Adipose Mesenchymal Stem Cells Combined with Platelet Rich Plasma Accelerate Diabetic Wound Healing by Modulating Notch Pathway

Abstract Background Diabetic foot ulceration is a serious chronic complication of diabetes mellitus characterized by high disability, mortality and morbidity. Platelet-rich plasma (PRP) has been widely used for diabetic wound healing due to its high content of growth factors. However, its application is limited due to rapid degradation of growth factors. The present study aimed to evaluate the efficacy of combined adipose derived mesenchymal stem cells (ADSCs) and PRP therapy in promoting diabetic wound healing in relation to the Notch signaling pathway. Methods Albino rats were allocated into 6 groups (control, sham, diabetic, PRP-treated, ADSCs-treated and PRP+ADSCs-treated groups). The effect of individual and combined therapy was evaluated by assessing wound closure rate, epidermal thickness, dermal collagen and angiogenesis. Moreover, gene and protein expression of key elements of Notch signaling pathway (Notch1, Delta like canonical Notch ligand 4 (DLL4), Hairy Enhancer of Split-1 (Hes1), Hey1, Jagged-1), gene expression of angiogenic marker (Vascular endothelial growth factor & stromal cell-derived factor 1) and epidermal stem cells (EPSCs) related gene (ß1 Integrin) were assessed. Results Our data showed a strong wound-healing effect of PRP+ADSCs compared to their individual use after 7 and 14 days. Combined therapy caused marked increase in area percentage of collagen, epidermal thickness and angiogenesis. Moreover, Notch signaling was significantly down-regulated, EPSCs proliferation and recruitment was enhanced compared to other treated groups and diabetic group. Conclusions These data demonstrated that PRP and ADSCs combined therapy significantly accelerated healing of diabetic wounds induced experimentally in rats via modulating Notch pathway, promoting angiogenesis and EPSCs proliferation.