Cerebral Organoids Grown From Stem Cells Offer a New Way to Study the Human Brain
Material below is adapted from the SfN Short Course Generating 3D Cerebral Organoids From Human Pluripotent Stem Cells to Model Cortical Development and Disease, by Paola Arlotta, PhD. Short Courses are daylong scientific trainings on emerging neuroscience topics and research techniques held the day before SfN’s annual meeting.
The human brain is a complex organ, and the most sophisticated part of it may be the cerebral cortex. Composed of billions of cells, multiple structural layers, and several different types of tissue, the cortex houses a diverse array of brain cell types, including nerve cells and supporting cells, or glia. In humans, the cortex processes information related to higher-order functions, such as thinking, sensory perception, and language.
This complexity has made understanding how the human cortex develops and works a difficult task for neuroscientists. The latest breakthrough involves growing human brain-like structures from stem cells in the laboratory. These cerebral organoids are a powerful investigative tool for understanding how healthy brains develop as well as where problems arise in neurological disorders.
Model animals like mice have been used to study brain growth. But mouse brains differ significantly from human brains in development, structure, and function. Cerebral organoids grown from human stem cells provide a new way of understanding the human brain. Researchers can model human brain development, opening a window into how nerve cells grow and function and increasing our understanding of both basic brain activities and neurological disorders.
A cerebral organoid starts off as a single cell taken from an adult. With the right nutrients and environment, that cell returns to stem cell-like state, able to differentiate into any kind of specialized cell in the body. These “reprogrammed” cells are called induced pluripotent stem cells (iPSCs). Under the right conditions, iPSCs can be coaxed to turn into brain cells. And when grown under appropriate conditions, these cells spontaneously organize themselves into complex, three-dimensional structures resembling the human brain in the first trimester of development.
Emerging data suggest cerebral organoids mimic aspects of the developing embryonic brain, including generating cell types and specialized layers of tissue unique to human brains. The organoids’ development in the laboratory recapitulates some of the properties of real-life human brain development. They are not quite “brains in a dish,” but they allow scientists to study normal growth as well as causes of and treatments for brain disorders.
For instance, researchers used cerebral organoids to study microencephaly. This is a condition characterized by an abnormally small brain, and it cannot be replicated in mouse models. Scientists used cells from a patient with microencephaly to grow a cerebral organoid that shared characteristics with the patient’s brain. They discovered that the cause of the disease could be related to a reduction in early neural stem cell populations along with premature neural differentiation.
Cerebral organoids have also been used to study neurodevelopmental defects in severe idiopathic autism spectrum disorder. Again, cells were taken from patients and turned into iPSCs, which then differentiated into brain cells. The patients had a type of autism associated with macrocephaly, an abnormally large brain. Researchers found that the dysregulation of a single gene, FOXG1, caused an over-production of specific nerve cells, and this may be one of the causes of autism with macrocephaly. This study demonstrates the power of cerebral organoids to not only uncover key mechanisms in neurodevelopmental disorders, but also to reveal targets for future treatments.
Many neuroscientists seek to understand how the human brain grows from just a few cells into the most complex organ known. Cerebral organoids offer a glimpse into this process. They are making it possible to ask questions and perform studies that were previously impossible. Now, researchers can watch how networks of living human brain cells develop and work as well as accurately model a wide range of neurological diseases.
