Dr. Sergiu Pasca Publishes Protocol for Developing Region-Specific Brain Organoids

What they did: NYSCF–Robertson Stem Cell Investigator Dr. Sergiu Pasca of Stanford University has pioneered a new method for generating 3D aggregates of region-specific brain tissue from stem cells. These aggregates, called “brain organoids”, approximate the neural structure and architecture of a region called the forebrain.

How they did it: Researchers used human pluripotent stem cells to generate the different cell types found in two regions of the forebrain. These cells were developed into mini-spheres specific to each region (called “spheroids”) and then combined to form a larger aggregate of tissue (called an “assembloid”) that mimics interactions between the two regions.

Why it matters: This new technique allows for researchers to isolate and examine a specific section of the brain using a 3D stem cell model instead of a biopsy. By following the protocol’s steps, scientists can use the model (which is more detailed than its predecessors) to study interactions between the different cells within the forebrain and explore how this region develops normally and in disease.

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A new method in Nature Protocols from NYSCF – Robertson Stem Cell Investigator and Stanford University Assistant Professor of Psychiatry and Behavioral Sciences Dr. Sergiu Pasca outlines a protocol for generating miniature, 3D tissue called “brain organoids” that model the human forebrain.

It is typically difficult to study brain tissue due to the limited availability of human samples. Organoids, however, are a promising alternative, as they provide an environment for various types of cells to grow and interact the way they would in an actual human brain. This allows researchers to observe brain development, study disease, and screen promising new drugs.

For this protocol, researchers were interested in creating organoids specific to a region of the brain called the forebrain. The forebrain is an important neural structure that contributes to speech, cognition, and emotion. It is also implicated in several neuropsychiatric conditions such as autism spectrum disorder and epilepsy.

To create forebrain organoids, the team first generated brain cells from human pluripotent stem cells and coaxed the cells to develop into miniature spheres of brain tissue called spheroids. One group of spheroids contained cells found in the upper portion of the forebrain and the other group contained cells found in the lower portion.

The researchers then combined these spheroids to form an assembloid— a larger aggregate of tissue that mimics interactions between the two regions. Assembloids are able to recapitulate more sophisticated neural circuits and let researchers examine how signals are sent between different portions of the brain.

The region-specific organoids generated in this study have several important features that represent improvements over previously generated organoids. In addition to their ability to model the diverse environment of the brain, they can be maintained in culture over a long period of time, allowing scientists to observe the later stages of human development. They are also easily scalable, making them a good fit for tests involving toxicology, gene editing, and drug screening.

Dr. Pasca is a pioneer in brain organoid technology who has played an integral role in the development of spheroids and assembloids as well as modeling of neuropsychiatric disorders. His work has earned him various recognitions, including the A.E. Bennett Award from the Society of Biological Psychiatry and the Vilcek Prize. His hope is that future versions of the model described in this paper will incorporate more cell types and allow scientists to generate other brain regions to study their role in development and disease.