Implantation of genetically manipulated BM cells for cardiac repair.

We have read with interest the original research article by Xu et al. [1] entitled ‘Implantation of BM cells transfected with phVEGF165 enhances functional improvement of the infracted heart’. The authors have successfully demonstrated transfection of the BM mononuclear cell (BMMNC) fraction with phVEGF165 (plasmid human vascular endothelial growth factor) to achieve /65% transfection efficiency, which is quite high considering the fact that it was mediated through a non-viral vector. The phVEGFtransfected autologous BM-MNC (4 /10 in a 100-mL volume) were transplanted in a rabbit heart model of myocardial infarction at four different sites bordering the infarcted zone. Non-transfected BM-MNC were transplanted in a control group of animals for comparison of the results. Measurement of the hemodynamic parameters and heart function analysis by echocardiography revealed significant improvement in the cardiac function in the hVEGF-transfected BM-MNC transplanted group compared with the non-transfected BM-MNC-transplanted animals. Another important finding of their study was the differentiation of donor BM-MNC into cardiac phenotype. BM-MNC consists of both hematopoietic as well as non-hematopoietic subpopulations of BM cells. Previous studies have shown that they express various cytokines in in vitro culture conditions. They have been extensively used for transplantation both in animal as well as phase-1 human studies for cardiac repair, with promising results [2 /4]. The underlying mechanism as to how they contribute towards improved cardiac function remains a contentious issue. Improvement in the regional blood flow through neoangiogenesis might be one contributory mechanism. However, to enhance mechanical contractile function of the left ventricle, the donor cell must undergo myogenic transdifferentiation to strengthen the weakened heart muscle and compensate for the cardiomyocyte loss at the site of the infarct. Previous studies have shown that the donor cells undergo fusion with the host cardiomyocytes to achieve cardiac phenotypes, whereas others have related this with the malleable plastic nature of the BM-MNC that helps these cells undergo transdifferentiation into cardiomyocytes [2,3,5]. Recent studies by Balsam et al. [6] and Murry et al. [7], however, have shown that BM cells do not undergo transdifferentiation into cardiomyocytes after transplantation into the infracted heart. These are interesting findings and have reopened this issue for extensive future studies. The authors in the present study [1] have not quantified the survival of the donor cells with and without transfection of hVEGF post-transplantation at the site of the graft. Furthermore, there is a dearth of information on the expression efficiency and time frame during which the donor cells continued to express VEGF after transplantation in vivo . It would have been interesting to compare hVEGF-transfected and non-transfected BM-MNC with respect to these parameters to assess their in vivo behavior and validate the superiority of their approach of combining angiogenic gene therapy with BM-MNC-based cell therapy for cardiac repair.