Human brain tissue grew to fill over 90% of missing cortex in mice

Stanford researchers have developed a groundbreaking method to study human brain development by transplanting lab-grown human brain tissue into specially engineered mice. The study, published in Nature, demonstrated that the human tissue not only survived but expanded to occupy over 90% of the cortical space in the mice, forming functional connections with the animal's brain and spinal cord.

The cerebral cortex, the outer layer of the brain responsible for complex thought, language, attention, and decision-making, has long been challenging to study due to the rarity of accessible human brain tissue. Previous animal models often failed to capture the unique features of the human cortex. To overcome this limitation, the Stanford team led by psychiatrist Sergiu Pasca spent over a decade perfecting the cultivation of three-dimensional clusters of human brain cells, called cortical organoids, derived from reprogrammed skin cells.

The researchers created a strain of mice with a genetic modification that prevented the formation of most of their neocortex and related structures. These "apallial" mice had only about 2% of the cortical tissue found in normal mice, creating a large cavity where the human organoids could be transplanted.

When the human cortical organoids, grown from healthy human donors, reached about two months old, they were surgically implanted into the brains of two-day-old apallial mouse pups. Over the following three months, the human tissue not only survived but thrived and expanded, occupying more than 90% of the cortical volume in the mice.

The human neurons extended projections, formed synapses, and integrated with the mouse's remaining brain regions and spinal cord, allowing them to perform broadly similarly to normal mice in behavior tests.

One of the most significant findings of this study was the emergence of von Economo neurons (VENs) in the human tissue inside the mice. These rare, large, cigar-shaped neurons are found in regions associated with social awareness and decision-making and are known to be affected in conditions such as frontotemporal dementia. Until now, VENs had only been observed in post-mortem human brains and some other large-brained social animals, not in lab-grown cultures or earlier rodent transplant models.

The ability to generate VENs from healthy donors or patients with specific neurological conditions opens up new avenues for studying how these neurons function in a living, behaving animal and testing potential therapies. Additionally, the model allows researchers to use cells from specific individuals to create mice whose human cortical tissue reflects the biology of a particular patient, whether healthy or affected by a neurodevelopmental disorder.

This could help scientists study how disease-associated changes in human circuitry manifest in an intact nervous system and test drugs that might correct them.

While the work raises ethical questions, the Stanford researchers have consulted with ethicists, neurobiologists, patient advocates, philosophers, and legal scholars over several years. They have also convened a conference in late 2025 to discuss the implications of this groundbreaking research.