Strategies to enhance the efficiency of endothelial progenitor cell therapy by Ephrin B2 pre-treatment and Co administration with Smooth Muscle Progenitor Cells on vascular function during wound healing process in irradiated or not condition

​Endothelial progenitor cell (EPC) transplantation has beneficial effects for therapeutic neovascularisation. We therefore assessed the effect of a therapeutic strategy based on EPC administration in the healing of radiation-induced damage. To improve cell therapy for clinical use, we used pre-treatment with ephrin B2-Fc (Eph-B2-Fc) or and co-administration with smooth muscle progenitor cells.

At Day 3, EPCs promoted dermal wound healing inboth non-irradiated and irradiated mice by 1.2 - and 1.15 -fold, respectively compared with animals injected with PBS. In addition, EPCs also improved skin blood perfusion and capillary density in both irradiated and non-irradiated mice compared with PBS-injected animals. We also demonstrated that activation with ephrin-B2-Fc increased wound closure by 1.6-fold compared with unstimulated EPC in non-irradiated mice. Interestingly, the beneficial effect of Eph-B2-Fc was abolished in irradiated animals. In addition, we found that Eph-B2-Fc stimulation did not improve EPC- induced vascular permeability or adhesiveness compared to unstimulated EPC cells. We hypothesised that this effect was due to high oxidative stress during irradiation leading to inhibition of EPC beneficial effect on the vascular function. In this line, we demonstrated that in irradiated conditions, N-acetyl-L-cysteine treatment restored the beneficial effect of EPC stimulation with Eph-B2-Fc in wound healing process.

In conclusion, stimulation by Eph-B2-Fc improved the beneficial effect of EPCs in physiological conditions and irradiated conditions only in association with antioxidant treatment. Additionally, cotherapy was beneficial in pathological conditions.