Human neurons have survived transplantation and integrated into the brains of young rats, building a new model to study human brain development.
Published in Nature, researchers at Stanford University grew human brain organoids from induced pluripotent stem cells and successfully transplanted them into the brains of rat pups. Cells from the rats migrated into the transplant and the transplanted human neurons were able to integrate into the rat neuronal circuitry, responding to environmental cues and influencing behaviour.
Lead author Professor Sergiu Pașca, from Stanford University, California, said, 'We can now study healthy brain development as well as brain disorders understood to take root in development in unprecedented detail, without needing to excise tissue from a human brain.'
Growing brain organoids in a dish provides a method to study brain development, however, a lack of blood supply and external input limits their growth and maturation. In this study, the transplanted cells grew six times larger and displayed more sophisticated dendritic branching patterns than those that remained in vitro.
Building on this, the team transplanted brain organoids derived from people with Timothy syndrome, a genetic disorder linked with autism and epilepsy. Despite growing within the rat brain, Timothy syndrome neurons were smaller with fewer dendritic branches.
'We've learned a lot about Timothy syndrome by studying organoids kept in a dish,' Professor Pașca said. 'But only with transplantation were we able to see these neuronal-activity-related differences.'
Furthermore, the team were able to show that the transplanted neurons received sensory input from the rats' whiskers. When the whiskers were stimulated with puffs of air, the human neurons electrically responded in synchrony with the air puffs.
The integrated neurons were also able to control rat behaviour. Before transplantation, the neurons were modified to become electrically active under blue laser light. Then, using Pavlovian conditioning techniques, blue light was pulsed to the neurons just before water was provided to the rats. After 15 days of Pavlovian conditioning, stimulating the neurons with blue light caused the rats to run to the drinking spout, suggesting that activation of the neurons triggered the drinking behaviour.
'This work has increased our confidence in that human organoids, complex tissues grown in a laboratory dish from stem cells, have the potential to revolutionise brain research' said Dr András Lakatos, neuroscientist and neurologist at the University of Cambridge, who was not involved in the study.
However, ethical concerns have been raised about mixing human and animal brain tissue. '... how such research should be overseen, and to the procurement of human biomaterials and donor consent... [and] whether an organoid can have consciousness and moral status.' Dr Grey Camp and Dr Barbara Treutlein from the University of Basel, Switzerland, wrote in Nature. 'Active discourse between researchers, bioethicists, regulators and the public are required to develop frameworks and boundaries for research that uses organoids to model the circuitry of the human brain.'
Sources and References
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Human brain cells transplanted into rat brains hold promise for neuropsychiatric research
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Maturation and circuit integration of transplanted human cortical organoids
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Scientists Spliced Human Brain Tissue Into The Brains of Baby Rats
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In a novel experiment, brain-like human tissue implanted in rat brains influenced the rodents' behavior
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In a first, researchers integrate and grow human cells in newborn rat brains
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Lab-Grown Human Cells Form Working Circuits in Rat Brains
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