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Heart Stem Cells Regenerate Cardiac Tissue Throughout Lifetime

Science, April 3, 2009

In an unusual application of radioactive carbon-14 dating, scientists have made some interesting discoveries regarding the natural activity of cardiac stem cells and the innate ability of the human heart to regenerate its own tissue throughout the entire human lifespan.

At the Karolinska Institute in Stockholm, Sweden, stem cell scientists have capitalized upon the unfortunate fact that a number of radioactive substances were released into the earth's atmosphere as a result of the above-ground nuclear weapons testing that was conducted during the Cold War era of the 1950s and early 1960s, during which time there was a sharp spike in atmospheric levels of radioactive carbon-14, among other chemicals. Even though such levels subsequently declined after the above-ground testing of nuclear weapons was banned, C14 still continued to find its way into the cells of the human body and all other living creatures for many years thereafter, along with additional products of thermonuclear explosion such as radioactive strontium-90 which was found in the deciduous teeth of North American children during the 1950s and 1960s. Also known as radiocarbon, C14 is a radioactive isotope of carbon which occurs naturally in the upper layers of the troposphere and stratosphere when nitrogen atoms absorb thermal neutrons as cosmic rays enter the atmosphere. In the upper atmosphere, however, C14 does not present much harm to humans, whereas on terra firma it can be extremely harmful to any living organism, human or otherwise, when absorbed in sudden, high dosages by bodily tissue. With a half-life of approximately 5,730 years, C14 is not quickly "metabolized", so to speak, and therefore has most typically been used as a reliable tool for calculating the age of organic archaeological remains, as it is readily absorbed by all living tissue. Indeed, as every first-year chemistry student knows, the presence of the element carbon is what distinguishes organic chemistry from inorganic chemistry, since biological life is not possible without carbon, and living creatures can just as easily absorb the radioactive carbon isotope into their bodily tissues as they can the regular carbon atom. Although C14 is one of the three naturally occurring carbon isotopes, it is the only one with an unstable nucleus as both C12 and C13 are stable isotopes.

Fortunately, the above-ground nuclear weapons testing that was conducted in several countries from 1955 to 1963 was finally halted as a result of the efforts of Dr. Linus Pauling who, along with his wife Ava, presented to the United Nations in 1958 a petition which called for an end to the above-ground testing and which was signed by more than 11,000 scientists from around the world. This petition, combined with subsequent pressure from the general public, resulted in an international moratorium on the testing and finally also the signing of the Test Ban Treaty in 1963 by U.S. President John F. Kennedy and Soviet Leader Nikita Krushchev. For his efforts in single-handedly mobilizing and leading such an effective public movement, Dr. Pauling received the 1962 Nobel Peace Prize, which was his second Nobel Prize, his first having been the 1954 Nobel Prize in chemistry for his elucidation of the chemical bond. Hence Dr. Pauling remains the only person ever to have won two unshared Nobel Prizes. After 1963, nuclear weapons testing continued but was transferred underground by the two major Super Powers of the Cold War era, so that radioactive fallout would not continue to contaminate the atmosphere and poison its inhabitants.

As with archaeological dating, C14 was used in this particular medical study as a cellular "clock" for measuring the age of cardiac cells in 12 deceased subjects whose ages at the time of death ranged from 19 to 73 years. Even in those individuals who had been born two decades prior to the start of nuclear weapons testing in the 1950s, C14 was still found to be abnormally elevated in their cardiac tissue, signifying that the tissue had absorbed the C14 years after birth. Similarly, in the younger deceased subjects, the C14 levels were also abnormally elevated but corresponded to a cellular age which was younger than the chronological age of the person, indicating a natural regeneration of the cells.

