Rat Neurons Repair Mouse Brains That Lack a Sense of Smell
With an injection of rat cells, mouse brains that were genetically engineered to be unable to smell could detect odors and even track down an Oreo cookie stash
By Claudia Lopez Lloreda
Minotaur.
JuanDarien/Getty Images
Chimeras, fictional creatures made up of a combination of body parts from different animals, such as the mythological Minotaur, have captivated thinkers, philosophers and scientists throughout history. In biology, a chimera is any organism made up of cells with different sets of genes. Now researchers have created a unique variety of chimeras in the form of mice with rat neurons that replace lost brain functions. The chimeric mice highlight the adaptability of the brain and raise hopes for studying neurological disease and for developing brain tissues that more closely resemble those of humans for transplantation.
The findings, reported in two studies in Cell this week, show that rat neurons can integrate into mouse brains and develop into missing circuits using a procedure called interspecies blastocyst complementation (IBC) in which researchers inject cells from one species into embryos of another and then implant the embryos into animals of their own species. Researchers had previously used this technique to develop a pancreas and kidneys in mice and rats but not brain tissue.
The new work is “a big step in the field,” says Andrew Crane, a cell biologist at the University of Minnesota, who was not involved with the two papers. “Both of these studies are answering key questions about how rat cells develop within a mouse.”
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One of the studies, conducted by Jun Wu of University of Texas Southwestern Medical Center and his colleagues, first sought to identify which genes the researchers needed to excise in order to block the development of specific brain areas. The team used the gene-editing technique CRISPR to quickly create mice without important genes needed for the animals’ development and found that knocking out the gene Hesx1 resulted in mice that lacked an area called the forebrain, which is mostly involved in complex cognitive and sensory processing. A void remained in the brains where the forebrains should have been.
Then the researchers performed IBC by injecting rat stem cells into host embryos of these genetically altered mice to see how they developed. The rat cells matured with the embryos, integrating with the host cells and creating the missing forebrains. The rat cells were capable of sending signals to other neurons when researchers activated them. Although the team also used mouse cells to restore the forebrains, the goal was to see if rat cells could do the same, opening the possibility of combining cell from different animals to create brain tissues. The study is a “technological tour de force,” says Walter Low, neuroscientist at the University of Minnesota, who was not involved with the research.
In parallel, Kristin Baldwin, a neuroscientist at Columbia University Irving Medical Center, and her colleagues used the same approach to examine how rat cells would populate a mouse brain. (Wu was also a co-author of this study.) In mouse embryos, they injected rat cells that also created functional connections.
Not only could the rat cells integrate into the mouse brains, but they also restored missing functions in mice that lacked the sensory neurons for smell. Without the sense that they use to look for food, the anosmic mice failed to find mini Oreo cookies buried in their bedding. But such mice without olfactory neurons that were injected with rat stem cells burrowed into the bedding to locate the cookies, showing that the donor neurons rescued smell and initiated food-seeking behavior. The mice effectively “perceived the world through the other species’ nose,” Baldwin says.
These studies provide key insights into developmental biology, Low points out. Even though rats typically develop more slowly than mice and rat brains are larger, rat cells timed their development to the pace of cells in their mouse host, taking cues from their environment to grow alongside their neuronal counterparts and mature to the appropriate size.
But not all of growth and development was dictated by the host: when Wu’s team looks at the genes expressed by the cells, they still retained their genetic identity. “There’s really intriguing cross talk between extrinsic and intrinsic factors,” he says. These chimeras could further help scientists to study the plasticity of the brain and what critical factors dictate development.
The IBC technique might help researchers develop improved brains tissue for research and, in the long run, transplantation. If this works in animals like non-human primates, the technology could complement animal models of neurological disease, says Bjoern Schwer, molecular biologist at the University of California, San Francisco who was not involved with the study.
These papers reveal critical factors for perfecting the technique, revealing the steps needed to synchronize the growth and development of the different cell types. “It’s that synchronization [of the mice and rat cells] that allowed them to integrate beautifully within the brain of the mouse,” Low says. “In the future, if we want to make human organs in a large animal like a pig, we need to synchronize cells’ development so that the cells match one another during the developmental process”.
In their research, Wu and his colleagues observed one possible hitch: as the embryos developed, the contribution of the cells, meaning what percentage of the donor cells were in the forebrain, started dwindling from about 100 percent to 60 percent, suggesting that mouse cells could be outcompeting the donor cells. This lack of control over how many cells were integrated into the embryo and eventually survived led some of the chimeric mice to have more rat neurons in their brain than others. Because of this, “each animal is different,” Baldwin says.
And ultimately, rat and mice genomes are very similar to one another but the technology could become more challenging if species more distantly related than mice and rats are used to make chimeras, as differences in brain physiology and the likelihood of immune reactions increase. Ethical issues also arise when creating a chimera. There are concerns as to whether donor cells from a rat or another species might affect the behavior and cognition in the host animal. “What would it mean if somebody tried to put human cells into a pig embryo [to develop a brain]?” Crane wonders.
The next steps are to refine these techniques and do chimera experiments in larger animals such as pigs to address these questions,Low says. Starting these studies will begin to reveal “the other variables that we’ll need to overcome in order to make growing human organs that we can transplant a reality”.
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