Calcium is crucial for heart regeneration by cardiac stem cells following cardiovascular problems say scientists in an article to be published in the journal Circulation Research this 9th of October. The study also identifies the body molecules controlling calcium levels in the stem cells and reveals, how their manipulation, can lead to the formation of new cardiac tissue. The work, that follows the recent surprising discovery of stem cells within the heart, can have important implications in the regenerative medicine of this organ in patients with cardiovascular diseases.

Heart injuries are extremely difficult to treat; the lack of blood flood following injury or during disease kills heart muscle cells and results - because the healing scar tissue does not function as the original muscle - in loss of function, which, depending on the extension of the injury, might lead to heart failure. The only alternative is heart regeneration through the production new cardiac muscle cells (cardiomyocytes) that replace the dead tissue. Unfortunately, cardiomyocytes once differentiated, scarcely divide again. The most promising alternative source of new cells are cardiac stem cells, but these - although found around the diseased tissue following a heart attack - appear to have very limited regenerative capability when disease occurs.



Trying to understand better the mechanisms and molecules behind these stem cells, in an attempt to improve their regenerative capabilities, led Joao Ferreira-Martins, Carlos Rondon-Clavo and colleagues at Harvard Medical School and the University of Milano-Bicocca in Milan to study their calcium levels. In fact, not only calcium levels have been specifically linked to the mechanical behaviour of cardiomyocytes, but they are also known to affect several physiological processes such as cell division, development and differentiation.

By using a calcium-sensitive fluorescent dye that could be measured the researchers were able to discover that human cardiac stem cells show spontaneous oscillations in their internal calcium levels, with the higher values being found right before cell division. They also identified three naturally occurring molecules regulating these oscillations: ATP, Histamine and insulin-like growth factor 1 (IGF-1). Interestingly, when cardiac stem cells grew in the presence of any of these molecules there was a substantial increase in cells showing oscillating calcium levels as well as in the frequency of these oscillations, and also in the numbers of cells dividing, all characteristics of what appears to be an “activated state”.

These observations raised the possibility that pre-treatment of cardiac stem cells with any of these molecules could render them more effective regenerating diseased cardiac tissue. To test this hypothesis Martins, Clavo and colleagues used fluorescence-marked human cardiac stem cells treated with ATP or histamine. These cells were injected into mice with suppressed immune systems (so that the injected human cells are not rejected) after a heart injury, and the results compared with those obtained from injections with non-treated cardiac stem cells (controls). The researchers found that, 48 hours after injection, pre-treated cells were surviving in higher numbers and dividing much more (10 time more) than non-treated cells. Even more interesting, by this time they start showing markers characteristic of cardiomyocytes and expressing molecules known to participate in cell-to-cell adhesion suggesting that pre-treated cells are differentiating into cardiomyocytes and regenerating the injured heart. And in fact, after 7 days, mice injected with pre-treated cells not only had three times more cardiomyocytes than control animals, but their heart function was also much better supporting the idea that heart regeneration had, in fact, occur.

These results suggest that cardiac stem cells, if induced to increase their internal calcium oscillations, can be activated to regenerate dead heart tissue after a heart attack stopping function loss and, as result, also the danger of future heart failure.

If Martins, Clavo and colleagues’ results can be transferred to patients they may pave the way to a completely different, and more effective, approach to the treatment of cardiovascular diseases, something particularly important in the times we live in. In fact, despite several advances in cardiovascular care 17 million people still die every year of a disease that seems irrevocably linked to the lifestyle of stress, bad diet and lack of exercise typical of developed societies. As such, and at least for now, disease numbers are predicted to keep increasing worldwide. A good example are the United States where it remains the number one killer, being responsible for almost a third of all deaths in the country, and where one million of people suffers a heart attack every year, with the American Heart Association predicting that in 2009 half a million Americans will experience their first heart attack and that, from these, 18 to 36% will suffer a second episode in 6 years.

1 Circulation Research – Online advance edition 2009 doi: 10.1161/CIRCRESAHA.109.206698 “ Spontaneous Calcium Oscillations Regulate Human Cardiac Progenitor Cell Growth”