Organoids, which are becoming increasingly complex, provides rare glimpses into human brain development.
|An organoid made of human nerve cells (bright green) grows and connects with its host after being transplanted into a rat brain. UNIVERSITY OF STANFORD
There are three magic words that can coax human nerve cells to thrive in a laboratory: location, location, location.
In many experiments, human nerve cells are grown in lab dishes. A new study, however, enlists some unconventional real estate: the brain of a rat. Researchers report online October 12 in Nature that implanted clusters of human neurons grow larger and more complex than their dish-grown cohorts.
Furthermore, human cells appear to be functional, albeit in very limited ways. The implanted human cells can both receive and influence rat cell signals, demonstrating "more substantial integration of the transplanted neurons," according to Arnold Kriegstein, a developmental neuroscientist at the University of California, San Francisco, who was not involved in the study. "This is a significant step forward."
Scientists have been developing increasingly complex brain organoids, 3-D clusters of cells derived from stem cells that grow and mimic the human brain, over the last decade (SN: 2/20/18).
These organoids do not mimic the full complexity of human neurons as they develop in the brain. However, they can provide insights into an otherwise enigmatic process — human brain development and how it can go wrong (SN: 9/3/21). "Even if they're not perfect," Kriegstein says, "[these models] are surrogates for human cells in a way that animal cells are not." "And that is very exciting."
Sergiu Pasca, a neuroscientist at Stanford School of Medicine, and colleagues surgically implanted human cerebral organoids into the brains of newborn rat pups to bring these cells closer to their full potential. Human organoids began to develop alongside their hosts.
Three months later, the organoids had grown to about nine times their initial size, eventually covering about a third of one side of the rat's cortex, the brain's outer layer. "It pushes the rat cells aside," explains Pasca. "It grows as a group."
Because rats' brains provide benefits that lab dishes cannot, such as blood supply, a precise mix of nutrients, and stimulation from nearby cells, these human cells thrived. Individual human neurons grew six times larger as a result of the environmental support than the same type of cells grown in dishes. Rat brain cells were also more complex, with more elaborate branching patterns and more cell connections known as synapses.
|A human nerve cell from an organoid in a rat's brain (right) grew larger and more complex than a similar cell grown in a laboratory dish (left). UNIVERSITY OF STANFORD
The cells appeared more mature, but Pasca and his colleagues wondered if the neurons would behave similarly. Electrical properties tests revealed that implanted neurons behaved more like cells that develop in human brains than cells grown in dishes.
These human neurons connected with their rat host cells over months of growth. The human organoids were implanted in the somatosensory cortex of the rat brain, which is responsible for whisker input. Some human cells responded when researchers blew air into the whiskers.
Furthermore, the human cells may have an effect on the rat's behavior. The organoids were genetically modified to respond to blue light in subsequent experiments. The neurons fired signals in response to a flash of light, and the rats were rewarded with water. When their human organoid cells sent signals, the rats quickly learned to move to the water spout.
In behavioral tests, rats with human implants showed no signs of increased intelligence or memory; rather, researchers were more concerned with deficits. After all, the human organoids were nipping at their hosts' brains. "Will there be memory loss?" Will there be any motor issues? "Are there going to be seizures?" Pasca inquired. "We couldn't find differences" after extensive testing, including behavior tests, EEGs, and MRIs, according to Pasca.
In other experiments, nerve cells from people with Timothy syndrome, a severe developmental disorder that affects brain growth, were used. The researchers reasoned that growing organoids made from these patients' cells in rats' brains might reveal differences that other techniques would not. Neurons in these organoids had less complex message-receiving dendrites than neurons in organoids derived from people who did not have the syndrome.
Pasca believes that organoids created from patient-specific cells could one day serve as test subjects for treatments. "Challenging disorders will necessitate daring approaches," he says. "In order to study these uniquely human conditions, we will need to build human models that recapitulate more aspects of the human brain."
Maturation and circuit integration of transplanted human cortical organoids, O. Revah et al. Nature. Online since October 12, 2022. doi: 10.1038/s41586-022-05277-w.