Lab-grown brain models gain a sense of place

Understanding the development of the human brain, particularly its organization into distinct regions, has traditionally been a challenging endeavor. The cerebral cortex, the brain's outer layer, is not a uniform sheet but rather a complex structure divided into different areas, each with unique functions such as movement, vision, memory, language, and social understanding.

This process of dividing the cortex into specialized regions, known as arealization, is crucial for the brain's overall functionality and may also shed light on conditions that impact brain development.

Engineers have long drawn inspiration from the brain's self-organizing nature for applications in computing and robotics. However, the intricacies of brain development have been difficult to replicate in lab-grown models, especially since much of this patterning occurs before birth. The human brain demonstrates a sense of place even at early stages of development, with chemical signals guiding developing cells to their specific locations, contributing to the differentiation of areas at the front and back of the cerebral cortex.

Researchers at the University of California, Irvine have made a significant breakthrough by developing a new method to engineer lab-grown human brain tissue with defined regional identities. This innovation allows the creation of organoids, small three-dimensional tissues grown from human stem cells, that mimic specific characteristics of either the front or the back of the developing cerebral cortex.

This advancement, published in Cell Stem Cell, opens up new avenues for studying brain development and the effects of disruptions in this process associated with neurodevelopmental disorders.

Lead author Momoko Watanabe, an assistant professor of anatomy and neurobiology at UC Irvine, explains that by introducing regional identity into these models, scientists can now explore questions about development and disease that were previously challenging to address with conventional organoids. The cerebral cortex, responsible for various functions from movement and sensory processing to higher-level thinking, exhibits region-specific development during early stages.

Chemical signals contribute to a biological map that guides different regions toward distinct identities, a process that traditional organoids often overlook.

The UC Irvine team overcame this limitation by exposing developing organoids to specific signals during their early growth, enabling them to steer the organoids toward characteristics associated with either the front or the back of the cortex. Upon examination, the researchers found that these organoids reproduced molecular characteristics associated with different regions of the prenatal human cortex.

Essentially, they provided lab-grown cortical tissue with a biological compass, establishing a reproducible sense of front or back.

In their investigation, the team explored fragile X syndrome, a genetic condition linked to intellectual disability and autism spectrum disorder. By comparing organoids from individuals without the condition to those modeling fragile X syndrome, they discovered that two crucial proteins, SOX4 and SOX11, exhibit differing levels in front and back tissue.

In the organoids of individuals with fragile X syndrome, this distinction became less pronounced. Although the study does not establish a direct cause-and-effect relationship between disrupted brain patterning and autism, it highlights a potential developmental process that can now be investigated in a more spatially detailed human tissue model.

The implications of this research extend beyond fragile X syndrome. Neurological and neurodevelopmental disorders often manifest differently across various parts of the brain. By endowing organoids with defined regional characteristics, researchers can now study not only the changes associated with a disorder but also the emergence of these changes during development.

Additionally, this approach contributes to the growing field of human tissue-based research models, complementing animal studies. As brain development is unique to humans, stem cell-derived organoids offer a means to investigate processes that are difficult to study directly in people or replicate in animals. This could ultimately aid scientists in understanding the impact of genetic and environmental factors on different regions of the developing cortex, advancing our knowledge of complex brain disorders.