Stem Cell Therapy in Myocardial Infarction: Still Therapeutic Hope?

Regenerative medicine has gained ground during past years due to new knowledge concerning stem cells’ ability to regenerate tissues, techniques in obtaining this type of cell, and means to induce them to target the troubled tissue. Treatment using stem cells has been used for some time, especially in bone marrow and blood disorders due to the abundance of regenerative cells in these tissues. Nowadays other illnesses are under consideration to be treated with stem-cell transplants, among them being myocardial infarction.

Stem cells are immature cells with the capacity to engender new cells in the process called differentiation. There are five main types of stem cells, types based on the extent of their ability to differentiate:

totipotent cells (the only cells of this kind are the zygote and blastomere because they give rise to a new individual, being the base for the development of other cells);

Figure 1

Embryonic stem cells are totipotent and pluripotent. Due to being fully differentiated and capable of producing a large range of cells, they are the ideal for stem cell cultivation, yet because of how they are obtained (from embryos that are either produced in the laboratory for study purposes or are left over from fertilization processes or resulting from abortion), which makes them the subject to ethical issues, and because their malignant transformation, they are the least used [1,3].

Stem cells of fetal origin are multipotent, a property that makes them more potent than stem cells of adult origin. Also, they do not exhibit malignant proliferation (as embryonic stem cells do) and have a lower immunogenic effect than adult stem cells, which makes them more suitable for allotransplantation. This group includes cells from the neural crest, and hematopoietic and mesenchymal stem cells. They can be obtained from fetal blood or other fetal tissues such as liver and bone marrow. Due to the fact that fetal blood is a source of stem cells, cultivating stem cells of fetal origin is not strongly subjected to ethical issues [2,4].

Infant stem cells, also called perinatal cells, are obtained from extraembryonic structures at the time of birth (amniotic fluid, placenta, umbilical cord) and have the advantage of being multipotent due to the fact that most of them are mesenchymal stem cells, less immunogenic than those of adult origin. They do not pose ethical issues [5].

Stem cells obtained from adult structures are either oligopotent (out of which the hematopoietic stem cells and mesenchymal stem cells have the highest value) or unipotent. Mesenchymal stem cells, unlike the hematopoietic ones, have a lower immunogenic effect as they lack antigens (HLA type). The major issue of adult stem cells is that their differentiating process is narrower than those of previous cells and obtaining them is part of a painful process. Also, the number of cells that can be obtained is usually smaller and may not be enough for therapy of an individual subject to the need for stem cell therapy [2,6,7].

Induced pluripotent stem cells are obtained in the laboratory from adult or infant cells that are directed to improve their differentiation potency by genetic modification to become similar to embryonic stem cells. Thus, these are embryonic-like cells with the advantage of not raising ethical issues. Their disadvantage is that they retain the high immunogenic effect of adult cells [8,9].

For many years it was thought that cardiomyocytes have no capacity to renew themselves because they are postmitotic cells that are no longer capable of mitosis. Recent studies have demonstrated that, in fact, in mammals, thus in humans, the embryonic, fetal, and early newborn heart (for a few days after birth) has the ability to regenerate cardiomyocytes. This property is lost soon after birth, this being the substrate of the heart's inability to repair after myocardial infarction, and instead of healing with restitutio ad integrum, a scar is the final point of the healing process [10].

The idea that stem cells can be used to renew cardiomyocytes lies in the fact that the heart and other body structures comprise progenitor and cardiac stem cells. In the last decades of the last century, it was believed that there were adult stem cells capable of generating cardiomyocytes and that these cells would exist both in the heart and in extracardiac structures, but it was not until the early 2000s that evidence was provided for this. In 2004, Messina et al. have isolated a population of cells called cardiospheres capable of engendering cardiomyocytes [11]. These cardiospheres are a cluster of cells situated in the core which exhibit c-kit receptors (whose ligand is the stem cell factor) and peripheral cells that express other markers of cardiac and stem cells [11]. Up-to-date studies support the aforementioned hypothesis that cardiac cells can regenerate. Mollova and col-laborators have outlined the mathematics of the hypothesis by counting the number of cardiomyocytes; they have determined that the number of cells increases in the first two decades of life (1.1 ± 0.1 × 109 cells in newborn heart versus 3.7 ± 0.3 × 109 in 20-year-old hearts) [12]. Carbon dating was used to measure the turnover of cardiomyocytes and it led to the conclusion that the turnover rate decreases with age, being the highest (yet small) in the first two decades of life (1% per year) and only 0.3% in subjects 75 years of age. Yet this conclusion strengthens the idea of the heart's regenerative capacity [13].

