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Trial set to test how stem cells heal a broken heart

A fresh supply of mitochondria does the trick, say researchers.

A shot of hope: Injecting stem cells gives damaged hearts a boost, perhaps by providing fresh mitochondria.

Some of the most heartening reports in stem cell research have come from doctors who showed that injecting damaged hearts with stem cells could revive them. But how the stem cells heal the heart has been far more controversial.

Scientists at the University of Pittsburgh have begun a trial with a new twist that they say will help settle the debate. The researchers are injecting stem cells into the hearts of individuals set for a heart transplant and then examining the removed hearts to see how the stem cells behave.

Based on preliminary evidence, the researchers say, the stem cells appear to fuse with heart cells and give them a much-needed boost of fresh mitochondria—but the idea has already met with skepticism.

I know we don't have true differentiation into a cardiac muscle. Amit Patel, University of Pittsburgh

Heart tissues that are starved of oxygen, either chronically or from a heart attack, are unable to pump blood efficiently, forcing the remaining muscle to try to compensate by pumping harder. Eventually, that stress leads to heart failure. Because the heart has a limited capacity to heal itself, the only option for these individuals was to have a transplant—until the stem cell therapy.

Studies had previously shown that injecting stem cells into mice that had suffered artificially induced heart attacks improved how the heart muscles contract. But some researchers warned that moving into human trials without understanding the exact effect of injecting stem cells was risky and premature (Nat. Med. 10, 445–446; 2004).

Since then, however, clinical studies have begun to show that injecting stem cells derived from the bone marrow can help heal damaged hearts. For instance, in one trial in Argentina, researchers injected 10 individuals who had suffered heart failure with stem cells taken from their own bone marrow.

The stem cells were injected along with a coronary artery bypass—in which healthy blood vessels are transplanted into the damaged area—to replenish blood flow. Six months later, those who received stem cells pumped blood more efficiently than the control group, who only had the bypass surgery (J. Thoracic Cardiovasc. Surg. 130, 1631–1638; 2005).

Researchers at the University of Rostock in Germany have found similar results in their study of 55 individuals. They are set to report their findings at the American Association of Thoracic Surgery in May. Mexican researchers last year also reported encouraging results from their trial in five individuals (Life Sci. 78, 279–283; 2006).

But scientists continue to question the mechanism behind the effect: do the stem cells transform into heart muscle? Do they merely fuse with the heart cells? Or does injecting stem cells stimulate the release of compounds that help the heart recover from damage?

Some researchers say it's extremely unlikely that the hematopoietic stem cells, which normally give rise to blood cells, would 'transdifferentiate' into a completely different cell type, such as a myocyte—a heart muscle cell.

But others, including Piero Anversa, director of New York Medical College's Cardiovascular Research Institute, maintain that this is precisely what happens. “I believe our data have shown unequivocally that [the cells] have the properties to transdifferentiate into cardiomyocytes and coronary vessels,” Anversa says.

The answers may be forthcoming from the new trials.

Doctors will inject stem cells into only one-half of the left ventricle of individuals slated for a heart transplant. The other half of the left ventricle gets a placebo saline injection. The idea is that, following the transplant, the removed heart would reveal the fate of the stem cells.

The trial began in February and as of mid-April, the researchers had data from three hearts. Their preliminary findings suggest that the stem cells are fusing with the host's ailing heart cells, creating a larger number of binucleated cells in the injected area than in the control. “I know we don't have true differentiation into a cardiac muscle,” says lead investigator Amit Patel, director of the Center for Cardiac Cell Therapy at the University of Pittsburgh.

Patel says the stem cells might help the heart by providing fresh mitochondria and allowing for stronger, synchronous contractions.

But he will need a lot more data to convince the skeptics.

“The notion of a mitochondrial donor would require a huge number of fusion events to have an impact on heart function,” says Loren Field, professor of medicine at Indiana University. At least in rodents, Field says “fusion is not a very prevalent event.”

Anversa doesn't buy the fusion theory either. “It seems more reasonable to me that bone marrow cells differentiated into new myocytes and improved function, rather than old myocytes being modified by fusion to become better cells,” he says.

Although the procedure is still in trials in the US, it is already in practice elsewhere. For instance, Patel in December 2005 treated Hawaiian singer and entertainer Don Ho in Thailand. At 75, Ho was not a heart transplant candidate, but following the therapy has improved enough to perform on stage twice a week. Several centers in South America and in St. John, Barbados, also offer the treatment.

Patel says he wants to understand how the therapy helps people, but what really matters in the end is that it does. “If it works, whether it's through a paracrine effect or fusion or true transdifferentiation, which is what everyone hopes for,” he says, “then that's fine.”

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Mack, G. Trial set to test how stem cells heal a broken heart. Nat Med 12, 483 (2006). https://doi.org/10.1038/nm0506-483

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