Seed-sized brain-like organoids that are reminiscent of one wrinkle in the human brain 15 to 19 weeks post-conception were created and grown in the lab by University of Utah (U of U). The organoids are being used to help scientists understand structural differences in the human brain that may contribute to the development of autism spectrum disorder (ASD).
“We used to think it would be too difficult to model the organization of cells in the brain,” said Alex Shcheglovitov, PhD, assistant professor of neurobiology at U of U Health and senior author of the paper detailing this work, published today in Nature Communications. “But these organoids self-organize. Within a few months, we see layers of cells that are reminiscent of the cerebral cortex in the human brain.”
With the ability to create a model of the human brain, Shcheglovitov and lead author Yueqi Wang, PhD, a former graduate student in his lab, see broad possibilities for these organoids to be used in research of neurological disorders as they can be subjected to experimental conditions human brains cannot.
For their work investigating a genetic abnormality—a gene called SHANK3—associated with ASD and human brain development, Shcheglovitov and team discovered that the organoids engineered to have lower levels of that gene had some distinct features. Even though the organoid appeared to be normal, some of the cells did not behave normally. These difference in function included:
- Neurons were hyperactive, firing more often in response to stimuli;
- Other signs indicated neurons may not efficiently pass along signals to other neurons; and
- Specific molecular pathways that cause cells to adhere to one another were disrupted.
Using these findings of some of the cellular and molecular drivers of ASD has implications for treating the condition, and their results, the authors say can also provide a better understanding of what goes wrong in the brain during various diseases.
“One goal is to use brain organoids to test drugs or other interventions to reverse or treat disorders,” said Jan Kubanek, PhD, a co-author and assistant professor of biomedical engineering at the U of U.
Growing the brain-like organoid
While the creation and use of organ models grown in a lab are not new in research, building a good model of the human brain, that was reproducible, has proved challenging.
For their efforts, the Shcheglovitov Lab’s team looked for clues on how to do this by studying how the brain develops normally. For their model, the researchers coaxed human stems cells to develop into neuroepithelial cells, a type of stem cell that forms self-organized structures, called neural rosettes. Over the course of months, the researchers noted that the neural rosettes continued to grow coalescing into spheres and increasing in size and complexity at a rate similar to the developing brain in a growing fetus.
At five months, the organoids were similar to “one wrinkle of the human brain,” Shcheglovitov said, containing neural and other cell types found in the cerebral cortex, the outermost layer of the brain involved in language, emotion, reasoning, and other high-level mental processes.
The organoids also self-organized in a predictable way forming neural networks oscillatory electrical rhythms, generating diverse electrical signals characteristic of a variety of different types of mature human brain cells.
“These organoids had patterns of electrophysiological activity that resembled actual activity in the brain. I didn’t expect that,” Kubanek says. “This new approach models most major cell types and in functionally meaningful ways.”
Since the organoids’ cell diversity and function model the complexity of the human brain so well and more reliably reflect intricate structures in the cortex, the new model can help researchers better understand how different brain cells arise and how they work together to perform more complex functions.
“We’re beginning to understand how complex neural structures in the human brain arise from simple progenitors,” Wang noted. “And we’re able to measure disease-related phenotypes using 3D organoids that are derived from stem cells containing genetic mutations.”
