Transplantation of induced endothelial progenitor-like cells pretreated with Defined Factors promotes Diabetic Wound Healing

Diabetic foot disease (DFD) is a major public health concern and is characterized by impaired angiogenesis. Transplantation of endothelial progenitor cell (EPC) holds great potential for treating DFD. However, the poor cell survival of transplant-derived EPCs limits their beneficial effects. Here, we report a preconditioning scheme for the generation of endothelial progenitor-like cells by chemical induction in nutrients deprivation and D-glucose-containing conditions with TGF inhibitor sb431542. The preconditioned endothelial progenitor-like cells (pEPCs) were induced from human umbilical vein endothelial cells (huvecs) and the expression of CD34 was markedly upregulated (༞90%) in pEPCs. Furthermore, pEPCs have the potential to resist pathological environmental stress, which is characterized by their high cell viability, oxidative stress tolerance and enhanced tubulogenesis under simulated DFD conditions. The protective effect of preconditioning in pEPCs is partly achieved by activating the PI3K/AKT pathway to up-regulate the expression of Nrf2 and HIF-1α. Importantly, due to its enhanced retention and angiogenesis, the transplanted pEPCs showed improved therapeutic potential for wound regeneration in diabetic mice. Overall, this study explores a novel preconditioning condition and provides an easy and efficient strategy to obtain pEPCs, which could be an ideal cell source for treating DFD and for endothelialization of tissue-engineered constructs.