Lab-grown human brain tissue can now be guided to develop characteristics of either the front or back of the developing cerebral cortex, giving scientists a more precise way to study how the brain organizes itself before birth and how that process may change in disorders such as fragile X syndrome.
Giving organoids a regional identity
The cerebral cortex, the brain’s outer layer, does not develop as one uniform sheet. Different areas take on different identities during early development, helping establish the organization needed for functions such as movement, vision, memory, language and social understanding.
This regional patterning is known as arealization. Chemical signals help developing cells respond differently depending on where they are in the growing brain.
Brain organoids can reproduce important features of developing human brain tissue, but conventional organoids generally do not reproduce this clear regional organization. Instead, they can contain a patchwork of different regions.
A team led by researchers at the University of California, Irvine, developed an approach that changes this. The researchers used carefully selected signals early in organoid growth to guide human neocortical organoids toward characteristics associated with either the front or back of the developing cortex.
The organoids were made from human stem cells and were designed to reproduce important features of developing cerebral cortex tissue.
The researchers then examined individual cells to determine whether the regional differences resembled those found during actual human development. Their analysis included more than 200,000 cells and found molecular characteristics associated with different regions of the prenatal human cortex.
Lead author Momoko Watanabe, Ph.D., an assistant professor of anatomy and neurobiology at the UC Irvine School of Medicine and a faculty member of the Sue & Bill Gross Stem Cell Research Center, said that adding regional identity to brain organoids could allow researchers to investigate developmental and disease-related questions that are difficult to study with conventional organoids.
Testing the model with fragile X syndrome
The researchers next used the regionally patterned organoids to examine fragile X syndrome, a genetic condition associated with intellectual disability and autism spectrum disorder.
They focused on whether the condition could affect the broader developmental pattern that organizes cells across different parts of the cortex, rather than affecting individual cells alone.
Two proteins involved in brain development, SOX4 and SOX11, normally occur at different levels in tissue from the front and back of the developing cortex. That regional difference was consistently present in organoids grown from donors without fragile X syndrome.
In organoids modeling fragile X syndrome, however, the difference between the front and back largely disappeared. The broader front-to-back pattern remained, but the difference in SOX4 and SOX11 levels had become much smaller.
Other researchers have reported a similar flattening of this regional difference in donated brain tissue from people with autism, where the usual gap in SOX4 and SOX11 levels between the front and back of the cortex is smaller than expected.
The findings do not establish that disrupted brain patterning causes autism. Instead, they identify a developmental process that can now be examined in greater spatial detail using a human tissue model.
A model for studying regional changes
The researchers say that regional organization could be important when studying neurological and neurodevelopmental disorders because such conditions may not affect every part of the brain in the same way.
Organoids with defined regional characteristics could allow researchers to examine not only what changes during a disorder, but also where those changes appear during development.
The approach also adds to efforts to use human tissue-based models alongside animal studies. Human brain development includes features that differ from development in other species, and stem cell-derived organoids provide another way to investigate processes that are difficult to study directly in people or reproduce in animals.
The researchers say the system could be used to examine how genetic and environmental factors affect different regions of the developing cortex and to investigate disease mechanisms and potential therapeutic strategies.
The study was published in Cell Stem Cell.
