Three magic words can be used to stimulate the growth of human nerve cells in a laboratory: location.
In lab dishes, many experiments have been done to grow nerve cells from humans. But a new study enlists some real estate that’s a bit more unconventional: the brain of a rat. Implanted clusters containing human Neurons grow larger and more complexResearchers report online on October 12th that their cohorts grew in dishes more than they did in dishes Nature.
However, the functionalities of human cells are not limited to this. The implanted human cells can both receive signals from rat cells and influence the rats’ behavior, connections that “demonstrate more substantial integration of the transplanted neurons,” says Arnold Kriegstein, a developmental neuroscientist at the University of California, San Francisco, who wasn’t involved in the study. “This is a significant advance.”
Scientists have created increasingly complex brain organoids over the past decade. These 3-D clusters are derived from stem cells, which grow and produce new cells. You can imitate the human brain (SN: 2/20/18). These organoids don’t re-create the full complexity of human neurons that develop in an actual brain. But they can be windows into an otherwise inscrutable process — human brain development, and how it can go awry (SN: 9/3/21). “Even if they’re not entirely perfect, [these models] are surrogates for human cells in a way that animal cells are not,” Kriegstein says. “And that’s really exciting.”
Sergiu Pasca, a Stanford School of Medicine neuroscientist, and his colleagues implanted human cerebral brain organoids in the brains of newborn rats to push them closer to their full potential. They began to grow together with their hosts. Three months later, the organoids were about nine times their starting volume, ultimately making up about a third of one side of the rat’s cortex, the outer layer of the brain. “It pushes the rat cells aside,” Pasca says. “It grows as a unit.”
These human cells flourished because rats’ brains offer perks that lab dishes can’t, such as blood supply, a precise mix of nutrients and stimulation from nearby cells. This environmental support coaxed individual human neurons to grow bigger — six times as large by one measure — than the same sort of cells grown in dishes. The brains of rats were more complex than those grown in dishes, with more intricate branching patterns and synapses.
Pasca and his coworkers wanted to see if the cells were more mature. The electrical properties of implanted neurons performed more like cells in the human brain than cells in dishes when tested.
These neurons developed connections with their host cells in rat brains over months. The organoids of human were placed in the somatosensory cortex, which is a part the brain responsible for handling whisker input. Some of the cells in the human body responded to researchers’ attempts to blow air at their whiskers.
What’s more, the human cells could influence the behavior of the rat. Further experiments revealed that the researchers had genetically modified the organoids to respond with blue light. The neurons responded to a flashing light and sent signals. Researchers then rewarded them with water. The rats began to learn to move to the water spout from signals sent by their human organoid cell.
In behavioral tests, rats with human implants didn’t show signs of higher intelligence or memory; in fact, researchers were more concerned with deficits. The human organoids were nudging out their hosts’ brains, after all. “Will there be memory deficits? Will there be motor shortages? Will there be seizures?” Pasca asked. But after extensive tests, including behavior tests, EEGs and MRIs, “we could not find differences,” Pasca says.
Another experiment used nerve cells taken from Timothy syndrome patients, which is a severe developmental disorder that impairs brain growth. Growing organoids created with these patients’ cells in rats’ brains might reveal differences that other techniques would not, the researchers reasoned. The researchers found that neurons in these organoids displayed fewer complex message-receiving and transmitting dendrites than organoids derived from patients without the syndrome.
Pasca claims that organoids made of patient-specific cells could be used to test treatments. “Challenging disorders will require bold approaches,” he says. “We will need to build human models that recapitulate more aspects of the human brain to study these uniquely human conditions.”
