Letter to the Editor
Cell-Based Ex Vivo Delivery of Angiogenic Growth Factors for Cardiac Repair
To the Editor,
The ever progressing filed of cardiovascular therapeutics has seen the emergence of molecular and cellular level approaches based on gene and cell delivery. Both of these approaches have successfully been used in both preclinical and clinical studies with promising results which have thus given hope to treat the root cause of the problem. A more fascinating and tantalizing approach is to combine these strategies to achieve the best of the two approaches. Depending on the choice of the cells and angiogenic growth factors, this combination therapy may be able to achieve both angiogenesis for enhanced regional blood flow through neovascularization and myogenesis to supplement for the cardiomyocyte loss and improve left ventricular mechanical contractile functions. Unlike the previous studies where cells with intrinsic ability to express angiogenic growth factors and cytokines or cells with myogenic potential such as skeletal myoblasts genetically modulated to express angiogenic growth factors have been used, Matsumoto and colleagues have used syngenic mesenchymal stem cells adenovirally transduced with exogenous human VEGF gene.1 The transduced cells were successfully transplanted in a rat heart model of acute coronary artery occlusion. The results have shown significantly enhanced development of collateral blood vessels and regional blood flow in the ischemic region. More interestingly, they have also observed a distinctly enhanced α-smooth muscle actin–positive cells expressing Lac-z reporter gene. An assessment of blood vessel density and the maturity of the collaterals developed and their stability over longer period of time would give more insight into the effectiveness of this approach. Use of mesenchymal stem cells led to mature blood vessel formation, and they may contribute to maturation of the newly formed blood vessels triggered by VEGF expression.
We have recently published a study using human skeletal myoblasts transduced with human VEGF165 for cardiac repair in a porcine heart model of myocardial infarction by coronary artery ligation.2 The xenomyoblasts were supported on transient immunosuppression for the initial 6 weeks after cell implantation using minimal dose of cyclosporine. At 3 months, xenomyoblasts were found surviving extensively in the host myocardium. Transient expression of VEGF was observed at the site of the graft as confirmed by polymerase chain reaction using human VEGF165 specific primers. Blood vessel density increased significantly in the periinfarct region in the VEGF transduced skeletal myoblast transplanted animals (Figure). Regional blood flow also showed significant improvement in the cell grafted region. We have also attempted to achieve angiogenic synergy together with myoblast transplantation.3
Cellular angiogenesis is advantageous for a localized and more regulatable expression of the delivered growth factors to alleviate the side effects associated with systemic expression. This definitely ensures site-specific delivery of the exogenous gene to the target organ. Together with implantation of potential myogenic cells, the functional benefits and prognostic outcome will be superior. The combination therapy approach may be a future potential treatment modality for myocardial infarction in clinical settings.
Matsumoto R, Omura T, Yoshiyama M, Hayashi T, Inamoto S, Koh Ki-R, Ohta K, Izumi Y, Nakamura Y, Akioka K, Kitaura Y, Takeuchi K, Yoshikawa J. Vascular endothelial growth factor–expressing mesenchymal stem cell transplantation for the treatment of acute myocardial infarction. Arterioscler Thromb Vasc Biol. 2005; 25: 1168–1173.
Lei Y, Husnain Kh Haider, HK Ge R, Law PK, Chua T, Aziz S, Sim EKW. Delivery of human myoblasts transduced with a novel bicistronic vector carrying humanVEGF165 and Angiopoietin-I forms mature blood vessel in the heart. J Am Coll Cardiol. 2004; 43 (5 suppl-A), 20A(Abstract # 1116–2).