Regeneration is the ability to restore and renew lost or damaged tissues or organs. The body is equipped with several strategies to regenerate, including the rearrangement of pre-existing tissue, the activation of resident stem cells, and the regression of a specialized cell or tissue to a simpler form by the process known as dedifferentiation. These strategies are directed toward the rebuilding of the appropriate tissue and organ structure. But this regeneration capacity varies in different organisms. For instance, planarians were shown to regenerate into a new worm successfully even when split into 279 pieces. Another striking example of regeneration has been observed in salamanders. When a limb of a salamander is removed, the limb can grow back and become functional in 1-3 months. Then there is the regeneration of the zebra fish heart. When 20 percent of the zebra fish heart is removed, it regenerates completely in 60 days by a process involving the dedifferentiation of heart muscle cells.

Heart regeneration in mammals

Such heart regeneration holds the promise for the treatment of heart failure following heart attacks. But so far, the adult human heart is known not to show adequate regeneration or replacement of dead tissue with functional tissue such as beating cardiomyocytes (cardiac muscles) and arteries. When a patient has successive heart attacks and myocardial infarctions (death of cardiac muscle resulting from interruption of the blood supply), the number of dead cells increases due to the decreased level of oxygen reaching the heart tissue. That’s one of the reasons heart disease is so deadly.

The rates of cardiac regeneration, from fish to amphibians to mammals, demonstrates a decreasing trend — high in fish, moderate in amphibians, and limited in mammals. The regeneration mechanism is thought to occur via incorporating stem cells, using differentiation into cardiac muscle and other cell types, or via dedifferentiation of cardiomyocytes. It is known that the heart of an adult zebra fish can regenerate without scar formation, whereas adult rodents and humans respond with a fibrous scar, without obvious cardiomyocyte regeneration. This remarkable phenomenon had been demonstrated in other fish and amphibians, but never before in a mammal. Recently, researchers at UT Southwestern Medical Center showed that a newborn mouse’s heart can fully heal itself.

Sadek’s group at UT Southwestern Medical Center at Dallas showed that the mammalian heart demonstrates a temporary regeneration capacity in newborn mice. After slowing down the body functions by cooling the body of a mouse, they performed a very delicate heart surgery, removing about 15 percent of the apex of a 1-day-old newborn mouse heart. Within a short period (three weeks), they showed that heart had healed and the function of heart had returned to normal. But when mice are a week old, this remarkable ability of regeneration disappears, and damage to the heart results in the thinning of the heart wall at the site of injury, and the loss of the pumping capacity of heart, also known as heart failure. There seems to be a barrier to regeneration after 7 days. This 7-day window in mice could correspond to a few months after birth in humans. Several reports suggest that human heart may also have some ability to regenerate in infancy.

If newborn animals and infants are able to regenerate their hearts, there could be ways to remind the heart how do this or restart this ability in adulthood to allow regeneration in a broader window. Could there be means to induce regeneration by gene therapy, using small molecules, drugs or hormones? This new discovery brings new approaches to study heart disease and hopes that one day, heart disease — the number one killer in the world — could be treated. More studies are needed and a number of labs have already started to invest in this new model of heart regeneration.

Human heart cell turnover and regeneration

The heart is the least regenerative organ in our body. Once cardiomyocytes are damaged through heart attacks, the heart heals by scar formation instead of regeneration. This results in a loss of contractile function and often ends in heart failure. Lack of regeneration in an adult heart is associated with the complexity and inability of cardiomyocytes to divide, along with the absence of adequate muscle-producing cardiac stem cells in the heart.

Cardiomyocytes proliferate extensively during embryonic development but slow dramatically around birth. The growth of heart continues after birth through the increase in cardiomyocyte size, known as hypertropy. This allows DNA synthesis and nuclear division and results in binucleated cardiomyocytes.

