Co-Delivery of G-CSF and EPO Released From Fibrin Gel for Therapeutic Neovascularization in Rat Hindlimb Ischemia Model

Objective: G-CSF and EPO have shown a notable capability in neovascularization. However, their use is limited because of untoward leucocytosis, erythrogenesis, and short half-life in the plasma. Herein, we examined whether G-CSF and EPO released from fibrin gel injected into ischemic tissues would synergistically promote neovascularization with limited systematic effects in a rat hindlimb ischemic model. Methods and Results: In vivo study, group Gel received an intramuscular injection of fibrin gel; group Gel+G-CSF received fibrin gel containing human G-CSF; group Gel+EPO received fibrin gel containing human EPO; group Gel+G-CSF&EPO received fibrin gel containing G-CSF and EPO; group G-CSF&EPO received G-CSF and EPO. Through promoting the expression of SDF-1, local high concentration of EPO could traffic CXCR4+ cells mobilized by G-CSF to enhance neovascularization in ischemic muscle. The treatment with Gel+G-CSF&EPO was superior to the other treatments on blood flow reperfusion, capillary density, and smooth muscle actin-positive vessel density. And this treatment induced a modest WBC count increase in peripheral blood. Conclusions: G-CSF and EPO released from fibrin gel had a combined effect on postischemia neovascularization. This treatment may be a novel therapeutic modality for ischemic peripheral artery disease.