of different viruses on organoid development. To model later stages of brain development, we will adopt state-of-the-art bioengineering approaches to improve the diffusion of media to the organoids and reconstitution of different cell types. And finally, we will develop a medium-throughput platform for compound testing and perform a pilot assay using compounds with known biological effects on viral-infected cells.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of Pennsylvania
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Christian, Kimberly M; Song, Hongjun; Ming, Guo-Li (2018) A previously undetected pathology of Zika virus infection. Nat Med 24:258-259
Ho, Cheng-Ying; Castillo, Nicolas; Encinales, Liliana et al. (2018) Second-trimester Ultrasound and Neuropathologic Findings in Congenital Zika Virus Infection. Pediatr Infect Dis J 37:1290-1293
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Song, Guang; Rho, Hee-Sool; Pan, Jianbo et al. (2018) Multiplexed Biomarker Panels Discriminate Zika and Dengue Virus Infection in Humans. Mol Cell Proteomics 17:349-356
Yoon, Ki-Jun; Vissers, Caroline; Ming, Guo-Li et al. (2018) Epigenetics and epitranscriptomics in temporal patterning of cortical neural progenitor competence. J Cell Biol 217:1901-1914
Qian, Xuyu; Jacob, Fadi; Song, Mingxi Max et al. (2018) Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat Protoc 13:565-580
Ye, Fei; Kang, Eunchai; Yu, Chuan et al. (2017) DISC1 Regulates Neurogenesis via Modulating Kinetochore Attachment of Ndel1/Nde1 during Mitosis. Neuron 96:1041-1054.e5
Yoon, Ki-Jun; Song, Guang; Qian, Xuyu et al. (2017) Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins. Cell Stem Cell 21:349-358.e6
Wen, Zhexing; Song, Hongjun; Ming, Guo-Li (2017) How does Zika virus cause microcephaly? Genes Dev 31:849-861

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