A new study by researchers at UCLA and Stanford University has found that three-dimensional “mini-brain” organelles derived from stem cells can mature in a way that is strikingly similar to human brain development.
For a new study, published in Nature Neuroscience February 22, senior authors dr. Daniel Geschwind of UCLA et al. Sergio Pasca of Stanford University conducted an extensive genetic analysis of organoids grown for up to 20 months in a laboratory vessel. They found that these 3D organelles track the internal clock that keeps them maturing in sync with the timeline of human development.
“This is new – so far no one has grown and characterized these organoids during this time, nor has it been shown that they will in most cases recapitulate the development of the human brain in a laboratory environment,” said Geschwind, Ph.D. Med., Distinguished Professor MacDonald of Human Genetics at the School of Medicine David Geffen at UCLA, member of Eli and Edythe Extensive Center for Regenerative Medicine and Stem Cell Research at UCLA, and senior associate dean and associate vice rector and director of the Institute of Precision Health at UCLA.
“This will be an important stimulus for the field. We have shown that these organoids can mature and replicate many aspects of normal human development – making them a good model for studying human diseases in food,” he said.
Organoids of the human brain are created by induced pluripotent stem cells, also known as iPS cells, which are derived from skin or blood cells that are reprogrammed back into an embryonic stem cell-like state, allowing scientists to create any type of cell.
These iPS cells are then exposed to a specialized mixture of chemicals that affect them to create a cell in a specific part of the brain. Over time and in the right conditions, cells self-organize to create 3D structures that faithfully replicate several aspects of human brain development.
Organoids derived from human stem cells have the potential to revolutionize medical practice by providing researchers with an unprecedented insight into how complex organs – including the brain – develop and respond to disease.
For several years, researchers have been cultivating human brain organoids to study human neurological and neurodevelopmental disorders, such as epilepsy, autism and schizophrenia.
The usefulness of these models is hampered by the widespread belief that the cells that make up these organelles remain stuck in a developmental state analogous to cells seen in fetal development. The study shows that it may be possible for cells to grow to maturity, which will allow scientists to better study adult diseases, such as schizophrenia or dementia.
There is a huge interest in human stem cell models. This paper represents an important milestone showing which aspects of human brain development are modeled with the greatest fidelity and which specific genes behave well in vitro and when they are best modeled. Equally important, we provide a framework based on unbiased genomic analyzes to assess how well in vitro models model development and function in vivo. “
Geschwind, dr. Med., Distinguished Professor MacDonald, Human Genetics, David Geffen School of Medicine, UCLA
The authors also provide a tool called GECO that allows researchers to search for their genes of interest to measure fidelity between the in vitro and in vivo brains.
“We show that these 3D brain organoids follow the internal clock, which progresses in the laboratory environment in parallel with what happens in a living organism,” said the first author, Dr. Aaron Gordon, post-doc at the Geschwind Laboratory at the David Geffen School of Medicine at UCLA. “This is a remarkable discovery – we show that they reach postnatal maturity in about 280 days in culture, after which they begin to model aspects of the child’s brain, including known physiological changes in neurotransmitter signaling.”
University of California, Los Angeles (UCLA), Health Sciences
Gordon, A., and others. (2021) Long-term maturation of human cortical organelles coincides with key early postnatal transitions. Nature Neuroscience. doi.org/10.1038/s41593-021-00802-y.