BackgroundExpanded endothelial progenitor cells (eEPC) improve global left ventricular function in experimental myocardial infarction (MI). Erythropoietin beta (EPO) applied together with eEPC may improve regional myocardial function even further by anti-apoptotic and cardioprotective effects. Aim of this study was to evaluate intramyocardial application of eEPCs and EPO as compared to eEPCs or EPO alone in experimental MI.Methods and ResultsIn vitro experiments revealed that EPO dosed-dependently decreased eEPC and leukocyte apoptosis. Moreover, in the presence of EPO mRNA expression in eEPC of proangiogenic and proinflammatory mediators measured by TaqMan PCR was enhanced. Experimental MI was induced by ligation and reperfusion of the left anterior descending coronary artery of nude rats (n = 8-9). After myocardial transplantation of eEPC and EPO CD68+ leukocyte count and vessel density were enhanced in the border zone of the infarct area. Moreover, apoptosis of transplanted CD31 + TUNEL + eEPC was decreased as compared to transplantation of eEPCs alone. Regional wall motion of the left ventricle was measured using Magnetic Resonance Imaging. After injection of eEPC in the presence of EPO regional wall motion significantly improved as compared to injection of eEPCs or EPO alone.ConclusionIntramyocardial transplantation of eEPC in the presence of EPO during experimental MI improves regional wall motion. This was associated with an increased local inflammation, vasculogenesis and survival of the transplanted cells. Local application of EPO in addition to cell therapy may prove beneficial in myocardial remodeling.

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Introduction : Recent studies demonstrate the vasculoprotective effects of cell-based therapies to inhibit limit restenosis. Delivery of autologous late outgrowth endothelial progenitor cells (eEPC) result in early reendothelialization and inhibition of neointimal hyperplasia. Additional anti-inflammatory treatment may further reduce neointima generation. Methods and Results : CD34+ cells were isolated using immunomagnetic beads and cultured in endothelial cell medium to obtain eEPC. Early passage cells were transduced ex vivo by a retroviral vector expression of IL-1ra (eEPC IL-1ra) or empty vector (eEPC pLXSN) and expanded up to 46 population doublings. Expression levels were confirmed by RT-PCR. Athymic nude rats underwent carotid balloon and wire injury immediately followed by local delivery of eEPCs, eEPC IL-1ra, eEPC pLXSN or buffer for 20 minutes (n=22). Elastica van Giesson staining revealed a decrease in the intima/media ratio from 1.53 ± 0.11 to 1.13 ± 0.09 (mean ± SEM) after transplantation of eEPC (p=0.009). However, no additional reduction in neointima generation was observed after transplantation of eEPC IL-1ra. Endothelial-cell specific staining demonstrated an enhancement of reendothelialisation by eEPCs 24 hours after vascular injury. After 2 weeks a reduction of Ki67+ proliferating cells from 37.0 ± 8.5 Ki67+ cells in the control group to 11.67 ± 2.85 Ki67+ cells after eEPC transplantation (P=0.03) was found. Yet, no additional anti-proliferative effects were observed after transplantation of eEPC IL-1ra. Thus, enhancement of reendothelialization through local delivery of eEPCs may be sufficient for the inhibition of neointima generation since additional anti-inflammatory treatment using eEPC IL-1ra had no beneficial effect. Conclusion : Local delivery of blood-derived expanded endothelial progenitor cells after vascular injury contributes to endothelial regeneration, inhibits neointimal smooth muscle cell proliferation and reduces neointima generation. Autologous cell transplantation after vascular injury may be a feasible strategy for promotion of reendotheli-alisation and improvement of vascular regeneration.

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