Human brain organoids implanted into mice that were engineered to lack more than 90 percent of their cerebral cortex restored most of the animals' cognitive and motor function, according to research published in Nature. The work, led by Sergiu Pașca at Stanford University in California, offers a new way to study human brain development and conditions such as cerebral palsy, epilepsy, schizophrenia and rare forms of dementia.
The team genetically engineered mice to develop without most of their cortex, the region responsible for memory, movement and thinking. Because the rodent brain adapts to compensate for the missing tissue, these animals, which the researchers call apallial mice, showed only partial memory and movement deficits rather than a complete loss of function.
In about half of the animals, the scientists surgically implanted four human brain organoids — tiny, lab-grown versions of the human cerebral cortex. The organoids were generated by bathing human stem cells in chemicals for roughly 40 days. Once implanted, they filled the cavity in each mouse's skull, producing what the team designated XCX mice. The remaining mice received no transplants.
A few months later, the apallial mice performed worse than normal mice on a memory test that required navigating a maze. In the XCX mice, that deficit was almost completely reversed. The transplanted animals also displayed a gait that fell between the unsteady movement of apallial mice and the normal stride of intact mice.
Scans showed that the organoids had grown into cortex-like grafts. «Half the volume of the brain is [initially] gone, and now largely 90 percent of that missing volume is covered by human cells,» Pașca said. The grafts were the first of their kind to contain von Economo neurons, a cell type linked to social skills, as well as neurons extending from the cortex to the spinal cord — a connection that may explain the improvements in motor skills.
Gabriel Balmuș at the University of Cambridge, who was not involved in the study, said the results were striking. «The mouse is [relatively] sick without a cortex, then you transplant these organoids in, and it behaves more like the normal mouse,» he said. He noted that the organoids were larger and more similar to the human cerebral cortex than those used in earlier experiments.
Previous studies had implanted human brain organoids into rat or mouse brains, but without removing such a large portion of the rodent brain beforehand. Those experiments showed that organoids could alter cognition rather than improve it. In one case, light stimulation prompted rats with human organoids to anticipate water.
The new work also demonstrated that the transplanted mice responded to hypoxia, or low oxygen levels, in a way that resembles the human response. Mice are naturally resilient to low oxygen because they evolved living underground, making this response difficult to replicate in ordinary rodents. Balmuș said the model could therefore offer a better way to study cerebral palsy, a movement disorder that can be caused by hypoxia around birth.
Not all researchers were convinced the grafts fully replicate cortical architecture. Jürgen Knoblich at the Institute of Molecular Biotechnology in Vienna said the organoids still lack the proper arrangement and structure of the cortex. «It's a bit of a mishmash of neurons» and other cells, he said. «Most of the cell types are there, but they're not separated into regions like in a normal cortex.»
Knoblich also raised ethical considerations surrounding experiments that place human brain tissue in animals. Such mice «deserve the same kind of protection that we ascribe to any animal experiment,» he said, including assurances against unnecessary pain and suffering and a match between experimental risk and medical benefit. He said the latest study met that standard.
A common concern is whether mice carrying human brain organoids might develop human-like consciousness. «The data so far doesn't say that putting [a human organoid] in makes the mouse smarter or more conscious than a normal mouse,» Knoblich said. «It's similar to taking a wheel from a car and putting it on a tree and saying that's a car.»
The researchers hope the approach will shed light on schizophrenia, epilepsy, intellectual disability and rare dementias, and eventually support the development of new treatments. The study appears in the journal Nature.