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Cellular Cardiomyoplasty and Cardiac Regeneration
Cellular cardiomyoplasty involves myogenic cell grafting within the myocardium to limit any consequences from the loss of contractile function of a damaged left ventricle.4,5 Cell-based cardiac repair offers the promise of regenerating damaged myocardium by rebuilding the injured heart from its component parts. Ideally, transplanted cells would mimic the lost myocytes morphologically and functionally, with the ability to contract and to establish electrical connectivity with the native myocardial cells. The goal of cell therapy in HF is replacement of akinetic scar tissue by viable myocardium in hopes of improving cardiac function, along with inhibition of the remodeling process. For myocardial infarction (MI), the target is to prevent HF by either rescuing the host myocardium or regenerating cardiac cells. Both for the clinician and to the public, the concept of not only preventing the progression and consequence of disease, but reversing the disease process by enhancing repair and regeneration of damaged tissues, has introduced a new and exciting paradigm to treat cardiovascular disease.
Mechanism of stem cell action. The mechanisms by which stem cells repair damaged myocardium or lead to improvement in cardiac function are largely unknown; however, the two fundamental activities of stem cells are (a) directly or indirectly improve neovascularization (vasculogenesis, angiogenesis and arteriogenesis); (b) differentiation into cardiomyocytes and formation of myocardial tissue. Functional benefits may also be mediated through paracrine secretion of growth factors or cytokines which indirectly promote survival of cardiomyocytes by inhibition of cardiac apoptosis, and may also lead to mobilization of endogenous progenitor cells, all of which affect remodeling.
Source of different stem cell types
1. Bone marrow–derived stem cells (BMC): Although the ability of BMC to transdifferentiate into cardiomyocytes remains highly controversial, much of the recent progress in regenerative cardiovascular research has been achieved using BMC populations, including hematopoietic stem cells (HSC), mesenchymal stem cells (MSC), and endothelial progenitor cells (EPC). Despite the failure of studies to definitely prove differentiation of HSC into cardiomyocytes in vitro, several studies in mice have demonstrated the potential of HSC to differentiate into cardiomyocytes or vascular cells after cardiac injury in vivo.6-8 EPC express the hematopoietic stem cell markers (CD133 and CD34 and the endothelial marker Flk-1 (VEGFR-2).9 EPC can be isolated directly from the bone marrow or from the peripheral circulation. MSC lack the typical hematopoietic antigens (c-kit, CD45, CD34, CD14), but express specific adhesion molecules (ALCAM/ CD44) and antigens.10,11 Studies have suggested that MSC are themselves capable of multipotency, with differentiation into chondrocytes, osteoblasts, astrocytes, neurons, skeletal muscle, and notably, cardiomyocytes.12-14
2. Skeletal myoblasts (SM): SM or satellite cells represent an autologous source of progenitor cells that normally lie in a quiescent state under the basal membrane of mature muscular fibers and normally mediate regeneration of skeletal muscle. Myoblasts were the first cell type to be used clinically for cardiac repair owing to their preclinical efficacy, autologous availability, ability to be amplified in vitro, and relatively good survival after implantation. To date, SMs have only been used in trials of heart failure, and not for acute MI, owing to the method of preparation and route of delivery.
3. Cardiac stem cells (CSC): These newly described stem cells from the heart are multipotent, giving rise to endothelial cells, smooth muscle cells, and functional cardiomyocytes. In addition, they supported myocardial regeneration after infarction in a rat model. Future research on CSC will help to answer these questions and may provide the means for efficient heart regeneration.15
4. Embryonic stem cells (ESC): ESCs are derived from the inner cell mass of blastocyst stage of the embryos; they grow indefinitely in an undifferentiated state while retaining the ability to differentiate to all cell types in the adult body, including cardiomyocytes.16 Because of unresolved ethical and legal issues, concerns about tumorogenicity and arrhythmogenecity of the cells, and the need to use allogeneic cells for transplantation, ESC have not been investigated broadly and will not be used clinically in the near future.
5. Umbilical cord stem cells (UCSC): UCSC have shown to possess a potential for plasticity at least similar to, most likely greater than human adult stem cells; also, their differentiation into cardiac myocytes has been demonstrated experimentally.17 As umbilical cord stem cells can be obtained without the need to sacrifice an embryo their isolation, use for research purposes and clinical application is not complicated by the ethical and political issues.
6. Amniotic stem (AFS) cell: DeCoppi et al reported the isolation of a new type of stem cell from amniotic fluid that has many characteristics of ESC without the ethical baggage.18 AFS cells seem to represent an intermediate stage between embryonic and adult stem cells in terms of their versatility. They are fully undifferentiated and pluripotent.
Cell delivery. The three most frequently used routes in clinical setting are intracoronary infusion, percutaneous endocardial or direct intramyocardial injection during surgery. Intracoronary infusion requires migration through the vessel wall into the damaged tissue. Direct delivery of progenitor cells into scar tissue or areas of hibernating myocardium by catheter or surgical-based needle injection may generate relative higher local retention and less systemic distribution.
Clinical trials. The most frequently tested cell types in clinical trials are skeletal myoblasts and bone-marrow or blood-derived progenitor cells. One major pitfall of using autologous cells is that the number of functional stem cells is generally depleted, with a markedly reduced proliferation potential in the elderly and in patients with cardiovascular disease.
Challenge and the future
Cardiac tissue engineering, a novel concept, involves grafting ex vivo engineered heart muscle. This approach may theoretically allow complete replacement of diseased myocardium or reconstitution of cardiac malformations, but is still in its infancy.19
Stem cell treatment of the heart has not been shown to lead to the development of large-caliber coronary vessels, but rather to capillaries and arterioles by both angiogenesis and vasculogenesis. Therefore, stem cells are either used as adjunct to percutaneous coronary intervention or coronary artery bypass graft surgery, or in patients with angiographically-proven coronary artery disease without viable percutaneous or surgical treatment options. Knowledge, created by basic scientists and clinicians, developmental biologists and engineers, has led to a better understanding of the molecular signals and cues of cardiac regeneration.
Despite the advances that have been made in this broad area, it is important to emphasize that there are still fundamental questions that need to be addressed both experimentally and clinically regarding potential features of cell repair. The most eminent unresolved issues are: cell delivery, optimization of cell retention, distribution, best route of delivery, time of transplantation, cell type, cell number, and viability of grafted cells. Hill et al20 observed a strong correlation between the number of circulating EPCs and the subjects’ combined Framingham cardiovascular risk factor score. Therefore, with the onset of disease (or the presence of risk factors), the relevant cells appear to decrease in number and lose their reparative function. Despite the high number of stem cell studies performed, there is still no consensus on the optimal/minimal cell number required to achieve any effect. Much more work needs to be done before cell-based therapy can be used routinely in the clinical setting for people.
References
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