Cell-Based Gene Therapies and Stem Cells for Regeneration of Ischemic Tissues

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Coronary (CAD) and peripheral (PAD) artery disease are major causes of morbidity and mortality, requiring bypass surgery or angioplasty in approximately one million patients/year in the world (MERIT-HF Study Group, 1999). While collateral vessel formation as an alternative pathway for blood supply occurs in some of these patients, many do not form vascular networks adequate to compensate for the loss of the original blood supply (Hirsch et al., 2006). These patients might therefore benefit from stem cell transplantation therapies that would accelerate natural processes of postnatal collateral vessel formation, an approach referred to as therapeutic angiogenesis. On the other hand, recent seminal reports have indicated that the adult heart is self-healing and self-renewing. Specifically, these studies have demonstrated that there is a pool of resident cardiac stem cells (CSCs) that are clonogenic and multipotent and are capable of differentiating into new blood vessels or into new myocytes, and of cardiac progenitor cells (CPCs) (Marban, 2007). This suggests the possibility of using a therapeutic angiogenesis approach to complement other treatments (e.g., stem cell therapy) that facilitate myocardial repair. Such combined modalities may facilitate myocardial regeneration by inducing endogenous cardiac cells to migrate, differentiate, and proliferate in situ, replacing lost endothelial cells and cardiomyocytes (Urbaneket al., 2005). However, despite recent progress in applying the approaches of regenerative medicine to the treatment of such diseases, valid strategies aimed at repairing the infarcted heart and, in general, at treating end-organ ischemia continue to be elusive. Major obstacles are the difficulty in isolating and delivering stem cells that are specifically effective in myocardial repair, and in stimulating recruitment of endogenous stem cells to the ischemic tissue. To address these issues, there has been increasing focus on novel biotechnologies or pharmacological strategies to enhance the implantation of exogenous stem cells or to boost endogenous regeneration of myocardial tissue. By employing three fundamental “tools”, namely stem cells, biomaterials and growth factors (GFs) (Lavik & Langer, 2004; Mikos et al., 2006), such tissue engineering strategies may enhance the efficacy of stem cell therapy in several ways: by mobilizing endogenous stem/progenitor cells in vivo; by promoting cell proliferation and differentiation; and by augmenting cell engraftment and survival in the injured myocardium. In general, because of