Scientists report a new model of brain organoids that uses mice bred without most of their cortex, then implanted with human neural tissue. The approach, described as an advance by outside experts, is designed to improve how researchers study early human brain development and disease.
Brain organoids are miniature, lab-grown clusters of human brain cells derived from stem cells. They are not full replicas of human brains, but researchers say these models offer a rare view into developmental processes that normally unfold in utero. “It is definitely an advance in the field,” said Dr. H. Isaac Chen of the University of Pennsylvania Perelman School of Medicine, who was not involved but has conducted related transplant experiments in rodents.
According to researchers, organoids help probe how structure and function emerge in the developing brain and how these processes may be altered in disease. Chen added that the new model opens options to examine larger volumes of human neural tissue at cellular and molecular resolution.
Making space for human cells in brain organoids
Most brain organoids are grown in dishes or specialized devices that keep them suspended in solution. Multiple organoids, including those representing distinct brain regions or from different individuals, can be combined to build more complex structures. Still, some teams transplant human organoids into animals because in vivo environments provide biological cues that in vitro systems lack, which can promote maturation and connectivity.
“There are some cues that are present in vivo that are really important, and we simply do not know what to add in, in vitro,” said study co-author Dr. Sergiu Pașca, a professor of psychiatry and behavioral sciences at Stanford University. In a 2022 study in rats, his team showed that transplanted organoids grew larger, formed more robust connections and were more active than those kept in dishes.
Transplanting human brain cells into rodents presents challenges. Human neurons mature much more slowly than rodent neurons. Pașca said that even in mice or rats, human cells develop about 20 times slower than the host’s, so host tissue can outpace and limit the space available to human cells. As rodent neurons mature, they become myelinated more quickly, creating a fatty barrier that human cells struggle to cross.
In work published Wednesday, Sept. 16, in Nature, Pașca and colleagues sought to give human neurons more room. Over years, they engineered a mouse that develops only about 2% of its cerebral cortex, and most of its hippocampus is also absent. Within days of birth, the team injects human cortical organoids into the open space. Pașca said about 90% of the grafts integrate and grow.
“We just took cortical organoids, about four of them, and transferred them with a syringe into that vacant space,” Pașca said. “They graft, and within a few weeks, they start to grow. And then within a few months, they have taken most of that volume.”
In the following weeks, the human cells extended projections and formed connections with underlying mouse tissue. The grafts did not assemble into the distinct layered architecture typical of the human cortex, but they contained many cell types usually present in human cortical tissue.
Future of the field
The team compared three groups: mice with organoid grafts, mice missing the same brain regions without grafts and unmodified lab mice. Despite the loss of most cortex and hippocampus, the modified mice functioned relatively well at a glance, Pașca said, though testing revealed subtle impairments in fine motor control, working memory and social behavior.
Chen noted that while the cortex is central to human function, it comprises a smaller fraction of the mouse brain, and prior studies indicate mice can compensate for its loss. He added that the transplantation procedure itself did not appear to significantly harm the animals.
It would be much more problematic if this was to happen in a species that has a larger brain and is closer to humans evolutionarily.
Dr. Sergiu Pașca, Stanford University
Researchers said the three-way comparison could help isolate how human tissue influences experimental outcomes. Pașca expects the platform will enable studies of prenatal injuries and exposures, including hypoxia and toxins or drugs, and allow genetic modifications in human organoids to model how variants affect development, structure and function. He suggested it could aid research into conditions such as cerebral palsy or autism.
Chen said the model’s larger volume of human tissue is a key advantage for examining early development at cellular and molecular scales, even if the grafts do not recapitulate the layered and lobar organization of a human brain.
On ethics, Pașca consulted Stanford experts and an external committee about animal welfare and the possibility that human grafts might confer new cognitive capacities. He said no new properties emerged over six months of growth, which corresponds roughly to a human fetal developmental stage. If grafts were to develop more human-like features, such as layers and lobes, concerns could increase, but both Pașca and Chen said such organization is unlikely in mice.
Pașca argued that ethical stakes would rise in species with larger, more human-like brains, such as pigs or nonhuman primates. Transplanting human organoids into monkeys is not justified at this time, he said. Related work on development and disease risk, such as accelerated biological aging tied to rise in early-onset cancer, is also reshaping how scientists think about early-life biology.