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3-D printers, lab-grown 'mini brains' used to study Zika's effect
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Researchers at Johns Hopkins University used some science nonfiction to confirm previous research that showed how Zika virus affects fetal brains and causes microcephaly.
With the help of a 3-D printer, the researchers engineered miniature spinning bioreactors and used them as a cost-effective way to grow brain organoids from human stem cells, allowing them to study Zika virus infection in developing neural tissues. They made pinhead-size organoids mimicking the front, middle and back of the human brain, and used the forebrain for the Zika study, according to a news release.
“One thing the mini-brains allowed us to do was model the effects of Zika virus exposure during different stages of pregnancy,” Guo-li Ming, MD, PhD, professor of neurology and neuroscience at Johns Hopkins, said in the release. “If infection occurred very early in development, the virus mostly infected the mini-brains’ neural progenitor cells, and the effects were very severe. After a while, the mini-brains would stop growing and disintegrate. At a later stage, mimicking the second trimester, Zika still preferentially infected neural progenitor cells, but it also affected some neurons. Growth was slower, and the cortex was thinner than in noninfected brains.”
Figure 1. A brain organoid infected with Zika virus.
Source: Xuyu Qian/Johns Hopkins University
Results confirmed prior findings
Ming and many of the other researchers, including her husband and research partner, Hongjun Song, PhD, professor of neurology and neuroscience and director of the stem cell program at Johns Hopkins, also were involved in a recent study that showed Zika directly targeted lab-grown human neural progenitor cells. Their previous findings bolstered the virus’ link with microcephaly ahead of the CDC’s confirmation in April that there was a causal relationship between Zika infection during pregnancy and various serious birth defects.
The recent study showed that both African and Asian Zika virus infected neural progenitors in the organoids.
“We have been working for 3 years to develop a better research model of brain development, and it’s fortunate we can now use this one to shed light on the major public health crisis posed by Zika infections,” Song said. “This more realistic, 3-D model confirms what we suspected based on what we saw in a 2-D cell culture: that Zika causes microcephaly mainly by attacking the neural progenitor cells that build the brain and turning them into virus factories.”
Method could be used to test potential antivirals
Using 3-D printers to make bioreactors was an idea formulated by three high school students who worked as summer interns in the lab, including Ming and Song’s son, according to the release. The researchers utilized computer-aided design software to design and print each component using a 3-D printer, reducing the cost of generating the organoids, according to the study, which was published in Cell Stem Cell.
The design and method can be further used to test potential antiviral drugs for Zika, the researchers wrote. Another use could be to grow replacements for cells that die off in Parkinson’s disease, according to Song.
“This is the next frontier of stem cell biology,” he said in the release. – by Gerard Gallagher
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Peter Hotez, MD
The early results of the effects of Zika virus point to a devastating impact on the brain of the growing fetus, both in terms of inhibiting the fetal development of the brain, as well as destruction of brain tissue. Early studies from Johns Hopkins and Florida State found that Zika can infect neural progenitor cells, pointing to a plausible mechanism of this sequence of events, but the studies reported here allow us for the first time to understand the molecular and cellular pathogenesis in three dimensions through novel uses of brain organoids. This approach will help us elucidate how neurotropic viruses like Zika exert their destructive effects, but it could become a useful model for other neurotropic viruses such as cytomegalovirus, HIV and herpes simplex virus, among others.
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