For the first time, neurons from rat stem cells regenerate brain circuits in mice

Two independent research teams have successfully regenerated brain circuits in mice using neurons grown from rat stem cells. Both studies use cross-species blastocyst complementation to study brain function and evolution, providing valuable insight into how brain tissue is formed and how it is lost through disease and aging. This provides a new opportunity to restore lost brain function.

“This study helps demonstrate the brain's potential flexibility in using synthetic neural circuits to restore brain function,” said Dr. Christine Baldwin, a professor at Columbia University. Baldwin's team used rat stem cells to restore the olfactory neural circuitry and its function in mice.

These two papers will be published consecutively. cell. The title of the paper from the Baldwin lab is “A functional sensory circuit constructed from neurons of two species.The other paper comes from the lab of Dr. Jun Wu, an associate professor at the University of Texas Southwestern Medical Center in Dallas, and is titled “Generation of rat forebrain tissue in mice”

Wu's team has developed a CRISPR-based platform that can efficiently identify specific genes that drive the development of specific tissues. They tested the platform by silencing Hesx1, a gene required for forebrain development in mice. They then used rat stem cells to restore the tissue. “If we can generate one type of brain tissue in another species, it will help us understand the development and evolution of brains in different species,” Wu said.

Mice and rats evolved independently over about 20 to 30 million years. In previous experiments, scientists successfully used rat stem cells to replace the pancreas of mice through the process of blastocyst complementation. To make this process work, researchers inject rat stem cells into the blastocysts of mice that lack the ability to develop a pancreas due to a genetic mutation. Later, the rat's stem cells developed into the missing pancreas and supplemented its function.

However, so far, the use of stem cells from different species to generate brain tissue by blastocyst complementation has not been reported. This time, Wu's team used his CRISPR to test his seven different genes and found that knocking out Hesx1 reliably produced mice without a forebrain. The researchers then injected rat stem cells into the blastocysts of Hesx1 knockout mice, and the rat cells filled the niche and formed the mouse forebrain. Rats have larger brains than mice, but their forebrains developed at the same pace and size as mice. Furthermore, neurons in rats were able to transmit signals to neurons in neighboring mice, and vice versa.

The researchers did not test whether the forebrain obtained from rat stem cells changed the behavior of the mice. “There is a lack of good behavioral tests to differentiate between rats and mice,” Wu said. “But our experiments show that these mice with rat forebrains don't seem to behave abnormally.”

Baldwin's team used specific genes to kill or silence mouse olfactory neurons and injected rat stem cells into mouse embryos. They found that blastocyst complementation restored olfactory neural circuits in mice in different ways depending on the model. When mouse neurons were present but silent, rat neurons helped form more organized brain regions compared to the lethal model. But when the researchers trained and tested rat-mouse chimeras to find hidden cookies buried in cages, they found that in the kill model, rat neurons were best at rescue behavior.

“This truly surprising result allows us to examine the differences between these two disease models and identify mechanisms that help restore function in both types of brain disease,” Baldwin said. . Her team also tested blastocyst complementation in disease model mice, using cells from mice with normal olfactory systems. They showed that intraspecific complementarity rescued the cookie finding in both models.

Although blastocyst complementation is still far from clinical application in humans, both studies suggest that stem cells from different species can synchronize their development with the host's brain. In addition to the research's implications in medicine, the research team is also interested in using this approach to study the brains of many wild rodents that have not been accessible in a laboratory setting.

“There are more than 2,000 species of rodents in the world, many of which behave differently than the rodents we commonly study in the laboratory. “Blastocyst complementation could open the door to studying how the brains of those species develop, evolve and function,” Wu said.