According to the results of this study, less than 50% of all cardiomyocytes are naturally regenerated by the heart throughout an entire human lifespan, and the rate of renewal slows with age. In the typical person who is 20 years old, for example, approximately 1% of all cardiomyocytes renew themselves each year, whereas in the typical 75-year-old person that percentage has decreased to around 0.45% of all cardiomyocytes. Mathematical modeling additionally revealed that those cells of the heart which develop into heart muscle have a lower turnover rate than do other types of heart cells, such as those that develop into blood vessels and connective tissue, which renew themselves at an annual rate of approximately 18%. Presumably it is the highly specialized nature of cardiac muscle which makes it so difficult to regenerate, since the unique electrical and mechanical properties of cardiac muscle distinguish it from all other types of muscle in the body. Precisely for such reasons, damaged heart muscle following heart attacks or traumatic injury has always been extremely difficult to heal and highly resistant to conventional therapeutic modalities.

Nevertheless, the natural potential for cellular regeneration in cardiac tissue is encouraging, albeit not statistically significant, and now scientists are turning their attention to the development of methods that might stimulate such a natural capacity.

As Dr. Jonas Frisen, a stem cell researcher at the Karolinska Institute in Stockholm who was involved in the study, explains, "We find that the beating cells in the heart, cardiomyocytes, are renewed. It has previously not been known whether we were limited to the cardiomyocytes we are born with or if they could be renewed. If we can understand how the generation of new cardiomyocytes is regulated, it may potentially be possible to develop pharmaceuticals that promote this process to stimulate regeneration after, for example, a heart attack." Dr. Ratan Bhardwaj, also of the Karolinska Institute, adds, "A lot of people suffer from chronic heart failure, which is the result of heart cells dying. Maybe one could devise a pharmaceutical agent that would stimulate heart cells to make new and more cells to overcome the problem they are facing."

The trick would be to increase the rate of regeneration to a level that exceeds the natural rate of cellular death, which is especially pronounced in some medical conditions which include chronic conditions such as heart failure and acute events such as a heart attack or traumatic injury. As Dr. Gregg C. Fonarow, professor of cardiology at UCLA, explains, "It was previously believed that the cardiomyocytes are terminally differentiated and cannot regenerate when the heart is damaged. Recent studies have suggested that cardiomyocytes can regenerate, but there has been substantial controversy as to the rate of cellular turnover. Whether there will be medical or gene therapies that can safely and effectively allow for higher rates of myocardial regeneration will require further study."

According to Dr. Charles Murry, director of the Center for Cardiovascular Biology at the University of Washington in Seattle, "I am very excited about how they have used this novel technology to get something useful out of such a terrible environmental disaster." Dr. Murry then adds, "A lot of us have been working on putting exogenous cells into the heart, but given the choice of growing my own heart back or taking all these cells from elsewhere, I would choose the pharmaceutical approach." Not everyone shares such a personal preference, however, such as Dr. Joshua Hare, director of the Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine, who cautions, "A drug may stimulate a biochemical pathway too crudely, and in regenerative medicine we need to be very careful to avoid unregulated cell growth that could cause tumors."

Adult stem cells are known to reside throughout the human body and have been definitively discovered in a variety of tissue types, although the search for a cardiac stem cell had been an elusive one until recently. In 2008, however, researchers at Children's Hospital in Boston identified a group of stem cells that differentiate into cardiomyocytes and which are located in the epicardium, which is the heart's outer layer of tissue. Their findings were published in the June 22, 2008 issue of the journal Nature, corroborating similar discoveries in 2006 at both Children's Hospital and Massachusetts General Hospital in Boston. Since then, independent researchers have also confirmed the presence of additional cardiac progenitor cells within the epicardium. (Please see the related article on this website, entitled, "Stem Cells Discovered in Surface of Heart", dated June 22, 2008, as originally reported in the journal Nature).

Whether through pharmaceutical stimulation or through a more natural means, scientists hope to be able to harness the innate ability of the heart to regenerate its own tissue with its own endogenous stem cells, one way or another. The mere fact that the heart is capable of such a feat, which had previously been debated for so long, is no small discovery.



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