Scientists create brain organoids with distinct cortical regional identity

The human brain is often described as one of the most complex structures in biology, and much of its power comes from how it's organized. Its outer layer, the cerebral cortex, is not one uniform sheet. As the brain develops, it divides into distinct areas that each take on different jobs, from movement and vision to memory, language and social understanding.

Scientists call this process "arealization," and they believe it underpins much of what the brain can do. It may also help explain what goes wrong in some conditions that affect brain development.

That organization draws interest well beyond neuroscience. Engineers have long borrowed ideas from the brain – which builds itself without a blueprint and runs on very little power – for work in computing and robotics. But the biology has been hard to study because most of this patterning happens before birth.

Even early in development, the human brain has a sense of place. Chemical signals help tell developing cells where they are, contributing to differences between areas at the front and the back of the cerebral cortex.

Until now, scientists have had difficulty reproducing that organization in lab-grown models of the human brain.

Giving brain tissue a biological compass

The cerebral cortex is the brain's outer layer and is involved in functions ranging from movement and sensory processing to language and higher-level thinking. But not every part of the cortex develops in the same way.

During early development, chemical signals help create a kind of biological map, guiding different regions toward distinct identities.

Ordinary brain organoids copy many features of developing brain tissue, but they usually miss this step. Each one ends up with a patchwork of random regions rather than a clear front or back.

The UC Irvine team found a way to introduce it.

By exposing the developing organoids to carefully selected signals early in their growth, researchers could steer some toward characteristics associated with the front of the cortex or toward characteristics associated with the back.

They then examined individual cells to determine whether those differences resembled actual human development. Their analysis of more than 200,000 cells showed that the organoids reproduced molecular characteristics associated with different regions of the prenatal human cortex.

In effect, the researchers gave lab-grown cortical tissue a biological compass, a reproducible sense of front or back.

Seeing fragile X syndrome in a new way

The team then used the new model to investigate fragile X syndrome, a genetic condition and a leading inherited cause of intellectual disability that's also associated with autism spectrum disorder.

The researchers wanted to know whether fragile X syndrome might affect not only individual brain cells but also the broader developmental patterns that help organize those cells across the cortex. They found that it did.

Two proteins important to brain development, called SOX4 and SOX11, normally appear at different levels in front and back tissue. That difference showed up reliably in organoids grown from donors without the condition. In organoids modeling fragile X syndrome, it largely disappeared. The broad front-to-back patterning was still there, but this particular difference had flattened out.

Other researchers have reported the same flattening in donated brain tissue from people with autism; the usual gap in SOX4 and SOX11 levels between the cortex's front and back is smaller than expected.

The findings do not show that disrupted brain patterning causes autism. Instead, they highlight a potential developmental process that researchers can now investigate in a human tissue model with greater spatial detail.

A more human-relevant model of brain development

The potential applications extend beyond fragile X syndrome.

In addition, the platform contributes to growing efforts to develop human tissue-based research models that can complement animal studies. Because important aspects of human brain development differ from those of other species, stem cell-derived organoids can provide researchers with another way to investigate processes that are difficult to study directly in people or reproduce in animals.

The researchers say the approach could be used to examine how genetic and environmental factors affect different regions of the developing cortex and, over time, help scientists probe disease mechanisms and potential therapeutic strategies.

Watanabe's lab at UC Irvine builds human brain organoid models to study brain development and neurological disease. It's part of a broader interdisciplinary effort at UC Irvine spanning anatomy and neurobiology, stem cell biology, developmental biology, tissue engineering, mathematics and computational approaches.

The research brought together investigators from UC Irvine's School of Medicine, School of Physical Sciences, Charlie Dunlop School of Biological Sciences, Sue & Bill Gross Stem Cell Research Center and NSF-Simons Center for Multiscale Cell Fate Research, along with a collaborator at the University of Pennsylvania.

Source:

University of California - Irvine

Journal reference:

https://www.sciencedirect.com/science/article/pii/S1934590926002742