ABSTRACT
SkMs can be used for autologous transplantation by overcoming problems related to cell availability, ethics, and immunogenicity; can be isolated with a simple surgical procedure; and display a high proliferative potential in vitro and a good tolerance to ischemia, the latter being an important feature for injection into an infarcted heart [18]. SkMs were widely used in animal studies with chronic heart failure, and amelioration of the left ventricular ejection fraction (LVEF) was found; similarly, Van Den Bos et al. [19], in an acute myocardial infarction (AMI) rabbit model, demonstrated an increase of the LV wall thickness and a reduction of postinfarction remodeling. Ghostine et al. [20] demonstrated that SkMs are able to differentiate into characteristic multinucleated myotubes and to repopulate the area of fibrosis after injection into the heart in a sheep model with AMI. However, if it seems that these cells integrate into the cardiac muscle, SkMs do not display the morphological changes typical of cardiomyocyte differentiation, maintain the sarcomeric structure of skeletal muscle cells, and fail to form intercalated discs and functional junctions with resident cardiomyocytes [21-23]. The lack of electromechanical coupling with the surrounding cardiac muscle represents a serious danger for the generation of arrhythmias, as observed by Leobon et al. [24] in 2003. Without cardiomyocyte differentiation capacity, SkMs are able to act in a paracrine manner, secreting molecules capable of increasing neoangiogenesis and promoting reorganization of the extracellular matrix (ECM). Fukushima et al. [25] demonstrated that SkMtreated rats showed less fibrosis and cardiomyocytes hypertrophy compared to untreated controls. The same group further confirmed that the benefit was mainly related to the influence of SkMs on ECM remodeling and the matrix metalloproteinase/tissue inhibitor of metalloproteinases (MMP/TIMP) balance [26]. BM cells contain different populations of progenitor cells: hematopoietic cells (HSCs), which give rise to lymphoid and myeloid lineages; endothelial progenitor cells (EPCs); and mesenchymal phenotypes (bone-marrow-mesenchymal stem cells [BM-MSCs]). BM cells can be obtained directly by BM aspiration or from the peripheral circulation after cytokine mobilization. HSCs (CD34+/CD133+ cells), have been used for cardiac transplantation, but at present their beneficial role is still unclear. In
2001 Orlic et al. suggested that a selected c-kit-positive subpopulation of HSCs was able to transdifferentiate into cardiomyocytes when injected into an infarcted heart and generating de novo heart muscle. More recently, other research groups [27-29] did not confirm this in vivo data. The positive effect related to the reduction of LV dilatation and the improvement of LV function upon HSC transplantation, suggesting a different mechanism than that of neocardiomyocyte generation. MSCs are a rare cell population resident in the BM and in the stroma of other mesenchymal tissues like adipose tissue. These cells are characterized by self-renewing and multipotency. MSCs demonstrated good cell plasticity in in vitro experiments, which confirmed, with promising results, also studies of AMI models where these cells showed the ability to engraft into the host heart and differentiate into vascular cells and cardiomyocytes [30, 31]. In the last years BM mesenchymal and mononuclear cells have been used in a great number of clinical trials. Lipinski et al. [32] published in 2007 a review based on the meta-analysis of clinical trials on intracoronary cell therapy after AMI. They collected and analyzed data from 10 studies (698 patients, median follow-up 6 months) and demonstrated that intracoronary cell transplantation following percutaneous coronary intervention for AMI appears to provide statistically and clinically relevant benefits on cardiac function and heart remodeling. The number of studies performed in chronic models has been more limited. Liu et al. [33] demonstrated that MSCs transplantation improved the LVEF, promoted neoangiogenesis, and decreased the infarct size one month later in a rat model. Similar results were obtained four weeks after induction of heart failure in rats by Li et al. [34]. In a large animal model, Waksman et al. [35] transplanted BM-MNCs in domestic swine. Four weeks later they found an improvement in angiogenesis and in the reduction of infarct size, but no clear improvements were found ventricular contractility. BM-derived cells have been also used in a few clinical trials for chronic myocardial ischemia. Interesting results were published in 2009 in Journal of the American Medical Association (JAMA) by Van Ramshorst et al. [36]. The authors investigated the effect of intramyocardial BM cell injection on myocardial perfusion and LV function in patients with chronic myocardial ischemia (50 patients,
randomized, double-blind 6-month follow-up). They found that intramyocardial cell transplantation resulted in a statistically significant but modest improvement in myocardial perfusion compared with a placebo, but they also observed that further studies are required to assess long-term results and efficacy for mortality and morbidity. Most of studies with MSCs suggested that their ability, similar to HSCs, to directly transdifferentiate into cardiomyocytes seems to be a rare event, and the majority of studies have demonstrated a paracrine activity with pro-angiogenic modulation and production of pro-survival factors like growth factors and anti-inflammatory cytokines. Moreover, another advantage of MSCs is related to their potential use in allogenic transplantation since they have low immunogenicity. In vivo studies showed that allogenic MSCs are not rejected by the recipient host [37]; this could represent a significant feature for their future clinical applications. Adipose-derived stem cells (ADSCs) described for the first time in 2001 by Zuk et al. [38] are localized in the stroma of adipose tissue. ADSCs are composed of a heterogeneous population and display features similar to that of mesenchymal BM-derived cells with respect to surface marker expression and plasticity. In the last decade, ADSCs have been intensively studied by different research groups, and Planat-Bénard et al. [39] in 2004 demonstrated, for the first time, the ability of ADSCs to be committed to the endothelial lineage and into beating cells with the features of cardiomyocytes. More recently, other authors also described the ability of these cells to differentiate into cardiovascular/vascular cells [40-43]. Nevertheless, the real potential of ADSCs to regenerate cardiac tissue in vivo remains still to be confirmed. CPCs were described for the first time in 2003 like an endogenous cell population with features of stem progenitor cells [44, 45]. Since 2003 different research groups started to study these cells, and two main populations were identified as candidates for cardiac regeneration-the Islet-1 [46] and c-kit-expressing [47] cells. Independently from the identifying marker, today most of scientists agree on the existence of endogenous cardiac stem cells and support the hypothesis that the heart is not a postmitotic organ. Recently, it has been clarified by Bergmann et al. [48] that the heart has an intrinsic renewal ability, and half of the cardiomyocytes of the heart are replaced by new ones by normal cell turnover throughout life.
