Priming With Angiopoietin-1 Augments the Vasculogenic Potential of the Peripheral Blood Stem Cells Mobilized With Granulocyte Colony-Stimulating Factor Through a Novel Tie2/Ets-1 Pathway

Abstract

Background— The low engraftment rate of stem/progenitor cells infused via the intracoronary route to the ischemic myocardium is one of the most important factors limiting the efficacy of cell therapy. We investigated the concept of priming peripheral blood stem cells enriched by granulocyte colony-stimulating factor mobilization and apheresis ( mob PBSCs) with angiopoietin-1 (Ang1), to enhance the engraftment into the ischemic tissue and neovasculogenic potential. Methods and Results— The expression of Tie2, the Ang1 receptor, was significantly higher in mob PBSCs than naïve peripheral blood mononuclear cells (19.2±3.0% versus 1.2±0.8% versus 1.2±0.2%; P <0.001 for mob PBSCs from acute myocardial infarction (AMI) patients with granulocyte colony-stimulating factor treatment for 3 days versus peripheral blood mononuclear cells from AMI patients versus peripheral blood mononuclear cells from stable angina patients). After 4 hours of cartilage oligomeric matrix protein (COMP)-Ang1 stimulation, mob PBSCs committed to the endothelial lineage with the induction of CD31 and VE-cadherin expression, mediated by Tie2/Ets-1 pathway. Priming of mob PBSCs with COMP-Ang1 induced the expression of α4β1 and α5β1 integrins, which are also Ets-1 downstream molecules, leading to enhanced adhesion to endothelial cells or fibronectin. In a rabbit ear ischemia/reperfusion model, priming of mob PBSCs with COMP-Ang1 improved first-pass engraftment to the distal vascular bed after intraarterial delivery. In a murine ischemic hind-limb model, intravascular delivery of primed mob PBSCs enhanced both engraftment and neovascularization. Conclusions— The short-term priming with COMP-Ang1 may be a feasible and promising option to activate mob PBSCs by enhancing differentiation and adhesiveness and to improve the efficacy of cell therapy for ischemic diseases.