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Despite many breakthroughs in cardiovascular medicine, myocardial infarction (MI), ischaemic heart disease, and heart failure are still amongst the most prominent health challenges of the developed world. Unlike many other tissues in the human body, the cardiac tissue has a diminished ability to repair itself following tissue injury. Damage to the myocardium initiates a cascade of processes, known as cardiac remodeling, which eventually leads to scar tissue formation and a diminished functionality of the cardiac muscle. Currently the clinically used therapeutic interventions are aimed at symptomatic relief, rather than correcting the underlying cause, i.e. loss of vessels and cardiomyocytes. Patients diagnosed with chronic heart failure have a five year survival rate of less than 50%, even worse than patients diagnosed with bowel cancer or breast cancer (Steward et al., 2001). Therefore, novel strategies aimed at regenerating and/or repairing the number of functioning cardiac muscle cells in the failing heart might hold the key for treating patients with advanced heart failure.
Recently, the characterization of several stem cells capable of contributing to tissue regeneration has raised the possibility of a cell based therapy for repairing damaged myocardium. Several cell types have been identified with the potential to initiate cardiac regenerations, including embryonic stem cells (ESCs), bone marrow derived stem cells, cardiac progenitor cells, and induced-pluripotent stem cells (iPSCs). The optimal cell to drive cardiac regeneration would need to fulfill several criteria. Firstly, these cells should be readily isolated in sufficient quantities and should be driven into a cardiomyogenic differentiation pathway. Furthermore, electromechanical integration with the hostââ‚¬â„¢s cardiac tissue should be achieved, without inducing an immune response. In this review we will describe up to date research and clinical trials involved in the characterization of potential cell based therapies for regenerating the failing heart.
Stem cells are pluripotent cells that can differentiate into all the specialized cells that impart function to tissue and organs. To date, the best characterized pluripotent stem cells are embryonic stem cells (ESCs) and bone marrow stem cells (BMC). ESCs are pluripotent cells that can be expanded indefinitely and possess the potential to differentiate into all lineages (Thomson et al., 1998). Despite being capable of differentiating into all the key components of the cardiac tissue (i.e. myocardial, endothelial and smooth muscle cells), several drawbacks have to be taken into account when experimenting with ESCs. These cells are primarily isolated from the inner cell mass of embryos at the blastocyst stage or from aborted tissue in the region destined to become testes or ovaries (Thomson et al., 1998; Shamblott et al., 2001), and as such the use of ESCs for research has been greatly debated due to its ethical implications. Furthermore, the transplantation of ESCs into damaged mouse knee cartilage results in teratoma formation and consequently further deterioration of the cartilage (Wakitani et al., 2003). Similar to ESCs, a population of adult stem cells has been identified in the bone marrow, which have the potential to repopulate neuroectodermal cells, skeletal myoblasts, cardiomyocytes, endothelium, hepatocytes, lung, gut, and skin epithelia (ref). Although the pluripotency of BMCs is of great significance for regenerative medicine, the administration of unselected BMCs for the treatment of MI in animal models resulted in severe myocardial calcification (Yoon et al., 2004). These results have led to increased efforts to identify better cell sources for regeneration and repair of the damaged cardiac tissue.
Therapeutic potential of Bone Marrow-derived stem/progenitor cells
Potential cell sources for cardiac regeneration in the bone marrow include endothelial progenitor cells (EPCs), haematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and other cell types with many desirable characteristics. In vitro, these bone marrow-derived cells can be induced to differentiate into the major cellular components of the cardiac tissue (ref). When these cells are injected into infracted myocardium, the cells have been shown to undergo myogenic differentiation and in some cases these cells become electromechanically coupled with host cardiomyocytes. In vivo studies using animal based models of MI treated with bone marrow-derived cells have demonstrated improvement to the ventricular ejection fractions and perfusion of cardiac tissue, combined with a decrease in wall thickening, thus an overall improvement of the cardiac functionality is observed (ref).
Due to the exceptional results obtained from in vitro studies and in vivo animal model experiments, several clinical trails were initiated using bone marrow derived cells. However, many of these trials were unable to detect a significant improvement in the cardiac function as a result of the bone marrow derived cells. A recent meta-analysis has compiled data of 13 randomized clinical trials of intracoronary autologous BMC infusion following acute MI in humans. This report concluded that as a result of the stem cell therapy, there was a mean increase in ejection fraction (EF) of approximately 3% ââ‚¬" 4%. This slight improvement in functionality appears to persist for at least 1 year, although certain studies suggested beneficial effects to persist even after 5 years while other trials observed a decrease in functionality after 12 months. Furthermore, these clinical trials failed to demonstrate myocardial regeneration as a result of the bone marrow cell therapies, suggesting the improved cardiac functionality to be due to paracrine effects (Martin-Rendon et al., 2008).
