Stanford Medicine researchers have successfully transplanted laboratory-grown human brain tissue into genetically engineered mice missing most of their cerebral cortex. Published September 16, in Nature, the study revealed that the human tissue expanded to occupy over 90 percent of the cortical space, forming functional connections with the animal’s nervous system.
Building Apallial Mice and Growing Cortical Organoids
The study, led by Stanford University neuroscientist Sergiu Pașca, bypassed a fundamental hurdle in neuroscience: human brain tissue cannot be easily studied inside a living human, while rodent brains differ substantially from human ones. According to Stanford Medicine, Sergiu Pasca serves as the Kenneth T. Norris, Jr. Professor II of Psychiatry and Behavioral Sciences, a member of Bio-X and the Wu Tsai Neurosciences Institute, the Bonnie Uytengsu and Family Director of the Stanford Brain Organogenesis Program, a CZ BioHub Investigator, and a science fellow of the Hoover Institution at Stanford. To solve this, researchers utilized skin cells reprogrammed into stem cells, coaxing them into three-dimensional clusters known as cortical organoids that mimic the structural and functional features of the developing human cerebral cortex.
However, prior attempts to transplant these organoids into newborn rodents ran into a major obstacle. Human neurons develop far more slowly than rodent neurons, meaning the host’s rapidly maturing native cortex typically crowded out the human tissue.
To remove that competitive disadvantage, the Stanford team genetically engineered mice so that most of the cerebral cortex and hippocampus never developed. According to Stanford Medicine, lead co-authorship for the study is shared by postdoctoral scholar Konstantin Kaganovsky, PhD; assistant professor of psychiatry and behavioral sciences Kevin Kelley, MD, PhD; neurosurgery instructor Tilo Gschwind, PhD; and medical student Paul Harary. These resulting apallial
mice possessed a vastly enlarged cavity in the brains.
Vast Expansion and Nervous System Integration
When researchers surgically placed human cortical organoids into the brains of 5–17-day-old apallial mouse pups, the outcome far exceeded prior laboratory models. Over the course of months, the human tissue expanded. By the three-month mark, more than 90 percent of the cortical tissue by volume was human-derived.
The grafted tissue did more than simply occupy space. It developed blood vessels, became electrically active, and extended projections all the way into the spinal cord, forming working connections with the surrounding mouse brain circuitry.
“The most important point is that these are still mice. They have a mouse nervous system, mouse sensory organs, and mouse subcortical structures. What is unusual is that most of the cortical tissue present in these animals is human-derived and that the human neurons grow, integrate, and form functional connections with the rest of the mouse nervous system.”
Sergiu Pașca, Stanford University
Emergence of Rare Human Cell Types
Inside the xenocortical mouse brains, the human cells displayed developmental milestones never before observed in isolated laboratory glassware. Stanford Medicine reported that the researchers were astonished to find, in these mice, an important nerve-cell type that hasn’t been previously glimpsed in laboratory culture and has been seen only in autopsied human brains.
Implications for Neurodevelopmental Disorders and Brain Injury
Pașca noted that the methodology should accelerate research into the biological causes of schizophrenia, epilepsy, cerebral palsy, and profound autism. Alison Singer, president of the Autism Science Foundation, emphasized the severe burden of such conditions, noting that one in every 218 American children meets the criteria for profound autism, requiring round-the-clock supervision and assistance with daily activities.