Human Adipose-Derived Endothelial Progenitor Cells Accelerate Epithelialization of Radiation Ulcer in Nude Mice

Background: Co-transplantation of adipose-derived stem cells (ASCs) and endothelial progenitor cells (EPCs) has shown superior angiogenic effects than ASCs alone in recent animal studies. However, EPCs could only be collected from blood vessels or bone marrow. Thus, we have established a method for purifying adipose-derived endothelial progenitor cells (AEPCs). We hypothesized that AEPCs would enhance the therapeutic effect of ASCs on radiation ulcer. Methods: Seven-week-old male nude mice (BALB/cAJcl-nu/nu) were irradiated on the dorsal skin (total 40 Gy) and twelve weeks later 6 mm diameter wounds were created. The mice were then treated with subcutaneous injection of human ASCs (1×10 5, n = 4), human AEPCs (2×10 5 or 5×10 5, n = 5), combinations of those (ASCs 1×10 5 + AEPCs 2×10 5 (n = 4) or 5×10 5 (n = 5)), or only vehicle (n = 7). Non-irradiated group was also prepared as a control (n = 6). The days required for macroscopic epithelialization was compared and immunostaining for human-derived cells and vascular endothelial cells was performed at Day 28. Results: AEPC-ASC combination-treated groups healed faster than ASC-treated group (14 ± 0 vs 17 ± 2 days, p < 0.01). Engraftment of the injected cells could not be confirmed. Only the non-irradiated mice had significantly higher vascular density (0.988 ± 0.183 vs 0.474 ± 0.092 ×10 -5µm -2, p = 0.02). Conclusions: The results suggested therapeutic potentials of AEPCs and an enhanced effect of combination with ASCs. This study is a xenogenic transplantation model and further validation in an autologous transplantation model is needed. Clinical Relevance Statement: Human AEPCs and its combination with ASCs accelerated epithelialization of radiation ulcer in nude mice. It was also suggested that administration of humoral factors secreted from AEPCs, e.g. treatment with culture conditioned media, could be used for the same purpose.