Therapeutic potential of embryonic stem cell derived progenitor cells
Recent studies using embryonic stem cells (ESCs) to investigate the early stages of cardiogenesis, have characterized two separate progenitor pools or heart fields from which the heart develops (Cai et al., 2003; Kelly et al., 2001; Mjaatvedt et al., 2001; Waldo et al., 2001; Zaffran et al., 2004). The first population, or first heart field (FHF), originates from the anterior splanchinic mesoderm and migrates to the heart, giving rise to the early heart tube and ultimately contributing to the left ventricle and atria (Dehaan, 1963; Zaffran et al., 2004). The second cardiogenic polulation, or second heart field (SFH), of the embryo is derived from the pharyngeal mesoderm. These cells are initially involved in the development of the arterial end of the heart tube and eventually give rise to the right ventricle and outflow tract of the mature heart (Kelly et al., 2001; Zaffran et al., 2004). As a result of these studies, novel ESCs derived cardiac progenitor cells have been characterized that hold great promise for cardiac regeneration.
These novel cardiac progenitor cells derived from ESCs have been identified on the basis of Brachyury/Flk1 (Kattman et al., 2006), Isl1/Flk1/Nkx2.5 (Moretti et al., 2006), cKit/Nkx2.5 (Wu et al., 2006), Isl1/Nkx2.5 (Domain et al., 2009) or Nkx2.5 (Christoforou et al., 2008) expression, all of which are key transcription factors of the cardiogenic differentiation pathway. Brachyury is a T-box transcription factor and one of the earliest markers defining the mesoderm lineage. The expression of brachyury in all nascent mesoderm cells gets downregulated ones the cells undergo patterning and specification (Kispert and Hermann, 1993; Kispert and Hermann, 2994). Prior to differentiation, the majority of the cardiac progenitor cells are labeled by a LIM homeodomain transcription factor, Isl1 (Moretti et al., 2006). Nkx2.5 is another homeodomain transcription factor expressed early in the crescent and crucial for heart development (Bodmer, 1993; Komuro and Izumo, 1993; Lints et al., 1993; Lyons et al., 1995). In vitro analysis of these cells have demonstrated that they posses a restricted capacity to differentiate into cardiac muscle, smooth muscle, and vascular endothelium (Kattman et al., 2006; Moretti et al., 2006; Wu et al., 2006; Domain et al., 2009; Christoforou et al., 2008). The transplantation of these cells into infracted mouse hearts resulted in the formation of cardiomyocytes, gap junctions, and even an increase in neovascularization. Furthermore, no teratoma formation was observed following the administration of these cardiac progenitor cells (Christoforou et al., 2010).
Although these studies using mouse ESC derived cardiac progenitor cells have proven to be extremely promising as a new cell-based therapeutic strategy, several obstacles have to be overcome before clinical trails can be initiated. Firstly, the transplantation of ESC in humans may lead to teratoma formation and graft rejection. Furthermore, the long term effects of the transplanted ESC-derivatives have to be determined.
Other multipotent cell sources for cardiac regeneration
Besides the already mentioned potential sources for cardiac regeneration, new developments in regenerative medicine have led to the identification of several novel cell sources. The discovery that pluripotent stem cells with a similar plasticity to that of ESCs can be produced from virtually any human cell by reprogramming the nucleus has revolutionized the field of regenerative medicine. Similar to ESCs, induced pluripotent stem cells (iPSCs) can be guided down a desired differentiation pathway prior to transplantation. However unlike ESCs, iPSCs might be able to circumvent the therapeutic limitations of ESCs, including improved host integration and reduced risk of host rejection. Several studies have shown that in vitro cardiomyocytes derived from iPSCs posses the ability to contract, form gap junctions, and even express the receptors essential for hormonal regulation of the hearts function (Pfannkuche et al., 2009; Gai et al., 2009). The effectiveness of iPSCs in treating MI was demonstrated by administrating these cells into a mouse model of acute MI. The transplanted cells were observed to successfully integrate into the hostââ‚¬â„¢s tissue, improve ejection fraction and fractional shortening, and even reduce the structural deterioration of the infracted tissue (Nelson et al., 2009). Although the use of iPSCs as a cell source for tissue regeneration holds great promise, cells developed with the current methodology have been shown to induce teratoma formation. Thus the risk of vector and/or pluripotency-associated teratoma formation has to be minimized prior to the initiation of clinical trials.
A population of cells expressing cell factor receptor (c-kit) and stem cell antigen-1 (Sca-1) have recently been identified residing within the adult myocardium. These cardiac stem cells (CSCs) are capable of proliferation and differentiation into both cardiomyocyte and vascular lineages (Beltrami et al., 2001). CSCs can be readily isolated by antigenic selection and expanded in culture (van Vliet et al., 2008). The advantage of CSCs over other cell sources is that they are patient specific, reducing the risk of host rejection, and are already committed to a cardiac fate.
Studies aimed at understanding the regenerative abilities of the zebrafish have led to the identification of a novel source of cardiac progenitor cells derived from the pro-epicardial organ (PEO). The pro-epicardium is a cluster of mesoderm-derived cells located near the liver primordium and septum transversum, which during embryogenesis are involved in forming the epicardium and contribute endothelial and smooth muscle tissue to the myocardium (Major and Poss 2007). During embryogenesis, these progenitor cells express the T-box transcription factor 18 (Tbx18). Interestingly, upon myocardial damage within zebrafish expression of Tbx18 is re-activated followed by a migration of these cells towards the site of injury (Kraus et al., 2000; Cai et al., 2007; Lepilina et al., 2006). This observation suggests a possible role of Tbx18 expressing cells in regeneration, and may hold the key in unlocking cardiac tissue regeneration in humans.