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Making Heart Cells

A cocktail of proteins converts embryonic cells into cardiac cells that might someday replace damaged tissue.
April 27, 2009

Treating embryonic cells from mice with a cocktail of proteins triggers production of new heart-muscle cells, according to research published today in the journal Nature. The recipe, developed by scientists at the Gladstone Institute of Cardiovascular Disease, in San Francisco, could someday be used to make tissue for cell replacement therapies that restore function to an ailing heart.

Growing hearts: Exposing mouse embryonic cells to a cocktail of proteins triggers differentiation of cardiac muscle cells, shown in red. The cells that have taken up the proteins are marked in green.

Working with mouse embryos about a week old, Benoit Bruneau and Jun Takeuchi discovered that a trio of proteins–including a pair of transcription factors and a protein that helps loosen tightly wound DNA–could direct certain embryonic cells to form cardiac-muscle cells, called cardiomyocytes. These cells not only produced proteins characteristic of early heart cells, but they eventually started to beat. “It’s like we’re telling these cells, ‘You will become heart, now. Go!’ And that’s what they do,” says Bruneau.

Human trials of cell therapies for heart disease, which have mostly used stem cells derived from a patient’s own blood, have yielded mixed results. It may be that transplanting cardiac myocytes rather than undifferentiated cells will prove more effective.

Scientists have previously managed to coax embryonic stem (ES) cells–special cells derived from embryos that are capable of forming any cell in the body–into forming beating heart cells in a dish. But those methods are less efficient, as they tend to produce other cell types, such as the smooth muscle cells that make up blood vessels, in addition to the myocytes that make up the heart muscle. In the new study, researchers created heart-muscle cells from tissue that was not destined to form heart. What’s more, they found that sections of tissue located outside the embryo–cells that would eventually form the placenta–were also transformed by their treatment. “Those cells have no intention of ever coming close to a heart in any part of their lifetime,” says Bruneau. “And we got beating cells to form there as well.”

The fact that scientists can turn partially differentiated cells into heart-muscle cells is good news for future therapies. Ultimately, “we’d like to be able to make cardiac myocytes from any cell type,” says Bruneau–in particular, cardiac fibroblasts, which are the cells that form scar tissue after a heart attack. “That would be the ideal therapy–to be able to turn those scar-tissue cells into cardiac myocytes and restore the function that’s been lost,” says Bruneau.

“If you could get fibroblast cells in culture to convert efficiently into cardiomyocytes, that would be fantastic,” says Christine Mummery of the Leiden University Medical Center, in the Netherlands. And if the whole thing could be done in the body–turning fibroblasts into myocytes within the heart itself–“you wouldn’t have to inject the heart with cells. However, that approach would require gene therapy to deliver the appropriate factors to the living heart, which carries its own risks, including promoting cancer.

Bruneau and his colleagues are trying to tweak their heart-making brew so that it works well on ES cells and in other adult cell types that might be therapeutically useful. “The dream is to be able to take a skin cell or a cardiac fibroblast, any kind of cell a person has a lot to spare, and turn those into myocytes,” he says. Those homemade myocytes could then be returned to the patient’s heart, where the hope is that the cells would replace damaged tissue. “That’s the dream scenario,” says Bruneau. “And we’re working hard to make it happen.”

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