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); pluripotent cells (they have a more specific differentiating process than that of the totipotent cells yet they are masters of cell differentiation because they can engender all the kinds of cells that constitute a human body, for example, a blastocyst); multipotent cells (they differentiate into a specific range of cells giving rise to a number of tissue types); oligopotent cells (the differentiation process is narrow, these cells being able to produce few related types; hematopoietic stem cells are the exponent for this group); and, unipotent cells (they have the most limited differentiation process because they can only turn into themselves) [1]. Based on their origin, stem cells are classified into five categories: embryonic, fetal, infant, adult, and induced stem cells (
Types of stem cells and their advantages and disadvantages
Zygote. | Higher differentiation potency. |
Subject to ethical issues due to methods of obtaining them. |
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Blastocyst. |
High differentiation potency. |
Subject to ethical issues due to methods of obtaining them. | |
Umbilical cord. |
Multipotent. |
Differentiation potency is lower than that of fetal cells. | |
Bone marrow. |
Oligopotent. |
Differentiation potency is the lowest. |
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Adult somatic cells genetically modified to resemble embryonic stem cells. | Obtained from adult and perinatal cells (not an ethical issue). |
Immunogenic effect. |
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 (
Types of stem cells and their effect in reviewed studies
Safety Efficacy | 15 in study group, |
24 hours after STEMI. | 8.37 × 106 | LVEDV, LVESV, LVEF by echocardiography (biplane Simpson method – apical two- and four-chamber). | Achieved safety. |
|
Safety Efficacy | 14 in study group, |
1 month after STEMI. | 7.2 ± 0.9 × 107 | LVEF by SPECT and echocardiography. | Achieved safety. |
|
Efficacy | 51 in |
5 × 107 – 5 × 108 | GLS and GCS by cardiac magnetic resonance. | None of time related treatment proved an improvement in cardiac parameters. | ||
Efficacy | 66 in study group, |
6–9 days after STEMI. | 100 × 106 | LVEF, LVEDV, LVESV, infarct size by cardiac magnetic resonance. | Study and control group had similar results at baseline, at 6-month follow-up and between times. | |
Safety Efficacy | 21 in study group, |
14.07 +/−9.53 days after STEMI. | 3.31 ± 1.7 × 106 | LVEF, LVEDV, LVESV by echocardiography (Simpson method) at 12 months and myocardial perfusion and metabolic activity by SPECT at 6-month follow-up. | Achieved safety. |
|
Safety Efficacy | 33 in study group |
Days 5–7 after STEMI. | 35 × 106 | Infarct size, LVEF, LVEDV, LVESV and wall motion score by cardiac magnetic resonance. | Safety was the primary endpoint, and it didn’t reveal any major cardiac adverse events or deaths at 6- and 12-month follow-up. No significant differences in assessed parameters between the groups at baseline and follow-up times. | |
Safety Efficacy | 90 in study group |
4 weeks to 12 months after STEMI. | 2.5 × 106 | Infarct size, LVEDV, LVESV, LVEF by cardiac magnetic resonance. | Safety endpoint was achieved. |
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 (
The biological parameter changes in trials proving the beneficial effect of stem-cell therapy in myocardial infarction
Allogenic CSC | CRP | Similar baseline values between groups. |
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NT-proBNP | Similar baseline values. |
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CK and TnT | Similar decreasing trend. | ||
Allogenic CDC | NT-proBNP | Greater decreasing level at 6 months in study group ( |
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Autologous BM-MNC | CRP, CK-MB, TnT, BNP | Similar baseline levels between the entire study group and control group but lower CK-MB, TnT, and BNP initial values in responders, with faster decrease in BNP levels in the entire study group and TnT levels in the responders. |
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?
There is conflicting evidence in literature of when is the best time to use stem-cell therapy in myocardial infarction. Too early treatment, hours or a few days after the event, might have no effect due to the inflammatory response in the myocardium as a response to the ischemia and necrosis, which can cause stem cell death caused by the inflammatory cells, while later therapy might be of no use due to the presence of the fibrotic scar. After acute myocardial infarction, two phases consisting of immunologic and cellular response occur, in order to create the scar. By day five a pro-inflammatory response takes place in the infarcted area, followed by an anti-inflammatory phase which peaks at day seven [21]. A study conducted in 2002 by Straurer has proved the beneficial effect of bone marrow mononuclear cells on left ventricle parameters after acute myocardial infarction. The time window used in this study was between five to nine days after infarction, suggesting that transplantation of stem cells in this period might have a hold upon the response of the left ventricle infarcted area [22].
The infarct size area depends on the culprit artery – the larger the vessel, the bigger the infarcted area. In trials proving the beneficial effect of stem cells, only one-vessel-disease patients were included. Occlusion of left anterior descendent artery (LAD) with anterior wall myocardial infarction was taken into consideration in both studies. In the trial from Peregud-Pogorzelska et al., out of ten patients with LAD occlusion who received stem cells by intracoronary injection, five have become responders (55.5%) with improvement in left ventricle ejection fraction, and five had no change in parameters, while among those with other vessels involved, the ratio of responders was lower (all patients with right coronary artery [RCA] occlusion responded to treatment while one out of the two patients with left circumflex [LCX] occlusion responded to treatment) [16].
All studies taken into consideration in our review have used different doses of stem cells (see Table), most of them numbering millions of cells. For comparison, Florea et al. proved that a dose of 25 million allogenic stem cells reduced the infarct size, but a higher dose of 100 million cells determined not just a change in size but also an improvement in left ventricle ejection fraction [23]. Yet, even if the dose of stem cells was different between trials, compared with earlier studies that included similar or lower or higher doses, a beneficial effect was not seen among all trials, probably because of the other factors that must be taken in consideration (time frame, culprit artery, cardiovascular risk factors).
To date, studies make use of multimodality imaging for assessing the effects of stem-cell therapy in myocardial infarction, cardiac magnetic resonance becoming somewhat of a standard of assessing cardiac function in this case, yet every study used echocardiography as a comparative tool. While magnetic resonance can be considered trustworthy, echocardiography is submitted to interobserver and interobserver variability, which can be a source of error in assessing left ventricular function.
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.