To induce human nerve cells to thrive in the laboratory, there are three magic words: location, location, location.
Many experiments involve growing human cells in lab dishes. But a new study documents something real that’s a little more unlikely: brain muscle. Clusters of implanted human neurons are becoming larger and more complex than their cohorts grown on plates, researchers report online on October 12. nature.
Not only those, but human cells also appear to be useful, albeit in very limited ways. Implanted human cells can also receive signals from stem cells and influence the behavior of mice, connections that “demonstrate a more solid integration of transplanted neurons,” says Arnold Kriegstein, a neuroscientist at the University of California, San Francisco, who was involved in the study. “This is significant progress.”
Over the last decade, scientists have built increasingly complex brain organoids, 3-D clusters of cells derived from stem cells that mimic and mimic the human brain (SN: 2/20/18). These organoids recreate the full complex of human neurons that develop in the actual brain. But they can be windows into an otherwise inscrutable process – the development of the human brain and how it can diverge (SN: 9/3/21). “You’re not perfect though; [these models] surrogate human cells so that they are not animal cells,” says Kriegstein. “And this is really exciting.”
To push these cells closer to their full potential, Sergiu Pasca, a neuroscientist at the Stanford School of Medicine, and colleagues surgically implanted human brain organoids into the brains of young puppies. Along with their hosts, human organoids began to grow. After three months, the organoids began to increase their volume by about nine times, and finally they were about a third of the rats’ cortex, the outer covering of the brain. “The rat’s cells were thrown out,” Pasca says. “It grows as a unit.”
These human cells have flourished because they offer mouse brains perks that lab dishes can’t, such as a blood supply, a precise mix of nutrients and stimulation from nearby cells. This environmental support forced individual human neurons to grow six times larger by one measure – than the same cells grown in dishes. Rat cells in the brain have grown even more complex, with more elaborate branching patterns and more cellular connections called synapses.
The cells looked more mature, but Pasca and his colleagues wanted to know if the neurons also behaved in this way. Testing of the electrical properties showed that the implanted neurons behaved more like cells grown in human brains than cells grown on plates.
Over months of growth, these human neurons made connections with their host cells. Human organoids are implanted in the somatosensory cortex, the part of the rat brain that processes auditory input. When the researchers blew air into the whiskers, some of the human cells responded.
Human cells could also influence rat behavior. In further experiments, the researchers engineered a type of organoid to respond to blue light. Stimulated by a flash of light, neurons fired signals, and the researchers rewarded the mice with water. Soon, the mice learned to move in front of the water with organoids sending signals from the human cell.
In behavioral measures, mice with human implants did not show signs of higher intelligence or memory; in fact, the researchers were more concerned about defects. The organoids of human brains were baring their tracks after all. “Will there be memory deficits? Will there be motor deficits? Will there be seizures?” asked Pasca. But after extensive tests, including behavioral tests, EEGs and MRIs, “we couldn’t find any problems,” Pasca says.
Other experiments included nerve cells from people with a genetic disorder called Timothy syndrome, a severe developmental disorder that affects brain growth. Organoids grown with these patients’ cells in the brains of mice would show differences that the researchers could not account for using other techniques. Sure enough, the neurons in these organoids had less complex dendritic messages than those from organoids from people without the syndrome.
Organoids made from special patient cells will one day also be used as experimental subjects for treatments, says Pasca. “Challenging disruptions will require bold approaches,” he says. “We need to build human models that recapitulate many aspects of the human brain to study these uniquely human conditions.”
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