Self-organizing
lumps of human brain tissue grown in the laboratory have been
successfully transplanted into the nervous systems of newborn rats in a
step towards finding new ways to treat neuropsychiatric disorders.
The 3D organoids, developed from stem cells to
resemble a simplified model of the human cortex, connected and
integrated with the surrounding tissue in each rat's cortex to form a
functional part of the rodent's own brain, displaying activity related
to sensory perception.
This,
according to a team of researchers led by neuroscientist Sergiu Pașca
of Stanford University, overcomes the limitations of dish-grown
organoids, and gives us a new platform for modeling human brain
development and disease in a living system.
"Most
of the work that my lab has been doing has been motivated by this
mission of trying to understand psychiatric disorders at the biological
level so that we can actually find effective therapeutics," Pașca
explained in a press briefing.
"Many of these psychiatric conditions, such as autism and schizophrenia,
are likely uniquely human, or at least, they are anchored in unique
features of the human brain. And the human brain has certainly not been
very accessible, which has precluded the progress we've been making in
understanding the biology of these conditions."
In
2008, scientists made a breakthrough: brain cells grown from induced
pluripotent stem cells. Mature cells harvested from adult humans were
reverse engineered (or induced) to return them to the 'blank' state of
stem cells – the form cells take before they grow into cells with
specializations, such as skin cells or cardiac cells.
These
stem cells were then guided to develop into brain cells, which
scientists cultivated to form lumps of brain-like tissue called
organoids. These models of key areas of brain anatomy, such as the
wrinkled outer cortex, could be used to study functions and development
of brains up close.
As
useful as they are, in vitro cortical organoids have limitations.
Because they aren't connected to living systems, they don't complete
maturation, depriving researchers of an opportunity to observe how they
integrate with other major parts of a brain.
In
addition, a brain organoid in a dish can't reveal the behavioral
consequences of any defects scientists might identify. Since psychiatric
disorders are defined by behavior, this stymies the ability to identify
the physiological characteristics of these disorders.
In
previous research, scientists have tried to overcome these hurdles by
implanting human brain organoids into the brains of adult rats. Because
of the developmental mismatch, the transplants didn't take: the
developing neurons in the organoid couldn't form a strong connection
with the fully developed network of an adult rat brain.
So
Pașca and his colleagues tried something else: grafting the human brain
tissue onto the brains of newborn rats, whose own brains have not yet
developed and matured.
Human
cortical organoids were cultured in a dish, and then transplanted
directly into the somatosensory cortex (the area of the brain
responsible for receiving and processing sensory information) of rat
pups just a few days old. These rats were then left to grow into adults
for another 140 days (rats are fully sexually mature between 6 and 12 weeks).
Then,
the scientists studied the rats. They had genetically engineered the
organoids to respond to blue light simulation, activating neurons when
blue light is shone on them. This stimulation on the human neurons was
performed while the rats were being trained to lick a spout to receive
water. Later, when the blue light was shone on the organoids, the rats
would automatically lick – displaying a response not seen in control
groups.
This indicated that not only was the organoid functioning as part of the rat brain, it could help drive reward-seeking behavior.
Another
group of neurons in the organoid showed activity when the scientist
pushed the rats' whiskers – evidence that the neurons can respond to
sensory stimulation.
Brain cells cultivated from three human patients with a genetic disease called Timothy syndrome were
also used for some of the organoids. Timothy syndrome affects the
heart, digits and nervous system, and usually results in early death.
After
the behavioral tests, the rats were euthanized and their brains
extracted and dissected, allowing the researchers to observe the
integration of the organoids on a cellular level. They found the
organoid neurons grew much larger than any neurons grown in vitro,
extending into the rats' brains and forming networks with the native rat
neurons.
The
neurons in the rats with Timothy syndrome transplants showed less
elaborate shapes, and formed different synaptic connections with the
surrounding brain tissue compared to control groups. This is a new
discovery, and could not have been discovered in a brain organoid in a
dish.
Although
the platform still has some limitations, the team believes that it has
the potential to become a powerful new tool for understanding brain
development and disease.
"Overall,
this in vivo platform represents a powerful resource to complement in
vitro studies of human brain development and disease," the authors write in their paper.
"We
anticipate that this platform will allow us to uncover new
circuit-level phenotypes in patient-derived cells that have otherwise
been elusive and to test novel therapeutic strategies."
The research has been published in Nature.