Published online 23 July 2009 | Nature | doi:10.1038/news.2009.714

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Heart, heal thyself

A mouse study finds that, surprisingly, heart muscle can be made to proliferate.

cardiomyocyteA protein factor may give adult heart muscle cells a new lease of life.R. Bick, B. Poindexter, UT Medical School / Science Photo Library

With a little prompting, adult hearts may be able to heal themselves — at least, they may do if a recent study in mice holds true for humans. The heart has long been considered one of the organs least capable of regenerating after injury, with heart transplants one of the few effective therapies available. But now a team led by Bernhard Kühn at the Children's Hospital and Harvard Medical School in Boston, Massachusetts, has shown that protein injections in mice not only prompt heart muscle cells, known as cardiomyocytes, to proliferate, but that this proliferation also reduces damage after a heart attack1.

"This is of major, major consequence if it turns out to be correct," says Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease in San Francisco, California. "There have been no reports of differentiated cardiomyocytes in the adult being able to re-enter the cell cycle and divide again."

Work published earlier this year showed that the heart does indeed make new cardiomyocytes in adulthood. But because the replacement rate is very low and the source of new cells unknown, whether this finding would prove useful for treating heart disease was unclear. Kühn, a practising pediatric cardiologist, says he is already working to turn his finding into a potential therapy2.

To hunt for factors that could cause adult tissue to make new cardiomyocytes, Kühn and his colleagues isolated heart cells from adult rats and exposed them to proteins already known to prompt fetal tissue to build hearts. Their search identified the well-studied protein neuregulin 1. Kühn's team then turned to mice, simulating heart attacks in dozens of them by tying off a major artery feeding the heart before giving half of them abdominal injections of neuregulin 1 for 12 weeks. After waiting two weeks for the direct effects of neuregulin 1 to wear off, the researchers found that scars resulting from the heart attack were 46% smaller in treated than untreated mice. Additionally, hearts in treated mice displayed less of the weakening cell overgrowth that is typically observed after a heart attack, and they could even pump more blood.

Cancer concern

But techniques that prompt regenerative, healthy proliferation in the heart could also trigger malignant growth elsewhere. In fact, the researchers found that neuregulin 1 works by stimulating a kinase receptor called ErbB4. The breast-cancer drug Herceptin (trastuzumab) works by inhibiting a related kinase receptor, and some women receiving the drug have suffered heart problems. Although the mice in the studies showed no signs of tumours, the possibility of cancer will need to be explored further or mitigated by making sure that any therapy works specifically in the heart, where cancers are very rare, says Kevin Bersell, first author on the study.

“This is of major, major consequence if it turns out to be correct.”

Deepak Srivastava
Gladstone Institute of Cardiovascular Disease

Another crucial step, he says, will be figuring out what is special about the proliferating cardiomyocytes. Only about 0.6% of cardiomyocytes divided, and whereas most cardiomyocytes have more than one nucleus, only mononucleated cells were observed to divide; of those, only about an eighth did so successfully. The fraction of mononucleated cardiomyocytes varies greatly within mammalian species, Bersell says, so it's unclear whether results from young, healthy mice are relevant for older, sicker humans.

Bersell and Kühn point out the advantages of stimulating endogenous cells rather than administering cell therapies: it is less invasive, and administering a protein (or a similar agent) has a more predictable effect than delivering proliferating cells. But it's also possible that this work could complement cell therapies, boosting the cells' regenerative effects, they say.

Old dogma

Other scientists note potential problems with the experiments. Neuregulin 1 has diverse effects, for instance, and labels used to track cells through their divisions are often unreliable. But Kühn says that such scepticism is typical of "chipping away at the 100-year-old dogma" that the heart cannot regenerate. He is "very certain" that the new cardiomyocytes came from differentiated ones. Besides the genetic tracing results, his paper shows videos of neuregulin-1-treated cardiomyocytes dividing in culture, as well as prepared slides of dividing cardiomyocytes from heart biopsies.

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"I was sceptical going into it, because there has been so much hype, but I like this paper," says Charles Murry, who directs the Center for Cardiovascular Biology at the University of Washington in Seattle. "There could be other mechanisms that contribute, but I do believe they are birthing new cardiomyocytes."

The field of regenerative cardiac medicine is contentious, with several researchers convinced that the particular cell they are studying has the greatest potential to result in therapies, often directly via cell therapy. It is generally difficult to determine which pool of cells is being reactivated in these kinds of studies, says Piero Anversa, who directs the Center for Regenerative Medicine at Brigham and Women's Hospital in Boston. Still, he says, that is less important than the notion "that regenerative medicine is feasible". Andre Terzic, a cardiologist at the Mayo Clinic in Rochester, Minnesota, agrees: "There is more and more evidence that the heart is not a passive structure; it contributes to its own renewal." 

  • References

    1. Bersell, K., Arab, S., Haring, B. & Kuhn, B. Cell 138, 257-270 (2009).
    2. Bergmann, O. et al. Science 324, 98-102 (2009).
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