New brain organoid model replicates human cortical domains

Jürgen Knoblich’s group at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences has developed a new method that allows scientists to grow brain organoids with distinct cortical areas and front-to-back patterns.

Together with collaborators from the Human Technopole and the University of Milan-Bicocca, they have presented a method that allows scientists to gain deeper insight into human-specific brain development and disorders. The study was published in Methods of nature September 18th.

Brain organoids are widely used to study human brain development. Derived from human pluripotent stem cells, the 3D models allow scientists to study the unique properties of the human brain. Researchers use cortical organoids to answer fundamental questions such as how the human brain can grow to its large size or how the human brain’s long-distance connections form.

However, cortical organoids are fairly uniform spherical cultures, like miniature soccer balls. This ball-like structure is very different from the oblong human cortex, which is structured into distinct domains from back to front, each with a distinct function.

The team therefore developed a new protocol to generate brain organoids organized into distinct domains along the longitudinal axis. The work was led by Camilla Bosone, Veronica Krenn and Davide Castaldi.

Experimental platform to understand brain disorders

During development, the forming brain is shaped by different signaling molecules, called morphogens. In the new method presented, the researchers first produced long, linear organoids that were then shaped by fusion with a group of cells that produce a factor called FGF8.

This single asymmetric source of FGF8 establishes gene expression and cell segregation along the longitudinal axis of the organoids, similar to the pattern observed in the human cortex. “We are able to generate this polarity consistently along the entire longitudinal axis of the organoid,” explains corresponding author Knoblich.

The scientists then demonstrated how structured cortical organoids can be used to study brain disorders. In patients with achondroplasia, the temporal lobe, an area of ​​the cortex, forms incorrectly. These malformations are linked to a mutation in FGFR3, a receptor for the FGF8 signal. In structured cortical organoids, this FGFR3 mutation also leads to changes in cell structure and proliferation along the longitudinal axis.

“Patterned organoids are a model for studying the patterning defects that underlie developmental disorders,” Knoblich adds. The organoids could even serve as an experimental platform to test the hypothesis that early patterning defects are responsible for transcriptional changes in the brains of autistic people. “Organoids offer a way to link genetic and environmental alterations linked to neuropsychiatric disorders to specific early cortical patterning events.”

A new model for cortex development

Using structured brain organoids, scientists have also gained insights into human development. During human brain development, many morphogens and signaling pathways interact, making it difficult to determine how each component individually contributes to development.

In contrast, in the structured brain organoids, FGF8 is the only signal that specifies the different domains. By analyzing the brain organoids, the scientists conclude that the source of FGF8 in the developing human brain, the anterior neural crest, plays a primary role in structuring the cortex.

“By fusing organoids that produce distinct morphogens and precisely controlling the timing and quantity of morphogen-producing cells in these fusions, polar cortical assembloids (PolCAs) serve as an optimal in vitro model to introduce and study individual signaling pathways in isolation,” says Bosone, one of the study’s first authors.

“Patterned brain organoids will provide a useful model to study in more detail how neurons acquire their identity during development,” Knoblich adds.

Provided by IMBA – Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH