Human Brain Tissue Takes Over Mouse Cortex in Novel Disease-Research Model

Scientists have engineered mice with a remarkable capacity for housing human brain tissue.

By genetically modifying animals that were born without most of their cortex, researchers created a living model in which pea-sized clusters of human neurons could expand, mature, and integrate into a developing nervous system — ultimately coming to dominate the mouse cortex, the brain’s outer layer.

The model offers a new way to study human neural circuits and brain disease, researchers reported September 16 in Nature.

After the transplant, the growing human neurons (green and red) form connections with the surrounding mouse brain (blue). S. Pasca lab, Stanford University

“Our goal has been to make aspects of human brain development and function accessible for investigation, so we can develop therapeutics,” says Sergiu Pașca, a neuroscientist at Stanford University.

The concept of cultivating miniature brain structures in a lab dish emerged in the early 2010s, when researchers in Austria demonstrated that stem cells could self-organize into three-dimensional tissue resembling aspects of the developing human brain. However, these small clusters of human nerve cells, known as organoids, lacked the connections and sensory inputs of a living brain.

In 2022, Pașca and his colleagues developed a method for transplanting human organoids into newborn rats, eventually coaxing the human cells to comprise roughly one-third of one side of the rat’s cortex. But rat neurons mature more quickly than their human counterparts, limiting how much the human tissue could develop in that rodent model.

Pașca and his colleagues then bred mice genetically engineered to develop without most of their cortex and the neighboring hippocampus — two structures involved in movement, learning, and memory that together account for about half of the brain’s total volume. Although the resulting animals exhibited some behavioral defects, they were “surprisingly functional,” Pașca says.

The spacious cavity left by the missing tissue proved capable of accommodating human brain organoids grown from healthy donor stem cells. The transplantation succeeded in 25 of 29 attempts.

Over the following three months, the human tissue expanded nearly fivefold in volume in these mice, ultimately filling more than 90 percent of the cortex. The tissue differentiated into a range of cell types, including rare neurons that have been nearly impossible to generate in a dish. While the tissue lacked some hallmarks of a mature cortex — including its characteristic layered structure — it still wired extensively into the mouse nervous system, providing a platform for studying human neural circuits that have gone awry.

The researchers used the mice to model cerebral palsy, a disability caused by damage to the developing brain. They subjected the grafted animals to oxygen deprivation. Afterward, the human tissue displayed cellular signs of injury, and the mice developed problems with gait and limb coordination — features that mirror the condition in humans.

“This could be used down the line to test many therapeutics that are being considered for cerebral palsy,” Pașca says. He plans to investigate frontotemporal dementia and genetic forms of autism using the mice, employing organoids derived from patient cells affected by those conditions.

The technique “is certainly bold,” says H. Isaac Chen, a neurosurgeon at the University of Pennsylvania who studies brain organoids but was not involved in the research. The extent of humanization raises questions about the ethical boundaries of such experiments, Chen notes, but Pașca has gone to unusual lengths to address those concerns. “He has done a lot more than others in terms of not just holding these discussions but actually driving them,” Chen says.

Pașca, for example, consulted an outside panel of experts led by Insoo Hyun, a bioethicist at the National University of Singapore Yong Loo Lin School of Medicine. Hyun acknowledges that this new mouse model raises legitimate questions about where to draw the ethical line, but says there is little evidence that these mice have crossed it.

What matters, he says, is not how much human tissue an animal contains, but what that tissue enables it to do. On tests of fine motor control and memory, the grafted mice performed between that of mice with intact brains and those lacking a cortex. “From a secular ethical point of view,” Hyun says, “it boils down to cognitive capacity” — and so far, these mice do not appear to have gained any obvious extra brainpower.

That may be a relief to anyone picturing the lab mice from Animaniacs, the genetically enhanced rodents who spend each night plotting to take over the world. In Pașca’s lab, there is little evidence of any plans for global domination. His mice, despite their predominantly human-derived cortex, remain far more Pinky than Brain.

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