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Mice get human brain cells and get smarter, too

University of Rochester Medical Center

Human brain cells in a mouse glow green because researchers have tagged them with a gene that looks green under fluorescent light. Mice with the human cell transplants were smarter than normal mice, the researchers report.

Researchers who transplanted human brain cells into newborn mice said the rodents grew up to be smarter than their normal littermates, learning how to associate a tone with an electric shock more quickly and finding escape hatches faster.

The experiments are aimed at making models to study human brain diseases such as Huntington’s and schizophrenia, as well as nerve diseases such as multiple sclerosis. But the team at the University of Rochester say their findings also suggest that these brain cells, called glial cells, may very well be one of the important factors that make humans different from other animals.

“Human cognitive evolution might be the product of glial evolution,” said Dr. Steven Goldman, who worked with his partner and wife Dr. Maiken Nedergaard on the study. Their findings also support the growing theory that glia cells, one of the important components of the brain’s so-called white matter, are far from being passive support cells and are in fact actively involved in brain function.

Down the road, Goldman hopes the findings might lead to procedures to transplant brain cells to treat diseases as diverse as multiple sclerosis, bipolar disease and even the brain shrinkage that causes memory loss in aging.

“There are a number of diseases that are specific to humans -- neuropsychiatric diseases, schizophrenia, bipolar disease. Animals don’t get these,” Goldman said in a telephone interview. Apes might – it’s not clear. “One of the possibilities is that neuropsychiatric disorders may have evolved with glial evolution.”

Writing in the journal Cell Stem Cell, Nedergaard and Goldman said they were trying to find ways to cure mice of multiple sclerosis, which is caused when nerve cells lose their fatty coating of myelin and stop working properly. They used immature cells called glial progenitor cells taken from aborted fetuses, infused them into the brains of newborn mice, and watched what happened.

Progenitor cells are partly along the path to from undefined to “adult” cells, and seem to have a better ability to flourish when transplanted. The human glial cells not only survived in the brains of the mice – they thrived, Goldman says.

"The human glia cells essentially took over to the point where virtually all of the glial progenitor cells and a large proportion of the astrocytes in the mice were of human origin, and essentially developed and behaved as they would have in a person's brain," said Goldman.

Human glia are far more complex than mouse glia, and they help form many, many more connections, called synapses, between neurons. The more synapses, the faster and better the brain works. Tests in lab dishes showed the mouse brains with human cells transmitted signals much more quickly than normal mouse brains.

“So here we have these brains where most of the glia are human. And we know that human glia are different from those of most of other species,” Goldman says. “Have their cognitive abilities been enhanced?”

They put the animals to the test -- first a simple one called a conditioned fear response. “You expose the animals to a tone and a very mild shock,” Goldman said. “Mice don’t like to get shocked and they learn to associate the tone with the shock. Mice, when they are afraid, they freeze.” The mice with the human glia froze faster and stayed frozen longer than thieir littermates without human glia, Goldman and Nedergaard found.

“It is a really dramatic effect,” Goldman said. Some learned after just one shock to fear the tone.

Another test involved learning to find and use an escape hatch. Again, the mice with human glial cells learned faster.

To make sure it wasn’t just the transplant of fresh cells that was improving learning, the researchers transplanted mouse progenitor glial cells into newborn mice. These animals did not learn any faster.

Goldman isn’t worried that he is somehow making mice with human brains. “We are not humanizing the mice,” he says. “We were affecting the brain activity with human glial cells ... These are still mouse brains, bottom line.” Transplanting neurons might be a different matter, he said.

There are many animals that carry human cells -- from the millions of lab mice injected with human tumor cells to study cancer, to sheep engineered to produce human liver cells. But the experiment raises a red flg, says bioethicist Arthur Caplan of New York University medical center.

"This experiment is the ethical equivalent of Superstorm Sandy," Caplan says. "It brings together a controversial source of stem cells -- obtained from aborted fetuses to create human-animal chimeras which frighten many members of the public and Congress.  The utility of the work for understanding diseases and the development of therapies for them is enormous but it is vitally important that an agreed upon, transparent and enforced set of rules and review processes be instituted to govern further research using stem cells from humans in animal brains or vice versa."

These new mice might be used to study ways to treat a range of human diseases. The technique of transplanting progenitor cells into newborns might hold special promise in treating genetic diseases such as Niemann-Pick or Tay-Sachs disease, Goldman says.

These diseases both are marked by abnormal brain cells, including glia. “It is possible that by introducing normal glial cells in these kids we may well be able to treat these disorders with cell transplants,” he said.  

The technique is most definitely not a way to make people smarter, he said. But it could restore some of the normal damage caused in aging. Some cases of vascular dementia are in fact not caused by little strokes in the brain, but are age-related white matter loss, Goldman asserts. “As we get older we lose more and more white matter,” he said.

It’s possible glial cell transplants could help. But transplants of brain cells into adult mice don’t work as well. The cells take up residence but they don’t multiply and take over the way they do in the newborns, whose brains are still developing, Goldman said.

Last month, Goldman and Nedergaard reported they made human glial progenitor cells out of ordinary human skin cells that had been reprogrammed so they acted like embryonic stem cells. These so-called induced pluripotent stem cells – iPS cells for short – might one day be used as grow-your-own transplants, made using a patient’s own cells. They’d be a perfect genetic match.

The science isn’t quite there yet but researchers hope iPS cells, which are made without creating a human embryo, would be a more ethically acceptable alternative to human embryonic stem cells. That would be the route to making brain cells to treat human adults, Goldman said.

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