"Abnormal" organoids
Organoids grown in the laboratory are more susceptible to stress than brain cells
Brain cells grown in test tubes are severely overloaded and confused. The cells in these clusters have an ambiguous identity and create more stress molecules than cells taken directly from the human brain, the researchers reported on October 22 at the annual meeting of the Society of Neuroscience, – writes Science News (Lab-grown organoids are more stressed-out than actual brain cells).
These cell clusters are grown using stem cells made from skin or blood, which, under the right conditions, can be formed into three-dimensional clusters of brain cells. It is believed that such organoids recreate some aspects of the early development of the human brain – a period that is difficult to study in any other way.
The new findings highlight the underappreciated differences between organoids and the human brain they are designed to mimic. "Most publications extol the virtues of organoids," says study co–author Arnold Kriegstein, a neuroscientist researcher at the University of California, San Francisco. "But the new study shows important issues that no one has considered yet."
Kriegstein and his colleagues compared the genetic activity of human cells from brain tissue in the early stages of development with human cells grown in an organoid. The cells in the organoids had more active genes involved in stress responses. Moreover, these organoid cells do not fit into the neat categories of cells in real brain tissue. Instead, some of the organoid cells showed signs of two different categories at the same time. "They're not normal," says Kriegstein.
Data from other laboratories have shown the same stress behavior of genes in organoid cells, says study co-author Aparna Bhaduri, a neuroscientist researcher also at UCSF. "It's a universal phenomenon," she says.
The findings are "scientifically satisfactory" because they draw attention to the problem faced by the use of organoids, says neuroscientist Michael Nestor of the Hassman Autism Institute in Baltimore. "There was a lot of hype about the potential of brain organoids," he says. "I'm excited too, but we have to take a step back."
Abnormal human organoid cells became slightly more normal when they were implanted into a more hospitable environment – the mouse brain. After several weeks of growth in a more normal environment with blood supply, the organoid cells looked less stressed. And the cells were no longer entangled in their identities.
Researchers don't know exactly what causes abnormalities in organoid cells. This may be due to the nutrient fluid that surrounds the cells, or even to differences in the mechanical forces that put pressure on them.
Nestor says that thanks to improvements, organoids grown in the laboratory can better reflect certain aspects of brain development. "You can find some combination of small molecules, the environment or the right temperatures that will lead you to the goal," he says. "It's just going to take time to figure out what this secret line–up is."
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