Organoid experts at Cincinnati Children's,
Mayo Clinic and UC San Diego overcome major hurdle in modeling
brain development—opening new doors for disease research and drug
development
CINCINNATI, May 20, 2024
/PRNewswire/ -- In a pioneering achievement, a research team led by
experts at Cincinnati Children's have developed the world's first
human mini-brain that incorporates a fully functional blood-brain
barrier (BBB).
This major advance, published May 15,
2024, in Cell Stem Cell, promises to accelerate the
understanding and improved treatment of a wide range of brain
disorders, including stroke, cerebral vascular disorders, brain
cancer, Alzheimer's disease, Huntington disease, Parkinson's
disease, and other neurodegenerative conditions.
"Lack of an authentic human BBB model has been a major hurdle in
studying neurological diseases," says lead corresponding author
Ziyuan Guo, PhD. "Our breakthrough
involves the generation of human BBB organoids from human
pluripotent stem cells, mimicking human neurovascular development
to produce a faithful representation of the barrier in growing,
functioning brain tissue. This is an important advance because
animal models we currently use in research do not accurately
reflect human brain development and BBB functionality."
What is the blood-brain barrier?
Unlike the rest of our bodies, blood vessels in the brain
feature an extra lining of tightly packed cells that sharply limit
the size of molecules that can pass from the bloodstream into the
central nervous system (CNS).
A properly functioning barrier maintains brain health by
preventing the entry of harmful substances while allowing essential
nutrients to reach the brain. However, that same barrier also
prevents many potentially helpful medicines from reaching the
brain. Also, several neurological disorders are caused, or
worsened, when the blood-brain barrier forms improperly or begins
breaking down.
Significant differences between human and animal brains have
resulted in many hopeful new drugs that were developed relying
heavily on animal models to fail later when tested in human study
participants.
"Now, through stem cell bioengineering, we have developed an
innovative platform based on human stem cells that allows us to
study the intricate mechanisms governing BBB function and
dysfunction. This provides unprecedented opportunities for drug
discovery and therapeutic intervention," Guo says.
Overcoming a long-running challenge
Research teams worldwide have been racing to develop brain
organoids—tiny, growing 3D structures that mimic the early steps of
brain formation. Unlike cell types grown flat in a lab dish,
organoid cells are connected. They self-assemble into spherical
forms. Their cells "talk" to each other like human cells normally
do during fetal development.
Cincinnati Children's has been a leader in developing other
types of organoids, including the world's first functional
intestine, stomach and esophagus organoids. But until now, no
research center had succeeded at making a brain organoid that
features the special barrier lining found in human brain blood
vessels.
The research team calls their new model "BBB assembloids." Their
name reflects the advance that made the breakthrough possible.
These assembloids combine two distinct types of organoids: brain
organoids that replicate human brain tissue and blood vessel
organoids that mimic vascular structures.
The combination process began with brain organoids measuring 3
to 4 millimeters in diameter and blood vessel organoids about 1
millimeter in diameter. Over the course of about a month, these
separate structures fused into a single sphere measuring slightly
more than 4 millimeters in diameter (about 1/8 of an inch, or
roughly the size of a sesame seed).
These integrated organoids recreate many of the complex
neurovascular interactions observed in the human brain, but they
are not complete models of the brain. For example, the tissue does
not contain immune cells and there are no connections to the rest
of the body's nervous system.
Research teams at Cincinnati Children's have shown other
successes at merging and layering organoids from different cell
types to form more complex "next generation" organoids. Those
successes helped inform the new brain organoid work.
Importantly, the BBB assembloids can be grown using neurotypical
human stem cells or stem cells from people with specific brain
diseases, thus reflecting gene variants and other conditions that
can lead to a malfunctioning blood-brain barrier.
Initial proof of concept
To demonstrate the potential utility of the new assembloids, the
researcher team used a line of patient-derived stem cells to make
assembloids that accurately replicated key features of a rare brain
condition called a cerebral cavernous malformation.
This genetic disorder, which is characterized by dysfunctional
blood-brain barrier integrity, results in clusters of abnormal
blood vessels in the brain that often resemble raspberries in their
appearance. The disorder significantly increases risk of
stroke.
"Our model accurately recapitulated the disease phenotype,
offering new insights into the underlying molecular and cellular
pathology of cerebral vascular disorders," Guo says.
Potential applications
The co-authors envision a variety of potential uses of BBB
assembloids:
- Personalized Drug Screening: Patient-derived BBB assembloids
could serve as avatars to tailor therapies for patients based on
their unique genetic and molecular profiles.
- Disease Modeling: A number of neurovascular disorders,
including rare and genetically complex conditions, lack good model
systems for research. Success at making BBB assembloids could
accelerate development of human brain tissue models for more
conditions.
- High-Throughput Drug Discovery: Scaling up assembloid
production could allow more accurate, and more rapid analysis of
whether potential brain medications can effectively cross the
BBB.
- Environmental Toxin Testing: Often based heavily on animal
model systems, BBB assembloids could help evaluate the toxic
effects of environmental pollutants, pharmaceuticals, and other
chemical compounds.
- Immunotherapy Development: Through investigating the role of
the BBB in neuroinflammatory and neurodegenerative diseases, the
new assembloids could support delivering immune-based therapies to
the brain.
- Bioengineering and Biomaterials Research: Biomedical engineers
and materials scientists will likely benefit from having a lab
model of the BBB to test novel biomaterials, drug delivery
vehicles, and tissue engineering strategies.
"Overall, BBB assembloids represent a game-changing technology
with broad implications for neuroscience, drug discovery, and
personalized medicine," Guo says.
About the study
In addition to Guo, the co-first authors of the study were:
Lan Dao, MS, and Lu Lu, PhD, from Cincinnati Children's;
Tianyang Xu from UC San Diego; and
Zhen You from the Mayo Clinic.
Co-corresponding authors were Sheng
Zhong, PhD, from UC San Diego and L. Frank Huang, PhD, from the Mayo Clinic.
Co-authors from Cincinnati Children's also included Avijite
Kumer Sarkar, PhD, Hui Zhu, PhD,
George Yoshida, BA, Yifei Miao, PhD, Sarah
Mierke, MD, Srijan Kalva,
Mingxia Gu, MD, PhD, and
Sudhakar Vadivelu, MD. The Single
Cell Genomics Facility at Cincinnati Children's and the NIH
NeuroBioBank also provided key support to the research.
Guo and Dao have a pending patent application ("Vascularized
brain organoids having a CCM-like feature and methods of making and
use," U.S. Application no. 63/510,463) related to this research.
Zhong is a founder of Genemo, Inc.
View original content to download
multimedia:https://www.prnewswire.com/news-releases/groundbreaking-advance-in-brain-science-creating-human-blood-brain-barrier-assembloids-302150148.html
SOURCE Cincinnati Children's Hospital Medical Center