We reviewed the latest five years of trials conducted on stem cell therapies in myocardial infarction provided in full text by PubMed in order to look for further perspectives in myocardial infarction management.

Despite the fact that stem cells comprise a variety, their use in myocardial infarction is limited to a few types, most trials focusing on using autologous stem cells rather than allogenic ones.

Autologous bone marrow-derived stem cells are, by far, the most frequently used in the latest five years of randomized and nonrandomized clinical trials in patients with myocardial infarction. Among this class, two types of stem cells have been used to date: bone marrow mesenchymal stem cells (BM-MSC) [14,15] and bone marrow mononuclear stem cells (BM-MNC) [16,17,18]. Their extended use relies on the ease with which they are harvested given that they do not require a donor but are obtained from myocardial infarction patients through bone marrow aspiration, and also for their ability to evade the immune system.

While most studies focus on the aforementioned cell variety, allogenic stem cells tend to gain ground in extended human studies comprising a larger number of enrolled patients, cardiac stem cells (CSC) [19], and cardiosphere derived cells (CDC) [20] being used in the latest five years of trials.

In recent studies, both autologous and allogenic cells proved their safety (Table 2), with few adverse events attributed to their use. Supraventricular and ventricular premature beats were the common arrhythmic adverse findings among studies. Regarding immunogenic side effects, the CAREMI trial reported three cases of hyperpyrexia and one case of allergic dermatitis probably attributed to therapy, all of these side effects occurring in the first month after intervention. Interestingly, none of the patients experiencing these side effects had developed donor antibodies [19].

All studies in our review had efficacy as endpoint, with similar study group characteristics between trials (patients with myocardial infarction with successful primary coronary intervention with thrombolysis in myocardial infarction [TIMI] flow grade 3 and reduced left ventricular ejection fraction [LVEF] less than 45% or 40%). Only a couple studies have demonstrated an improvement in left ventricular function parameters after stem cell therapy, but both had as inclusion criteria single-vessel coronary disease, and they assessed left ventricle ejection fraction and volumes but not the infarct size, which raises the question of whether the size of the infarcted area can be inversely proportioned to the expected effect [14, 16].

Changes in biological parameters have been measured by both CAREMI and ALLSTAR trials and by Peregud-Pogorzelska et al., with comparable results (Table 3). Although the CAREMI and ALLSTAR trials did not validate an improvement in left ventricular function, they have showed changes in laboratory parameters. CRP levels have decreased more rapidly by day 7 in the study group (p=0.04) of the CAREMI trial compared to levels of CRP in the trial of Peregud-Pogorzelska. Regarding natriuretic peptides, NT-proBNP was assessed in both the CAREMI and ALLSTAR trials but only the last one proved a statistically significant difference (p=0.02) for it at follow-up (a decreasing value of −429 ± 884.1 pg/ml in study group versus −126 ± 621.5 pg/ml in control group). BNP was assessed by Peregud-Porozelska, which observed a faster decrease in the study group.

Looking back to the early 2000s, when studies on stem cells in the cardiology field seemed to give rise to a new era with a bright outlook for a future therapy in myocardial infarction, nowadays a question is evident, with possible answers that need to be addressed: why the conflicting evidence in efficacy with the balance tipping to a “no” answer?

At the moment, trials considering therapy with stem cells in myocardial infarction are offering conflicting evidence regarding its beneficial effect on improving ventricular function. Further studies without the limitations of the present ones need to be conducted in order to have a clear view of the benefits or detriment in stem cells’ potential reparatory effects.