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

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 the short half-lives of GFs in the body and the necessity to deliver them to specific target sites, GF injections themselves do not always produce the anticipated therapeutic effect. At present, GF delivery in regenerative medicine basically relies upon two strategies: 1) delivery of the GF genes; 2) direct delivery of GFs by incorporating them into a vehicle. In the gene delivery approach, delivery of the GF gene may result in higher and more constant levels of protein produced, since the gene - rather than a degradable protein - is being delivered (Haastert & Grothe, 2007). Two major problems are associated however with this approach: 1) the complexity of cloning and integrating the gene into the target cells; 2) safety and efficiency of transduction. At present, there are insufficient well-controlled long-term studies in the preclinical area to make any conclusive statements about the clinical suitability/efficacy of gene delivery in humans. If resolved, cell-mediated synthesis of GFs should be associated with more efficient targeting of receptors and, consequently, a more robust and predictable approach in ischemic tissue regeneration.