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Cellular biology

Unexpected effect

Adult stem cells stimulate the formation of blood vessels in the heart, but do not generate cardiac muscle

DENISE CHAN / WIKIMEDIACOMMONSMatters of heart, acrylic on canvas, Denise ChanDENISE CHAN / WIKIMEDIACOMMONS

Though it may seem to stimulate the production of blood vessels in the area near a lesion, the use of adult stem cells taken from patients themselves is incapable of producing cardiac muscle and therefore of directly repairing heart damage in someone who has suffered a myocardial infarction. This is the main conclusion of an article published on April 14 in the journal Science Translational Medicine. In this study, the Brazilian physician José Eduardo Krieger, from the University of São Paulo (USP), and the researcher Christine Mummery, from Leiden University, in the Netherlands, carried out a broad review of trials with animals and humans involving the use of adult stem cells to repair myocardial infarction lesions (the death of part of the muscular substance in the heart due to lack of blood irrigation), which causes 12% of  deaths in the world.

In experiments conducted in various countries, including Brazil, different research teams injected millions of stem cells into the blood stream or applied them directly to the heart’s damaged area. These immature cells were expected to take the place of  dead cells and, upon maturing, to undertake the function of the dead cells. “Promising short-term cardiac function improvement [observed in animals] led to the use, at an unprecedented speed and scale, of stem cells taken from the bone marrow in clinical trials with people who had had a myocardial infarction,” wrote the researchers. However, in the long term, the results were not as good as expected. Though the human trials indicated that implanting adult stem cells in the heart is safe, the blood-pumping capacity improvement in general was very small: only 3% and below the 5% considered necessary to diminish symptoms and improve patient survival rates.

This finding did not lead the scientists to entirely discard the clinical use of such biological material, however. If on one hand these stem cells are of no use to repair a damaged heart, on the other hand, injecting bone marrow cells, which apparently are able to improve the organ’s vascularization, might help to avoid heart problems among high-risk patients, such as obese people in imminent danger of having a heart attack.

Many of the studies analyzed by Krieger and Christine used stem cells taken from the bone marrow, the tissue that fills the body’s long bones. Studies published at the beginning of this decade suggested that these cells, after adhering to the heart, would turn into cardiomyocytes, i.e., the heart cells that contract and cause the heart to pump blood to the rest of the body. However, subsequent research showed that the stem cells merged with the cardiomyocytes instead of transforming them. This observation led to a new interpretation of results: the improvement resulted not from the replacement of dead cells, but from preventing cell death after the infarction.

According to Krieger and Christine, there is currently a consensus to the effect that the improved cardiac function results are not due to a larger number of contracting cells, but to the transplanted cells’ secretion of compounds such as blood vessel growth factors, which presumably would help to avoid cell death in the infarction area – an effect apparently produced by stem cells of different origins. “Pre-clinical studies show that different types of stem cells (taken from the umbilical cord, from fatty tissues or from peripheral blood) behave like the cells extracted from the bone marrow and implanted directly into the heart, or like those that settle in the heart after being injected into the blood stream,” they state.

No integration
In vitro tests indicate that cardiomyocytes obtained from stem cells taken from embryos or obtained by reprogramming adult cells do indeed conduct electric current, an essential feature for controlling heartbeats. However, they do not always connect as they should to the heart cells. Experiments on rodents showed that in many cases the cardiomyocytes derived from stem cells were separated from the original heart cells by fibrous tissue. According to Christine and Krieger, there is a suspicion that this incomplete integration can lead to heart arrhythmia.

Merely producing new heart cells or avoiding the loss of the original ones, however, is insufficient to keep the heart working properly. Together with researchers from California, Krieger and Sérgio de Oliveira, both of them from USP’s Heart Institute (InCor), emphasized in earlier publications that heart geometry is important for the organ to maintain its blood-pumping capacity.

Shaped somewhat like an egg in healthy people, the heart may acquire a spherical shape in the case of several heart diseases. This deformation diminishes its capacity to pump blood and is connected with a higher patient mortality rate. According to Krieger, to repair the heart, one not only needs viable tissue to receive the cell transplant, but one must also maintain or recover the heart’s geometry. “This shape issue has been underestimated not only in determining the best clinical strategies but also in the interpretation of the results of pre-clinical studies conducted with small rodents,” states Krieger, who advocates carrying out more basic and pre-clinical trials before stem cells are made available for the treatment of human beings.

In the Science Translational Medicine review, he and Christine also suggest the development of  new models of experiments on rodents, to enable the evaluation of the implant of stem cells at different stages after infarction. Additionally, they advocate tests on larger animals, such as pigs, whose post-infarction cardiac alterations are more similar to those observed in humans, plus studies comparing the use of different types of stem cells and different doses in large animals.

According to Krieger, in order to have a greater impact on the treatment of infarction patients, the research studies will have to find ways to generate cardiac muscle. The marrow stem cells may even play an indirect role in preventing heart lesions, but they lack the muscle-generating therapeutic potential. Therefore, the studies that are designed to find effective treatments for heart lesions must focus on three types of stem cells that are theoretically more promising than bone marrow ones, although their use is less safe and has been less studied: embryo stem cells, which, in theory, can become any cells whatsoever, including heart cells; adult stem cells, such as those of the skin, which might be reprogrammed to behave like embryo stem cells or already differentiated heart cells; and heart stem cells, which must exist in the heart. “We could remove the heart stem cells from patients themselves or from a young donor, select them and amplify them,” comments Krieger. “These are three long-term research avenues.”

Scientific article
MUMMERY, C. L.; DAVIS, R. P. ; KRIEGER, J. E. Challenges in using stem cells for cardiac repairScience Translational Medicine. v. 2 (27). 14 April 2010.

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