About this item:

513 Views | 665 Downloads

Author Notes:

Correspondence: shongju1@jhmi.edu (H.S.), gming1@jhmi.edu (G.-l.M.)

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.

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., K.M.C. contributed to additional data collection and writing.

We thank Hopkins WSE machine shop and Nathaniel Leon for help of 3D printing, and members of Ming and Song laboratories for discussion, L. Liu and Y. Cai for technical support, and Dr. Robert B. Tesh at NIAID and the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA) for the Cambodian strain ZIKVC.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • SELF-ORGANIZATION
  • HUMAN NEOCORTEX
  • STEM-CELLS
  • DIFFERENTIATION
  • NEURONS
  • TISSUE
  • SCHIZOPHRENIA
  • DYSREGULATION
  • HYPOTHALAMUS
  • MICROGRAVITY

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

Show all authors Show less authors

Tools:

Journal Title:

Cell

Volume:

Volume 165, Number 5

Publisher:

, Pages 1238-1254

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2016 Elsevier Inc.

Export to EndNote