Cell Stem Cell
Volume 20, Issue 3, 2 March 2017, Pages 397-406.e5
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Short Article
Recent Zika Virus Isolates Induce Premature Differentiation of Neural Progenitors in Human Brain Organoids

https://doi.org/10.1016/j.stem.2016.12.005Get rights and content
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Highlights

  • Recent American/Asian ZIKV isolates readily infect human iPSC-derived brain organoids

  • Infection triggers premature differentiation of NPCs, leading to progenitor depletion

  • Infected NPCs show centrosome disruption and alterations in division plane

  • NPC depletion leads to cortical thinning resembling ZIKV-associated microcephaly

Summary

The recent Zika virus (ZIKV) epidemic is associated with microcephaly in newborns. Although the connection between ZIKV and neurodevelopmental defects is widely recognized, the underlying mechanisms are poorly understood. Here we show that two recently isolated strains of ZIKV, an American strain from an infected fetal brain (FB-GWUH-2016) and a closely-related Asian strain (H/PF/2013), productively infect human iPSC-derived brain organoids. Both of these strains readily target to and replicate in proliferating ventricular zone (VZ) apical progenitors. The main phenotypic effect was premature differentiation of neural progenitors associated with centrosome perturbation, even during early stages of infection, leading to progenitor depletion, disruption of the VZ, impaired neurogenesis, and cortical thinning. The infection pattern and cellular outcome differ from those seen with the extensively passaged ZIKV strain MR766. The structural changes we see after infection with these more recently isolated viral strains closely resemble those seen in ZIKV-associated microcephaly.

Keywords

neural progenitor cells
NPCs
3D human brain organoids
centrosomes
cilia
Zika virus
premature NPC differentiation
microcephaly

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These authors contributed equally

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