Dish-grown brain-like organoids offer window into autism
06 October 2022 09:00
Whatever you do, don’t call them “mini-brains,” say scientists at the University of Utah Health. Either way, the seed-sized organoids — which are grown in the lab from human cells — provide insight into the brain and reveal differences that may contribute to autism in some people.
“We used to think it would be too difficult to model the organization of cells in the brain,” says Alex Shcheglovitov, PhD, assistant professor of neurobiology at U of U Health. “But these organoids self-organize. Within months, we see layers of cells reminiscent of the cerebral cortex in the human brain.
Research describing organoids and their potential for understanding neural disease is published in Nature Communication on October 6 with Shcheglovitov as lead author and Yueqi Wang, PhD, a former graduate student in his lab, as lead author. They conducted the research with postdoctoral scientist Simone Chiola, PhD, and other collaborators from the University of Utah, Harvard University, University of Milan, and Duomo State University. Montana.
“These organoids self-organize. Within months, we see layers of cells reminiscent of the cerebral cortex in the human brain.
Having the ability to model aspects of the brain in this way gives scientists insight into the inner workings of a living organ that is otherwise nearly impossible to access. And since organoids grow in a dish, they can be experimentally tested in ways that a brain cannot.
Shcheglovitov’s team used this approach to study the effects of a genetic defect associated with autism spectrum disorders and human brain development. They found that organoids engineered to have lower levels of the gene, called STEM3had distinct characteristics.
Even though the organoid model of autism appeared normal, some cells were not functioning properly:
- Neurons were hyperactive, firing more often in response to stimuli,
- Other signs indicate that neurons may not transmit signals efficiently to other neurons,
- Specific molecular pathways that cause cells to adhere to each other have been disrupted.
These findings help uncover the cellular and molecular causes of symptoms associated with autism, the authors say. They also demonstrate that lab-grown organoids will be useful in better understanding the brain, how it develops, and what goes wrong during disease.
“A key application is to use brain organoids, derived from each patient’s genetic material, to test drugs or other interventions to treat disorders in a personalized way,” says study co-author Jan Kubanek, PhD. and assistant professor of biomedical engineering at the U. “It would really help realize the potential of personalized medicine.”
Building a better brain model
Scientists have long searched for suitable models for the human brain. Organoids grown in the laboratory are not new, but previous versions have not grown reproducibly, making the experiments difficult to interpret.
To create an improved model, Shcheglovitov’s team took inspiration from normal brain development. The researchers tricked human stem cells into becoming neuroepithelial cells, a specific type of stem cell that forms self-organizing structures, called neural rosettes, in a dish. Over the months, these structures coalesced into spheres and grew in size and complexity at a rate similar to brain development in a growing fetus.
After five months in the lab, the organoids looked like “a wrinkle of a human brain” 15 to 19 weeks after conception, Shcheglovitov says. The structures contained an array of neural and other cell types found in the cerebral cortex, the brain’s outermost layer involved in language, emotion, reasoning and other high-level mental processes.
Like a human embryo, the organoids self-organized in predictable ways, forming neural networks that pulsed with oscillatory electrical rhythms and generated various electrical signals characteristic of a variety of different types of mature brain cells.
“These organoids had patterns of electrophysiological activity that resembled the electrophysiological rhythms of the brain. I didn’t expect that,” says Kubanek. “This new approach models the functional brain networks of human nervous tissue.”
Shcheglovitov says these organoids, which more reliably reflect complex structures in the cortex, will allow scientists to study how specific types of cells in the brain arise and work together to perform more complex functions.
“We are beginning to understand how complex neural structures in the human brain arise from simple progenitors,” says Wang. “And we are able to measure disease-related phenotypes using 3D organoids derived from stem cells containing genetic mutations.”
He adds that by using the organoids, researchers will be able to better study what happens in the early stages of neurological disorders, before symptoms develop.
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Visit the UBrain browser to visualize cells and electrical responses detected in organoids.
The research published under the title “Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes.”
Support for the work came from the National Institutes of Health, Brain Research Foundation, Brain and Behavior Research Foundation, Whitehall Foundation, University of Utah Neuroscience Initiative, and University of Utah Genome Project Initiative.
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