Abstract
Critical limb ischemia (CLI) is the leading cause of lower limb amputation. Traditional treatments for CLI have limitations. Studies have shown that thrombospondin-4 (TSP4) can promote the growth of neovascularization. In this study, we observed the angiogenesis efficiency of TSP4-overexpressing BMSC transplantation in CLI treatment. The recombinant FT106-tsp4-gfp lentiviral vector plasmid was constructed and transfected into 293FT cells. Primary BMSCs were successfully infected with the tsp4 virus, and TSP4 overexpression was confirmed before TSP4-BMSCs infusion. A rat CLI model was established, and 60 CLI rats were randomly divided into the CLI, BMSC + CLI and TSP4-BMSC + CLI groups. The effect of TSP4-BMSC on angiogenesis was detected by the motor function, immunohistochemistry and immunofluorescence staining assays. Neovascular density was detected by digital subtraction angiography (DSA). Our results demonstrated that TSP4-BMSCs improved the motor function score of the CLI rats and increased MMP2, MMP9, Ang-1, VEGF and vWF protein expression in tissue of the ischaemic area. Meanwhile, new blood vessels can be observed around the ischemic area after TSP4-BMSCs treatment. Our data illustrate that TSP4-BMSCs can promote the recovery of motor function in diabetic hind limb ischaemic rats. TSP4-BMSCs have better therapeutic effects than BMSCs.
Highlights
Critical limb ischemia (CLI) is the leading cause of lower limb amputation
Our results demonstrated that TSP4-Bone marrow-derived stromal/stem cells (BMSCs) obviously increased TSP4, Vascular endothelial growth factor (VEGF), Ang-1, MMP9, MMP2 and p-Cdc42/Rac1 expression in endothelial cells
New blood vessels can be observed around the ischemic area after TSP4BMSCs treatment
Summary
Critical limb ischemia (CLI) is the leading cause of lower limb amputation. Traditional treatments for CLI have limitations. With the development of the stem cell field, more and more researches has been conducted on therapeutic angiogenesis, which has achieved great progress [9, 10].According to the principle that stem cells have multiple differentiation potentials and can provide various angiogenic cytokines, patients' autologous stem cells are isolated and transplanted to the ischaemic site to generate a new capillary network and improve the localized ischaemic symptoms of the patients. The clinical application of autologous BMSCs in transplantation has defects, including a low quantity and low efficiency of angiogenesis, which limit its clinical efficacy in the treatment of CLI [12]. In this study, we evaluated whether TSP4 overexpression in BMSCs could promote angiogenesis and further improve the efficacy of BMSC transplantation for CLI treatment
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