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New embryonic stem cells from rats are able to differentiate into specialized cells that form muscle, skin and gut.IMAGE CREDIT: M. Buehr, et al., Cell, 12/24/08

Scientists have finally succeeded in deriving embryonic stem cells from rats, providing the research community with a new tool for modeling human disease. The method used may prove to be a general recipe to create stem cells from many different animals, the researchers say. The findings appear in two companion papers in the Dec. 26 Cell.

Embryonic stem cells are lauded for their unique ability to develop into every kind of cell. Given the right signals, a stem cell in its undifferentiated state could turn into any cell in an organism, potentially growing into tissue for a heart, a gut or skin.

Scientists first isolated these shape-shifting cells from mice decades ago, creating an extremely useful model for studying many biological processes. But, notes study coauthor Qi-Long Ying, some human diseases, including high blood pressure, diabetes and Parkinson’s, are more closely approximated in rats. Isolating and maintaining generations of stem cells from rats, or any animal other than mice, however, has proven difficult.

The usual way to create stem cells is to add growth signals that instruct embryonic, or undifferentiated, cells to grow and divide, ensuring self-renewal. But the exact recipe of chemical signals that keeps mouse stem cells dividing hasn’t worked in other mammals, including rats.

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A new study successfully derived rat stem cells. Of the whole rat embryo (inset, top), the green cells were derived from stem cells (inset, below). A mother rat harboring implanted stem cells — marked with white fur — had an albino pup derived from the stem cells. The white pup's dark sibling was not derived from stem cells.Inset credit: M. Buehr, et al., Cell, 12/24/08 Image credit: Austin Smith

“When mouse embryonic stem cells were first isolated, we thought rat cells would be easy,” says Sir Martin J. Evans, a developmental biologist from Cardiff University in Wales who was not involved with the new research. “But we completely failed to do it.” It soon became clear that even though the early development of rats and mice looks similar, the two are actually quite different, says Evans, who shared the 2007 Nobel prize in physiology or medicine for his pioneering research on stem cells in mice.

In a study published in May, Ying and his colleagues took what seemed like a counterintuitive approach. Instead of adding growth signals to keep mouse stem cells dividing, the researchers blocked the normal signals that would have made the stem cells develop into differentiated cell types.

“Our discovery was that if you want to maintain cells in the undifferentiated state, you must block signals, not activate them,” says Ying, a stem cell researcher at the University of Southern California in Los Angeles. By repressing differentiation, the researchers could hold the cells in what they call a “ground state,” a blank slate ready to turn into any tissue in the body. This method promised to be widely applicable to cells from other kinds of animals, including notoriously finicky rat cells.

Two teams of scientists, one led by Ying and the other by Austin Smith at the University of Cambridge, worked together to create rat stem cells by applying a cocktail of three key blockers of differentiation, similar to the ones used successfully in mice. The researchers were then able to coax the newly isolated rat stem cells into forming muscle cells, gut cells and brain cells. After a particular treatment, researchers even saw what they call “spontaneously beating areas” in dishes, signaling newly formed heart cells.

But the ultimate test of stem cells is whether the cells can grow into an entire adult animal. So the researchers marked rat stem cells with a gene for green fluorescent protein, a marker that glows green under ultraviolet light. The green cells were implanted into another, unmarked group of undifferentiated cells destined to become a rat embryo. As the embryo developed, the original green stem cells formed all types of different cells that were distributed throughout the embryo.

Because the green marker could be harmful to the animal and interfere with development, the researchers did a similar experiment using cells from rats with white fur color, a less noxious marker than the green fluorescent protein. Some of the rat embryos grew into healthy, white-furred adults, although others were plagued with genetic abnormalities

With this supply of new stem cells, researchers may soon be able to do experiments that weren’t previously possible. As they’ve done in mice, scientists will now be able to introduce specific genetic mutations into the DNA of rat stem cells. These stem cells could then grow into a fully formed rat, which could be put through its paces to find the effect of the mutation. These mutated rats could also be used in studies on a wide range of human diseases. “The prospective benefits of gene targeting in rats are clear,” Smith says.

Although Evans agrees that rats have some key benefits over mice, he says the mouse system is deeply entrenched. Using mouse embryonic stem cells, scientists have already created thousands of strains of mice with specific mutations. “You’d be starting from square one with a rat,” Evans says.

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