ABED AL FATTAH MANSOUR, SALK INSTITUTEMouse brains make nice homes for human brain organoids, researchers report today (April 16) in Nature Biotechnology.
Brain organoids, also known as mini-brains, are tiny clumps of brain
cells grown from stem cells that researchers are using to investigate
the neural underpinnings of autism and other neurological disorders. But
the organoids typically grow in culture for only a few months before
they die, limiting their usefulness as models of real brains.
Transplanting the three-dimensional clumps of human brain tissue into
the brains of mice allows the organoids to continue to develop,
sprouting life-sustaining blood vessels as well as new neuronal
connections, the new study reports. The work takes a step toward using
brain organoids to study complexities of human brain development and
disease that can’t be investigated with current techniques. Brain
organoid transplantation may even one day offer a treatment option for
traumatic brain injury or stroke.
“Although organoids are a great advance in human neuroscience, they are
not perfect. They are missing blood vessels, immune cells and
functional connections to other areas of the nervous system,” Jürgen Knoblich, a molecular biologist at the Institute of Molecular Biotechnology in Vienna who was not involved in the study, tells The Scientist by email. “The goal of the transplantation experiments is to show that integration with those other tissues is possible.”
Study coauthor Fred “Rusty” Gage,
a neuroscientist at the Salk Institute for Biological Studies in La
Jolla, California, and his colleagues first started thinking about the
health of brain organoids a few years ago when they began working with
the structures. Many cells in the center of the 3-D clump of tissue
would die, Gage tells The Scientist. “Those cells weren’t getting the blood and nutrients they needed to survive.”
As he thought about the problem, Gage was reminded of work he did in Sweden with neuroscientists Ulf Stenevi of the University of Gothenburg and Anders Björklund
of Lund University in the 1970s and 1980s: the researchers transplanted
neuronal rat tissue into cavities made in rats’ brains to see if the
tissue would grow. It did. Gage envisioned that each human brain
organoid would slip right into a tiny cavity made in a mouse’s brain. He
was right.
Gage’s team used human pluripotent stem cells to develop brain
organoids, which were grown in culture for 40 to 50 days. Then, the team
inserted the organoids into cavities made in mice’s retrosplenial
cortex—a region critical for movement and spatial learning. The mice had
“humanized” immune systems, Gage says, meaning that their immune cells
had been engineered not to attack human tissue. Around day 5 after
transplantation, blood vessels in the organoids could be detected using a
fluorescent dye, and by day 14 an extensive network of vessels had
grown deep within the human tissue graft. Levels of certain markers in
the organoids, such as NeuN+ and PSD95, also showed that the human
neural precursor cells were maturing into neurons and forming synapses
to connect to each other. At 90 days after implantation, the scientists
traced axons extending from the graft deep into the brains of the mice.
Calcium imaging also showed that the neurons in the organoid were not
firing sparsely, with isolated activity, as in cultured brain organoids,
but in synchronized patterns, suggesting an active neuronal network was
developing. Additionally, optogenetics experiments showed that the
organoids’ neurons were integrated into synaptic circuits in the mice’s
brains.
“The ultimate test of functionality of an organoid is to show that it can integrate into a host,” molecular geneticist Hans Clevers of the Hubrecht Institute in Utrecht, the Netherlands writes in an email to The Scientist.
Clevers, who was not involved in the study, and others have shown such
functionality of “relatively simple organoids,” such as intestinal
epithelium, liver, or pancreas tissue. But, he says, mini-brains are “by
far the most complex structures that have been grown as organoids.”
Gage and his colleagues “provided evidence that blood vessel- and
neuronal connection are created extensively between the grafted
‘mini-brain’ and the mouse brain,” he adds.
The result, he notes, confirms what he finds “the most amazing
phenomenon of organoids—their almost unstoppable drive to reach ever
increasing levels of self-organization.”
Such organization is why researchers want to study organoids,
specifically cerebral ones, in vivo. “The function of the brain arises
not just from interactions between individual neurons but also from the
combined activity of groups of neurons arranged in specific structures,”
neurosurgeon Isaac Chen of the University of Pennsylvania who not involved in the study, tells The Scientist
by email. “In cell culture, this structure does not exist, and thus
there are inherent limitations to what types of experiments can be
performed and what conclusions can be drawn.” Studies of the brains of
model organisms do allow for investigations of how brain activity arises
from groups of neurons and how different groups of neurons interact
with each other. But, he says, significant species differences limit
generalizing the results to the human brain.
Implantable brain organoids could allow researchers to learn more about
normal human brain development over time, Chen says. Organoids derived
from patients with specific diseases could also be transplanted to
create more accurate models of those diseases. And the existence of a
workable transplantation method could allow scientists to study the
advantages and limitations of using brain organoids as a treatment
option to replace tissue lost or damaged by traumatic brain injury,
stroke, and other neurological conditions.
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