Priming with erythropoietin enhances cell survival and angiogenic effect of mesenchymal stem cell implantation in rat limb ischemia

INTRODUCTION: Bone marrow mesenchymal stem cells (BMMSCs) ameliorate tissue damage after ischemic injury. Erythropoietin (Epo) has pleiotropic effects in addition to hematopoietic activity. The aim of this study was to investigate whether Epo enhanced cell survival and angiogenic effect of BMMSC implantation in rat limb ischemia model. METHODS AND RESULTS: MSCs were isolated from BM in GFP-transgenic rats. In a culture study, Epo promoted BMMSC proliferation in normoxia and enhanced cell survival under the culture condition mimicking ischemia (1% oxygen and nutrient deprivation). BMMSCs with and without 48 h of pretreatment by Epo (80 IU/ml) were locally administered to rat hindlimb ischemia models in vivo. At 3 days after implantation, BMMSC engraftment in the perivascular area of the injured muscle was significantly higher in the cells preconditioned with Epo than in the cells without preconditioning. Stromal derived factor-1α and fibroblast growth factor-2 expressions were detected in the engrafted BMMSCs. At 14 days after implantation, the Epo-preconditioned BMMSCs significantly promoted blood perfusion and capillary growth compared to the controls in laser Doppler and histological studies. In addition to promoting neovascularization, the Epo-preconditioned BMMSCs significantly inhibited macrophage infiltration in the perivascular area. CONCLUSION: Epo elicited pro-survival potential in the BMMSCs. Pharmacological cell modification with Epo before implantation may become a feasible and promising strategy for improving current therapeutic angiogenesis with BMMSCs.