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Organoids Shown Not Developing Like Real Brains

Arnold Kriegstein

Arnold Kriegstein (University of California – San Francisco)

30 Jan. 2020. Brain organoids, three-dimensional collections of brain cells grown from stem cells, are found in lab tests to not become fully functioning cells and tissue. Researchers from University of California in San Francisco describe their tests and findings in yesterday’s issue of the journal Nature (paid subscription required).

A team from the lab of UC San Francisco neuroscientist Arnold Kriegstein is seeking to precisely describe the way different genes contribute to brain development, part of an ongoing project to develop a comprehensive map of gene expression in the brain, begun two years ago. This map or atlas of gene activity in the brain is hoped to provide a more accurate model for researchers and drug developers than lab animals, whose brains are more limited than in humans.

Building this atlas involves cataloging and characterizing human brain tissue samples, but when other researchers began producing organoids from those samples, they found the brain cells in organoids do not accurately represent the complexity found in human brain tissue. This lack of equivalence between organoids and brain tissue samples raises questions about the value of organoids as models for drug development and testing.

The team led by postdoctoral researchers Aparna Bhaduri and Madeline Andrews, the paper’s co-first authors, extracted more than 235,000 cells from 37 brain organoids in the lab’s collection. The 37 organoids were produced from four different original cell lines, using three different culturing processes. The team compared gene expression from the organoid cells to some 189,000 brain cells derived from different regions of the brain and in various stages of development.

Their analysis shows the organoid cells are able to represent broad classes of brain cells, but beyond that point, the comparisons diverge. The researchers find stem cells in organoids do not follow the same trajectory in transforming into mature brain cells, and as a result do not represent all of the sub-types of brain cells. In addition, organoids express abnormally high levels of genes resulting from cellular stress, as when for example they’re deprived of oxygen, and activate stress pathways where they do not normally occur in human brain tissue.

The UC San Francisco researchers hypothesized these higher levels of stress-related proteins may be the culprit in disrupting the transformation of stem cells into functioning brain cells. To test this hunch, the team transplanted developing stem cells from organoids into brain cells of lab mice, and found stress proteins in the transplanted cells decrease to more normal levels. In a similar test, the researchers transplanted developing neurons from lab cultures into organoids, where transplanted cells activated more stress genes and followed the more disrupted transformational path seen in organoids.

“We find that organoids do not develop the distinctive cell sub-types or regional circuit organization that characterize normal human brain circuits,” says Kriegstein in a university statement. “Since most human brain diseases are highly specific to particular cell types and circuits in the brain, this presents a grave challenge to efforts to use organoids to accurately model these complex conditions.”

The researchers say organoids can still be useful for tests that do not require a completely accurate model of human brain cells. Science & Enterprise reports regularly on organoids developed in industry and academic labs for drug development and testing, particularly for treatments where a patient’s own stem cells can transform into healthy cells for transplants. Last week, for example, a story reports on researchers that use organoids to train a patient’s immune system cells to attack cancer cells, which may remove the need for immunotherapy drugs.

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