The use of human stem cell-derived organoids to study disorders has been hindered by the widespread belief that the cells that make up these self-organized three-dimensional tissue cultures remain stuck in a developmental state analogous to the cells seen in fetal development. But a new study from UCLA and Stanford University researchers finds that brain organoids can in fact mature in a manner that is strikingly similar to human brain development. The findings indicate that it may be possible to grow the organoid cells to a maturity that will allow scientists to better study adult-onset diseases such as schizophrenia or dementia.
Daniel Geschwind, MD (RES ’95, FEL ’97), PhD, Gordon and Virginia MacDonald Distinguished Professor in Human Genetics and director of the Institute for Precision Health at UCLA, and collaborators at Stanford conducted an extensive genetic analysis of organoids that had been grown for up to 20 months in a lab dish. They found that these 3D organoids follow an internal clock that guides their maturation in sync with the timeline of human development.
“This is novel,” Dr. Geschwind says. “Until now, nobody has grown and characterized these organoids for this amount of time, nor shown they will recapitulate human brain development in a laboratory environment, for the most part.”
Human brain organoids are created using induced pluripotent stem cells, also known as iPS cells, which are derived from skin or blood cells that have been reprogrammed back to an embryonic stem cell-like state. These iPS cells are then exposed to a specialized mix of chemicals that influences them to create the cell of a certain region of the brain. With time and the right conditions, the cells self-organize to create 3D structures that faithfully replicate several aspects of human brain development.
Human stem cell-derived organoids have the potential to revolutionize the practice of medicine by giving researchers unprecedented insights into how complex organs — including the brain — develop and respond to disease. For several years, researchers have been growing human brain organoids to study human neurological and neurodevelopmental disorders, such as epilepsy, autism and schizophrenia.
The study reveals “that these 3D brain organoids follow an internal clock, which progresses in a laboratory environment in parallel to what occurs inside a living organism,” says Aaron Gordon, PhD, a post doc in Dr. Geschwind’s lab. “We’ve shown that these organoids can mature and replicate many aspects of normal human development,” Dr. Geschwind says, “making them a good model for studying human disease in a dish.”
— Marrecca Fiore
“Long-term Maturation of Human Cortical Organoids Matches Key Early Postnatal Transition,” Nature Neuroscience, February 22, 2021