Increasing evidence strongly suggests that the human heart shows a degree of cardiomyocyte repopulation (introduction of new cardiomyoctes). It is always challenging to study human heart cellular homeostasis, as it is limited in the availability of human samples and the means to work on it. Who knew nuclear testing during the Cold War would help to uncover dynamics of human cardiomyocyte turnover? Using a technique based on radiocarbon dating of DNA with carbon-14, released from nuclear tests, Bergmann and his colleagues from the Karolinska Institute in Sweden showed that the cardiomyocyte turnover rate is about 1 percent per year at age 20, with a decline to 0.4 percent per year at age 75. This is based on the idea that people born during nuclear tests following World War II until the Limited Nuclear Test Ban Treaty (1963), any cardiomyocyte repopulation should result in lower carbon-14 concentrations. These findings imply that around age 50, about half of the cardiomyocytes in the human heart are generated after birth. However, another study puts emphasis on the importance of cell deaths (apoptosis) for heart cell turnover, asserting that these rates could be much higher (7-40 percent per year). Those findings bring new hopes to heart disease. If the repopulation potential of heart could be therapeutically targeted, the rate of turnover could be extended to overcome the inability to recover cardiomyocyte loss and cardiac contractility after heart attacks.

The better regenerative capacity of fish and amphibians, compared to that of mammals, seems to stem from the presence of species-specific differences. It has been suggested that the limited regeneration potential of mammalian hearts following injury increases survival by prioritizing homeostasis and fibrosis (scar formation by excess connective tissue). Bleeding from the heart in a high-pressure circulation probably favors the more rapid fibrous healing, instead of regeneration, whereas small animals have a low-pressure circulatory system and oxygenation isn’t needed all the time. This phenomenon probably applies to the regeneration of the newborn mouse heart, which also made the removal of the apex of the newborn mouse heart possible.

Cardiac stem cells for regeneration

The heart is a mosaic of various cell types including valvular, arterial, smooth muscle, pacemaker, endothelial, autonomic ganglia, fibroblasts and cardiomyocytes. Those cells have essentially the same genetic makeup but they show a great diversity. Could there be a common cardiac stem cell that gives rise to all those cell types in the heart? There are a number of studies suggesting the presence of such stem cells, though why they fail to regenerate the heart following heart attacks remains unknown.

There have been a number of attempts to discover cardiac stem cells. Some stem cells have been studied in animals and even considered as possible therapies in human trials. Sources of those stem cells could be classifies as resident and non-resident (exogenous) cells of heart. Exogenous stem cell types include skeletal myoblasts, hematopoietic stem cells, mesenchymal stem cells from bone marrow and circulating endothelial cells. Many approaches to identify resident cardiac stem cells are based on knowledge from hematopoietic stem cells. Using surface proteins on the cells known to enrich bone marrow stem cells, several types of resident stem cells are shown to exist in the heart. There are limited improvements in cardiac function using those cells, but the benefits of those cells are thought to be through other mechanisms instead of replacement of dead tissue in the damaged heart.

A study demonstrating the renewal of a newborn mice heart does not completely rule out resident cardiac stem cells as a source of new beating heart cells, but points out the likelihood of their originating from cardiomyocytes by dedifferentiation. Along with a number of attempts to treat heart failure by using stem cells, recent findings offer hope that researchers and doctors will one day able to cure heart disease. Knowing that “there is no disease that God has created, except that He also has created its treatment,” our duty is to study hard and to develop new technologies to find the prospective treatments for heart failure to serve humanity.

References

• Porrello et al. 2011. “Transient Regenerative Potential of the Neonatal Mouse Heart.” Science 25 February: 1078–1080.
• Bergmann et al. 2009. “Evidence for Cardiomyocyte Renewal in Humans.” Science, 3 April: 98–102.
• Charles E. Murry and Richard T. Lee. 2009. “Turnover after the fallout.” Science, V324.
• O.Bergmann et al. 2009. Science 324, 98.
• Simonetta Ausoni and Saverio Sartore. 2009. “From fish to amphibians to mammals: in search of novel strategies to optimize cardiac regeneration.” JBC. 184 (3).
• Martin-Puig et al. 2008. “Lives of a hear cell: Tracing the origins of cardiac progenitors.” Cell Stem Cell 2. April.
• Nevada Nuclear Testing Site: http://mason.gmu.edu/~kcherrix/atomichome.html
• Sahih al-Bukhari, Vol. 7, Book 71.