In a first step toward finding new treatments for neuropsychiatric disorders, self-organizing brain tissue from humans has been successfully transplanted into the nervous system of newborn rats.
The 3D organoids, created from Stem cellsIt is a simplified version of the human cortex. The cortex of each rodent is connected to the surrounding tissue and integrated to create a functional part of its brain. This allows for sensory perception activity.
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 conditions, such as psychiatric disorders, can be attributed to a psychiatric condition like Autism schizophreniaThese conditions are most likely to be unique to human beings, or are at least anchored in the unique human brain. “The human brain isn’t very accessible which has hindered our efforts to understand the biology of these conditions.”
Scientists discovered that brain cells could be grown from induced pluripotent (iPS) stem cells in 2008. 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.
The stem cells were then directed to become brain cells. Scientists then cultivated these cells to create organoids, which are brain-like tissues. These models could be used to examine the functions and development of brains, including the wrinkled outer cortex.
In vitro cortical organoids are not as useful as they could be. They are not connected to living systems so they don’t mature fully. This leaves researchers without the opportunity to see how they interact with other parts of the brain.
Additionally, scientists can’t see the behavioral effects of any defect a brain organoid might have in a dish. This is because psychiatric disorders can only be diagnosed by their behavior.
These hurdles were overcome by scientists who tried to implant human brain organoids into adult rats’ brains in an earlier research. The transplants failed because of the developmental mismatch. The organoids’ developing neurons couldn’t connect with the fully developed brain 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.
The human cortical organoids of the brain were first cultured in a dish and then transplanted into the somatosensory cortex of the rats. This is the area of the brain that receives and processes sensory information. These rats were then allowed to become adults for 140 more days. 6-12 Weeks).
The scientists then examined the rats. The scientists had genetically engineered organoids that respond to blue light simulation. This activates neurons when the blue light hits them. The stimulation of the human neurons took place while the rats were being taught to lick water spouts. Later, when the blue light was shone on the organoids, the rats would automatically lick – displaying a response not seen in control groups.
This suggested that the organoid could be functioning as part and parcel of the brain of a rat, and it could 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.
Three patients suffering from a genetic condition called “Genetic Disease” were used to cultivate brain cells. Timothy syndromeThey were also used to make some of the organoids. Timothy syndrome is a condition that affects the nervous system, heart, and digits. It can lead to early death.
After the behavioral tests were completed, the rats had to be killed and their brains taken out. The dissection allowed the researchers to examine the cellular integration of the organoids. They discovered that organoid neurons grew to be larger than in vitro neurons, and extended into rats’ brains, creating networks with the native rats neurons.
The Timothy syndrome-transplanted neurons showed less complex shapes and made different synaptic connections to the surrounding brain tissue than the control group. This is an entirely new discovery and cannot have been found in a brainorganoid in the dish.
The platform has its limitations but the team believes it can be a powerful tool to understand brain development and disease.
“Overall this in-vivo platform provides a powerful resource to supplement in vitro studies about human brain development, and disease.” The authors wrote in their paper.
“We expect that this platform will enable us to discover new circuit-level characteristics in patient-derived cell lines that were previously elusive, and to test new therapeutic strategies.”
The research was published in Nature.
