As Sergiu Pașca’s team worked out how to grow human brain tissue inside mice, he sought input from ethicists, patient advocates, philosophers, and legal scholars. The researchers were creating a model in which human neurons could grow and connect with an animal’s nervous system, raising questions about how those cells might change the mouse’s abilities and how its welfare should be protected.
The discussions also involved the people the research might eventually help. Many neurological disorders remain difficult to treat, and researchers have few ways to examine living human brain tissue as disease develops.
Pașca’s Stanford team has now transplanted lab-grown human brain tissue into newborn mice genetically engineered to develop without most of their cerebral cortex, the brain’s outer layer. The human tissue grew into that space, making up more than 90 percent of the animals’ cortical tissue by volume within three months. The rest of their brains remained mouse tissue. The human nerve cells formed networks that fired together and extended fibers as far as the spinal cord.
Published in Nature, the study gives researchers a way to investigate how developing human brain cells respond to injury inside a living nervous system, with the longer-term goal of studying disease and testing treatments.
Explore All Options“These animal models offer a unique opportunity to study how disease-associated alterations in human brain circuitry manifest in an intact nervous system,” Pasca said in a press release.
Growing Human Brain Organoids Inside Mice
The team had previously transplanted human brain tissue into newborn rats. The cells developed more fully than those kept in a dish, but the rats’ own neurons matured faster. Competition for space and connections limited the human tissue’s growth.
For the new experiment, the team grew human stem cells into organoids, small clusters of tissue that reproduce some features of the developing cortex. They then placed those clusters into the extra space in the newborn mice’s brains two days after birth. Each cluster contained about 100,000 cells.
As the tissue grew, Pașca and his colleagues tracked its electrical activity and watched how the mice moved and explored. The animals could still walk and investigate their surroundings, although tests showed differences in paw coordination and movement patterns.
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Following an Injury Through the Mice’s Footsteps
Oxygen deprivation during pregnancy or around birth can contribute to cerebral palsy. To explore how an injury to developing human brain tissue might affect movement, Pașca’s team recorded the mice walking, exposed them to five hours of low oxygen, and tested them again two days later.
The transplanted tissue showed signs of injury and inflammation, and the mice changed how they walked. They spent more time with three or four paws on the ground and kept their hind paws planted longer. Mice without human grafts underwent the same oxygen exposure but did not show those changes.
The human tissue came from healthy donors, giving the team a way to study how oxygen deprivation alone could injure the developing cells.
Studying Cells That Have Been Hard to Reach
The grafts also contained large, elongated cells resembling von Economo neurons, a type of nerve cell found in brain regions involved in social awareness and decision-making. These neurons have been difficult to grow in lab models and are especially vulnerable in frontotemporal dementia, which can change someone’s personality, behavior, or language abilities before prominent memory problems appear.
Pașca hopes to grow tissue from patients with frontotemporal dementia to find out why these cells are vulnerable and whether treatments could protect them.
“An overriding argument questioned the ethics of not conducting this research in the face of the suffering of hundreds of millions of people afflicted with neurological disorders that today are [incurable] but tomorrow could yield treatments we discover by using this model,” he said in the press release.
This article is not offering medical advice and should be used for informational purposes only.
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Article Sources
Our writers at Discovermagazine.com use peer-reviewed studies and high-quality sources for our articles, and our editors review for scientific accuracy and editorial standards. Review the sources used below for this article:
- This article references information from a study published in Nature: Developmental xenocortication using human-derived organoids in mice
