US researchers grow brain organoids in a lab, just like they would develop in the fetus

Researchers at the University of Utah have developed seed-sized brain organoids that can not only organize themselves but also provide us insights into the causes of autism, a press release said.

Studying the diseases of the brain is often challenging since it is difficult for scientists to study the organ's inner workings. Although advances in technology allow us to image the brain to a certain degree, there is a lot that we still need to learn about how the brain develops.

Organoids, tiny clusters of tissue derived from stem cells, allow researchers to replicate the complex organs outside the body while also controlling conditions around them. The use of organoids in scientific labs is not new. However, scientists have faced trouble developing them in a reliably consistent way, making results difficult to interpret.

Copying from nature

Alex Shcheglovitov, a professor of neurobiology at the University of Utah, and his team turned to nature to make their organoids reliably. They used human stem cells and then prompted them to become neuroepithelial cells. These specific types of stem cells can self-organize in Petri dishes into structures called neural rosettes.

The researchers allowed these cells to grow on their own in the lab and found that the structures coalesced into spheres and increased in size at a rate similar to that of a developing brain in a growing fetus.

After five months in the lab, the organoids were similar to the human brain as seen 15-19 weeks after conception, Shcheglovitov said in the press release. The structures contained cells found in the cerebral cortex, the outermost layer of the brain that plays a role in various mental processes such as language, emotion, reasoning, etc.

Interestingly, these organoids also pulsated with oscillatory electrical rhythms seen in neural networks while generating electrical signals in mature brain cells.

Insights into autism

Shcheglovotiv's team used organoids to investigate the effects of genetic abnormality associated with autism spectrum disorder. They engineered the organoid to have lower levels of the SHANK3 gene.

The autism organoid appeared normal at the outset but showed some distinct traits. The neurons were hyperactive and fired more often in response to stimuli, while some signs indicated that the neurons did not pass signals to other neurons. The researchers also found that specific molecular pathways responsible for adhering cells to each other were also disrupted.

The researchers are confident that such organoid systems will aid in a better understanding of the brain, its development, and what goes wrong during disease. "We’re beginning to understand how complex neural structures in the human brain arise from simple progenitors,” said Yueqi Wang, a former doctoral student at the university. “And we’re able to measure disease-related phenotypes using 3D organoids that are derived from stem cells containing genetic mutations.”

The research findings were published today in the journal Nature Communications.

Abstract

Human telencephalon is an evolutionarily advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remain largely unknown. We produce human telencephalic organoids from stem cell-derived single neural rosettes and investigate telencephalic development under normal and pathological conditions. We show that single neural rosette-derived organoids contain pallial and subpallial neural progenitors, excitatory and inhibitory neurons, as well as macroglial and periendothelial cells, and exhibit predictable organization and cytoarchitecture. We comprehensively characterize the properties of neurons in SNR-derived organoids and identify transcriptional programs associated with the specification of excitatory and inhibitory neural lineages from a common pool of NPs early in telencephalic development. We also demonstrate that neurons in organoids with a hemizygous deletion of an autism- and intellectual disability-associated gene SHANK3 exhibit intrinsic and excitatory synaptic deficits and impaired expression of several clustered protocadherins. Collectively, this study validates SNR-derived organoids as a reliable model for studying human telencephalic cortico-striatal development and identifies intrinsic, synaptic, and clustered protocadherin expression deficits in human telencephalic tissue with SHANK3 hemizygosity.