Human brain tissue grows and connects inside engineered mice

Human organoids transplanted into mouse brains can grow and form connections with the surrounding nervous system.

Human brain organoids are 3D structures grown in the laboratory which contain living, interconnected human neurons. They are made by reprogramming human skin cells into stem cells, which can develop into various neuronal cell types. Although organoids have been used in research for over a decade, they remain an in vitro model of the human brain. To overcome some of the limitations of this approach, a team from Stanford University, California, implanted human organoids into the brains of bioengineered mice that lack most of their cerebral cortex. This model allowed the researchers to investigate aspects of human brain development.

Professor Sergiu Pasca, senior author of this study and professor of psychiatry and behavioural sciences at Stanford University, said: 'These animal models offer a unique opportunity to study how disease-associated alterations in human brain circuitry manifest in an intact nervous system.' He added that, with existing organoid models: 'We couldn't study complex human behaviour in a dish.'

Previous studies have already implanted human brain organoids into living mice. However, this work, which was published in Nature, used bioengineered mice designed to accommodate human brain tissue. The researchers developed mice that were genetically engineered to lack most of the cerebral cortex and hippocampus. They implanted human cortical organoids derived from healthy donor cells, each containing around 100,000 cells, into the brains of two-day-old mice. Three months later, more than 90 percent by volume of the measured cortical tissue in the mice's brains was human-derived, with human neurons also extending through the mouse brain and as far as the spinal cord.

The team then explored how this model could be used to study human brain disease. The human tissue developed into specialised neurons, including rare von Economo neurons. These are particularly vulnerable in frontotemporal dementia and have never been grown in laboratory culture before.

The researchers also investigated neurological movement disorders. After exposure to low oxygen levels, similar to those that can occur around birth and are associated with cerebral palsy, only mice with human brain tissue developed motor coordination problems resembling those seen in people with the condition.

The research has also raised questions about the ethics of combining human brain tissue with animals. Professor Benjamin Hurlbut, a biosciences ethicist at Arizona State University who was not involved in the study, said the research is 'experimenting with concepts that are socially and morally meaningful, like the demarcation between human and nonhuman.' Professor Madeline Lancaster, a neurobiologist at the University of Cambridge who was also not involved, said: 'The goal here is clearly not to make a mouse that's super intelligent…[the goal is] so you can start using it to understand human neurobiology and human neurological diseases.'

Professor Pasca has stated that: 'Throughout several years of experimentation, we have received input from ethicists, neurobiologists with expertise in primate and human cortical biology, patient advocates, philosophers and legal scholars.' The team plans to use this model to investigate how human brain tissue responds to oxygen deprivation in cerebral palsy, as well as to study other conditions, such as schizophrenia and autism.