Editorial[Hot Topic:Stem Cell Therapy for Cardiovascular Diseases:Are We Still at the Beginning of A Long Road?(Guest Editor:Lino M Goncalves)

Cell and tissue repair is an essential mechanism not only to the survival of organisms in their constant struggle to preserve homeostasis, but also for the evolution of life in Earth's often harsh environment. In some tissues this ability to regenerate is extremely effective, while in others it is virtually nonexistent. Some organisms, such as the zebrafish and newt, have excellent regenerative capacities and can completely regrow an amputated limb or tail [1]. They can even regenerate part of the heart that has been excised, by producing a mass of undifferentiated cells [1]. Unfortunately, under normal conditions mammals do not possess this extraordinary ability [2]. However, the inability of mammals to regenerate cardiac tissue can, at least in theory, be circumvented by various mechanisms [3]. The potential role of stem cells in cardiovascular diseases is well recognized. Stem cells contribute to cardiac repair, but they only have a limited capacity to achieve this effect. Stem cells use has been an important area of both basic and clinical research during the last years. Various types of cells have been used for transplantation targeting cardiac repair, including bone marrow cells, resident cardiac stem cells, endothelial progenitor cells, skeletal myoblasts, adipose progenitor cells, mesenchymal progenitor cells, and embryonic stem cells. Besides intracoronary administration, two other methods are used to apply stem cells: percutaneous endocardial (intramyocardial) and surgical (epicardial). The advantage of intracoronary application is that the cells reach the infarct border zone, an environment where they are likely to develop. However, this route means that the cells must migrate through the arterial wall to myocardial tissue, and so ischemic areas will receive fewer cells than non-ischemic areas. In addition, while stem cells derived from bone marrow or blood are able to migrate through the vessel wall, this is not the case with skeletal myoblasts, which can obstruct coronary microcirculation and cause microinfarctions. Intramyocardial administration has the advantage of applying the cells directly at the desired site without the need for migration and without provoking distal embolization. However, this requires perforation of the myocardium, and cells are less likely to survive in necrotic tissue with limited perfusion, particularly in the first few days post-MI. Most cells injected in these circumstances in fact die [4]. Moreover, a recent study showed that intravenous bone marrow mononuclear cell injection was ineffective to target myocardium and that the presence of myocardial infarction did not affect myocardial cell distribution [5]. Another important point is that stem cells mainly home to the spleen [6]. In fact, in one study, myocardial regeneration was only induced in splenectomized animals [7]. Safety is an essential consideration in any new therapy introduced into clinical practice. Stem cells have the potential to transform not only into cardiomyocytes but also into fibroblasts, which may worsen myocardial scarring and create a substrate for malignant arrhythmias [8]. This pro-arrhythmic effect may be strengthened by the incomplete integration of stem cells into myocardial tissue, which could affect electrical conduction and hence the synchronicity of myocardial contraction. This effect of stem cell therapy had not been seen in animal studies before its use in humans [9, 10]. However, enthusiasm for injecting skeletal myoblasts into myocardial scar, with the aim of repairing the damaged tissue, has waned after patients receiving the treatment began to suffer from malignant arrhythmias [11]. These may be caused by the failure of skeletal myoblasts to produce connexin-43, preventing electrical coupling with the surrounding myocardium [12]. Intracellular monitoring of skeletal myoblasts transplanted into infarcted myocardium in rats showed that the myoblasts' contractile activity was independent of neighbouring cardiomyocytes [13]. This could trigger fatal arrhythmias. As a consequence, intramyocardial administration of skeletal myoblasts must be accompanied by implantation of a cardioverter-defibrillator [11]. Teratomas can also form as a result of stem cell therapy. The application of unselected cell populations from bone marrow, containing stem cells that are specific to various organs, can result in the development of non-cardiac tissues [14]. Furthermore, four weeks after intramyocardial administration of unselected bone marrow cells in rats, myocardial calcification was found in 30% of the animals [15].