Broken hearts are hard to heal. No one knows this better than the researchers who are using stem cell therapy to graft new cardiac muscle cells to the scar tissue of infarcted hearts. It's hard to create the right cells, to get enough of them, and to have them survive in the heart. This month, Charles Murry from the University of Washington in Seattle and colleagues report in Nature Biotechnology1 that they have succeeded in coaxing heart muscle cells derived from human embryonic stem cells to stop progression of heart failure in rats. This is the first time human embryonic stem cells have been used to ameliorate the kind of damage caused by heart attacks.

The researchers injected a suspension of cardiomyocytes derived from human embryonic stem cells into hearts in rats subjected to experimentally induced heart attacks. They let the cells grow for four weeks. Then they looked at the rats' hearts.

They stained the hearts for molecules that are present only in human heart muscle cells. They also looked to see if the graft cells had differentiated into non-cardiac tissues and whether they had migrated to other organs. Finally, they assessed the function of the rats' hearts. The experiments showed the human heart muscle cells had grafted onto the injured rat hearts and improved heart function. No abnormal cells or structures were found in the brain, kidney, liver, lung or spleen.

Why did this attempt succeed where others have faltered? Earlier experiments by the same group repeatedly showed that its techniques were not generating enough pure cardiomyocytes and that cardiomyocytes died off when grafted into the damaged region.

The team conquered their set backs by directing the differentiation of human embryonic stem cells with activin A and bone morphogenic protein 4, generating at least 50 times more cardiomyocytes than they did with the old technique. They also concocted a pro-survival cocktail that targeted key points of several cell death pathways. The cardiomyocytes were in this cocktail when they were delivered to the heart.

Despite this success, there is still work to be done. Other researchers have found that improvements observed at 4 weeks may not last. Cardiomyocytes, they say, may not be prone to long-term engraftment. Before clinical trials are possible, the experiments need to be carried out in a model whose heart rate and size more resembles that of humans. This presents scale up issues. Where the rats received 10 million cells, 1 billion cells may be required to repair a human heart. The other piece of the puzzle is to find out whether the grafted cells are truly beating in synch with the heart or positively influencing the host tissues in another way.

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