Lab-grown organoids are more stressed-out than actual brain cells

CHICAGO — Brain cells grown into clumps in flasks are totally stressed-out and confused. Cells in these clumps have ambiguous identities and make more stress molecules than cells taken directly from human brains, researchers reported October 22 at the annual meeting of the Society for Neuroscience.

These cellular clumps are grown using stem cells made from skin or blood, which under the right conditions can be coaxed into forming three-dimensional clusters of brain cells. These clusters, a type of organoid, are thought to re-create some aspects of early human brain development, a period that is otherwise difficult to study (SN: 2/20/18). 

The new results highlight underappreciated differences between these organoids and the human brains they are designed to mimic. “Most of the papers out there are extolling the virtues of these things,” says study coauthor Arnold Kriegstein, a developmental neurobiologist at the University of California, San Francisco. But the new study reveals “significant issues that nobody has addressed yet.”

Kriegstein and colleagues compared genetic activity in human cells from brain tissue in early development with human cells grown in an organoid. Cells in the organoids had more active genes involved in stress responses. What’s more, these organoid cells didn’t fit into the neat categories of cells in actual brain tissue. Instead, some of the organoid cells showed features of two distinct categories simultaneously. “They are not normal,” Kriegstein says.

Data from other labs showed the same stressed-out gene behavior in organoid cells, says study coauthor Aparna Bhaduri, a developmental neurobiologist also at UCSF. “It’s a universal phenomenon,” she says.

The findings are “scientifically satisfying” because they draw attention to a challenge the organoid field faces, says neuroscientist Michael Nestor of the Hussman Institute for Autism in Baltimore. “There’s been a lot of hype,” about brain organoids’ potential, he says. “I’m excited too, but we’ve got to take a step back. I think this work does that.”

Abnormal human organoid cells became a little bit more normal when implanted into a more hospitable environment — mice’s brains. After growing for several weeks in a more normal environment with a blood supply, the organoid cells seemed less stressed. And the cells no longer seemed as confused about their identities.

The researchers don’t know exactly what causes the abnormalities in the organoid cells. It might have to do with the nourishing liquid that surrounds the blobs, or even differences in the mechanical forces that press against them.

Nestor says that with refinements, organoids grown in lab dishes can better approximate certain aspects of brain development. “There may be some mix of small molecules or media or temperature regulation that will get you there,” he says. “It’s just that it is going to take a while to figure out what that secret sauce is.”