A new study from UCLA and Stanford University researchers finds that three-dimensional human stem cell-derived ‘mini brain’ organoids can mature in a manner that is strikingly similar to human brain development.
For the new study, published in Nature
Neuroscience February 22, senior authors Dr. Daniel Geschwind
of UCLA and Dr. Sergiu Pasca of Stanford University conducted 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 — 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,” said Geschwind, MD, PhD, MacDonald
Distinguished Professor in Human Genetics at the David Geffen School of
Medicine at UCLA, member of the Eli and Edythe Broad Center of Regenerative
Medicine and Stem Cell Research at UCLA, and the senior associate dean and
associate vice chancellor and director of the Institute for Precision Health at
UCLA.
“This will be an important
boost for the field. We’ve shown that these organoids can mature and replicate
many aspects of normal human development — making them a good model for
studying human disease in a dish,” he said.
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 allowing scientists to create any cell type.
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 utility of these models
has been hindered by the widespread belief that the cells that make up these
organoids remain stuck in a developmental state analogous to the cells seen in
fetal development. The study shows that it may be possible to grow the cells to
a maturity that will allow scientists to better study adult-onset diseases,
such as schizophrenia or dementia.
“There is huge interest in
stem cell models of human disease,” Geschwind added. “This work represents an
important milestone by showing which aspects of human brain development are
modeled with the highest fidelity and which specific genes are behaving well in
vitro and when best to model them. Equally important, we provide a framework
based on unbiased genomic analyses for assessing how well in vitro models model
in vivo development and function.”
The authors also provide a
tool called GECO that allows researchers to browse their genes of interest for
measuring fidelity between in vitro and in vivo brain.
“We show that these 3D brain
organoids follow an internal clock, which progresses in a laboratory
environment in parallel to what occurs inside a living organism,” said first
author Aaron Gordon, PhD, a post doc in The Geschwind Lab at the David Geffen
School of Medicine at UCLA. “This is a remarkable finding — we show that they
reach post-natal maturity around 280 days in culture, and after that begin to
model aspects of the infant brain, including known physiological changes in
neurotransmitter signaling.”
Source: https://www.uclahealth.org/
Journal article: https://www.nature.com/articles/s41593-021-00802-y
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