Researchers have achieved a major milestone in brain organoid technology, successfully growing 3D “mini-brains” from human fetal tissue that closely mimic the structure and functionality of the human brain.
Fetal Tissue-Derived Brain Organoids Show Unprecedented Similarity to Developing Brain
Scientists from the University of California San Diego School of Medicine, Stanford University, and the Allen Institute published a study00024-1) this week in Cell Stem Cell announcing the development of a new technique to create brain organoids from human fetal tissue. Unlike other organoids grown from stem cells, these fetal tissue organoids contain diverse cell types that self-organize to form various brain regions and structures that accurately reflect the gene expression patterns, cellular composition, and 3D organization of the developing human brain.
This unprecedented similarity to an actual developing brain gives the organoids significant potential to revolutionize the study of early human brain development, evolution, and neurodevelopmental disorders.
“These organoids can help us answer fundamental questions about what makes the human brain special,” said senior author Dr. Alysson Muotri of UC San Diego. “We don’t fully understand all of the cellular interactions and migrations that allow our neurons to self-assemble into the intricate circuits that give rise to our unique capabilities.”
By studying the organoids across developmental stages, his team hopes to gain key insights into the complex cellular mechanisms involved in early neural development.
Organoids Form Various Brain Regions, Show Spontaneous Neural Activity
Remarkably, without any external intervention, the organoids developed over time to form discrete brain regions including the cortex, choroid plexus, retina, and meninges. They also displayed extensive axonal projections between neurons located in different regions, reflective of the brain’s structural connectivity.
Sophisticated gene analysis confirmed that the organoids expressed developmentally regulated genes in patterns corresponding to mid-gestation human fetal brains. This shows that cells in the organoids are able to self-organize and differentiate at the appropriate times, activating the gene programs involved in human neurogenesis.
Perhaps most impressive is the demonstration of neural activity within the organoids, indicating functionally mature neurons. The researchers observed synchronized bursts of spontaneous calcium fluxes in neural networks that strengthened in longer organoids, similar to the activity of developing neural circuits in vivo.
“The fact that these organoids show discrete brain regions undergoing neurogenesis with mature, active neurons is truly groundbreaking,” said neuroscientist Dr. Hongjun Song of the University of Pennsylvania, who was not involved in the study.
“This suggests a whole new realm of experimentation to understand the emergence of human cognitive abilities.”
Organoids to Accelerate Studies of Neurodevelopment, Disease, Evolution
The researchers highlight several applications that will be accelerated by this advance in brain organoid modeling:
- Study early stages of human neurodevelopment in more detail, including neural migration, axon guidance, and synapse formation
- Model neurodevelopmental disorders like autism spectrum disorder and neural tube defects to uncover mechanisms
- Gain insight into human brain evolution compared to other species
- Test pharmacological treatments for early brain abnormalities
- Develop more physiologically relevant models for drug screening and toxicology testing
“This new fetal brain organoid system overcomes previous limitations and gives us an unprecedented view into early human brain development,” said Dr. Muotri.
“We now have a reliable source of complex human neuronal tissue for experimental manipulation and observation that will speed so many avenues of neuroscience research.”
Organoids Ethically Sourced But Controversial
To enable these studies, the research team obtained donated fetal brain tissue following elective pregnancy terminations, following strict ethical guidelines. The organoids were derived from regions of the brain that would otherwise have been discarded.
While regulated use of discarded fetal tissue is legal in many places, it sparks ethical concerns from groups that see abortion as immoral. This latest study is likely to ignite debate around balancing the significant scientific value of such tissue with moral objections.
“We recognize these are difficult issues society is grappling with,” said Dr. Muotri. “We have aimed to follow best ethical practices for tissue donation, and we believe if anything this research underscores the tremendous potential of this precious tissue to save lives.”
Outlook: Integration With Other Organ Systems
Looking forward, a major goal will be integrating brain organoids with other “organ-on-chip” systems to create interconnected tissue models.
For example, linking neural tissue with cardiac, liver or immune system organoids could enable revolutionary experiments on neurotransmitter effects, inflammation-brain interactions, and multi-tissue drug testing.
“This latest work really raises the benchmark for what we can achieve by bringing human biology into the lab,” said bioengineer Dr. Linda Griffith of MIT.
“With this new capacity to create structured neural tissue, we can now start connecting multiple organoids into physiological systems unlike anything that’s been possible before. That’s hugely powerful.”
While additional challenges around organoid maturation and variability remain, this latest advance seems poised to drive a new generation of integrative human experimental models.
“We’re entering an exciting new era in organoid and tissue modeling,” Dr. Muotri concluded. “I can’t wait to see what we discover next about ourselves.”
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