Published online 5 August 2010 | Nature | doi:10.1038/news.2010.394

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Cell identity switched in mice without the use of stem cells.

If generating heart muscle cells from other adult cells works in humans as well as mice, it could be a boon for the millions with heart failure. IStockphoto

By simply switching on three critical genes, researchers have coaxed mouse skin cells into becoming heart muscle cells — without their first reverting back to an embryonic, stem-cell-like state.

If the technique works in humans, it could provide a source of new heart muscle for the millions of people who develop heart failure each year. It is also the latest example of a process called 'transdifferentiation', in which adult cells take on an entirely different identity.

Even as labs around the world rush to perfect the latest stem-cell technologies, increasing numbers are trying to manipulate cell identity without using stem cells at all. The technique could allow researchers to avoid some difficulties associated with stem-cell therapies, including the potential to seed cancer, and the difficulty of coaxing stem cells to take on a particular cellular identity.

"I don't know that this will entirely replace stem cells," says Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease in San Francisco, California, and lead author on the study, published today in Cell1. "But it will offer another strategy that might remove some of the concerns of using stem cells."

End of the line

Once it is damaged, heart muscle cannot repair itself. Increasing damage over time weakens the heart, eventually causing it to fail. In the United States, 5 million patients have heart failure, but only 2,000 heart transplants are performed each year.

Srivastava and his colleagues have previously tried to use stem cells to generate heart muscle cells. But their attempts failed, he says, because the heart muscle cells they made stalled in an immature state: although the cells contracted spontaneously — a hallmark of cardiac muscle cells — their contractions were not as strong as those of mature heart muscle cells.

So his team decided to try a different approach. They searched for genes that are expressed at high levels in heart muscle cells, and then narrowed the list down to three that were sufficient to convert another type of heart cell, structural cells called cardiac fibroblasts, into heart muscle cells.

Activating those three genes was sufficient to convert the cardiac fibroblasts or similar cells in skin to heart muscle cells. When implanted into mouse hearts, the cells made from cardiac fibroblasts contracted normally.

The results raise the possibility that a similar approach could be used to convert cardiac fibroblasts already in the heart to muscle cells, without the need for cell transplants, says Srivastava. His team is now investigating whether the same three genes are enough to switch cell identity in humans.

Identity crisis

Srivastava's work represents major progress in a field with a chequered past, says George Daley, a stem-cell biologist at the Children's Hospital Boston in Massachusetts. About 10 years ago, reports emerged from several labs that bone-marrow cells had been converted to many other cell types. This later turned out to be an experimental artefact: instead of taking on a new identity, the bone-marrow cells had simply fused to other types of cells.

After that, says Daley, the tide turned against transdifferentiation. In fact, researchers in the field shy away from that label altogether, says Marius Wernig, a stem-cell researcher at Stanford University in California. In January, Wernig and his colleagues reported the conversion of fibroblasts into neurons, a process that he calls "direct conversion" rather than transdifferentiation2.

But in 2006, Shinya Yamanaka, a stem-cell researcher at Kyoto University in Japan, reported that he could convert fibroblasts into a new kind of stem cell, called 'induced pluripotent stem cells', by simply switching on four genes. The finding convinced Wernig and others in the field that there was hope for transdifferentiation after all.

Since then, the field has picked up steam. Daley estimates that there are more than a hundred labs now racing to directly convert cells from one identity to another. Earlier this year, Wernig's research prompted stem-cell biologists Cory Nicholas and Arnold Kriegstein of the University of California, San Francisco, to write: "Such are the developments in cell transdifferentiation that one might ask if stem cells will be dispensable in the quest for regenerative medicine3."

More to learn

But Wernig hesitates to dismiss stem cells just yet. "It is still very early in the direct conversion field," he says. "Probably there will be applications where stem cells have advantages." In particular, Wernig notes, stem cells proliferate well and therefore may be more useful when large quantities of cells are needed.

Daley, meanwhile, says the field still needs to learn more about transdifferentiated cells. "There's a lot of speculation right now," he explains.

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Daley and his colleagues recently reported that induced pluripotent stem cells bear what Daley calls "significant memories of their former lives" in the form of characteristic DNA modifications that can affect gene expression4. Although Srivastava's team looked for such modifications near some genes, they have not yet performed a genome-wide scan.

"If, in fact, these transdetermined cells carry more of this memory of their tissue of origin, it does make you worry," says Daley. Such a finding could limit the flexibility of the technique, he notes, forcing researchers to minimize these differences by interconverting only closely related cells.