Cellular Reprogramming Picks Up Speed

Improved recipe. After 6 days of reprogramming, nearly 100% cells that lack Mbd3 (right) have become reprogrammed (yellow). Few unaltered cells (left) have made the transition, remaining red.

Given the right instructions in the lab, mature cells can turn back into embryoniclike ones that researchers covet, but the process is frustratingly slow and inefficient. By removing a molecular brake, scientists have now figured out how to reprogram cells with almost 100% efficiency.

In a process called cellular reprogramming, researchers increase the expression of four genes in skin, blood, or other mature cells to turn them into induced pluripotent stem cells (iPSCs), which can become any of the body’s cell types. Scientists value the method because it allows them to make patient-specific cells in the lab that they can use to study disease—and perhaps someday to treat patients. However, the reprogramming procedure is hit-and-miss. The most efficient methods reprogram only about 10% of mature cells into iPSCs.

Now, stem cell researcher Jacob Hanna and his colleagues at the Weizmann Institute of Science in Rehovot, Israel, have identified a protein that acts as a brake on reprogramming. When the protein, called Mbd3, is removed—either by mutating its gene or by slashing its expression—the four reprogramming genes can turn nearly 100% of cells into iPSCs within a week, Hanna and his colleagues report online today in Nature.

The group also found that the Mbd3 gene forms a feedback loop with the four reprogramming genes. When they are active, they switch on production of the Mbd3 protein, which in turn inhibits their further expression. During development, Hanna says, the protein likely helps coordinate when cells begin to differentiate.

To better study the protein, the researchers made genetically altered cells in which expression of Mbd3 can be turned off and on. They found that when Mbd3 is removed, the cells respond to the reprogramming genes with surprising synchrony as they revert to an embryoniclike state. Usually it takes weeks or even months to reprogram a handful of cells, and there’s no way to predict which cells will “take” and which won’t. But the genetically altered cells went through the process at the same time, and virtually all of them were reprogrammed in a week, the researchers found.

“It’s unexpected that the depletion of a single [protein] can have such a dramatic effect,” says Konrad Hochedlinger, who studies reprogramming and pluripotent stem cells at Harvard Medical School in Boston. He wonders if there might be other molecular brakes that, when removed, have similar effects. The interactions between Mbd3 and the reprogramming genes help explain why reprogramming has been such an unpredictable process, Hanna says. Only in rare cells can the reprogramming genes overcome the resistance that Mbd3 provides.

The ability to study entire populations of synchronized cells as they are reprogrammed should allow scientists to better understand the molecular events that drive the mature cells back to an immature state, Hochedlinger says. It might also allow researchers to isolate and study partially reprogrammed cells. “They might be therapeutically interesting,” Hochedlinger says, because they would be able to grow into useful tissue types without seeding tumors, which fully reprogrammed cells can do.

It won’t be easy to use the technique to make patient-specific iPSCs, however. The genetic modifications that Hanna and his colleagues introduced might interfere with the cells’ later behavior in unpredictable ways. Hanna says that he and his colleagues are looking for a small molecule that could block Mbd3 temporarily, removing the brake just long enough to allow cells to be reprogrammed.

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