| Cyclosporine A(CsA)is one of the most important immunosuppressive drugs due to its immunologic properties,which make it an attractive agent for immunosuppression following solid organ transplantation and autoimmune diseases.The therapeutic benefits of CsA are limited by its main side effect,i.e.nephrotoxicity.Acute or chronic CsA-induced nephrotoxicity leads to renal function impairment and histopathological and ultrastructural damages.In recent years,several studies have reported that mesenchymal stem cell(MSC)transplantation can prevent or attenuate drug-induced renal injury,but their effect in CsA-induced nephrotoxicity is not clear.MSCs are adherent,fibroblast-like cells,derived from different tissues and organs,including adipose tissue,bone marrow,umbilical cord blood,lung,heart,among others.MSCs are multipotent cells with the capacity to proliferate and differentiate into osteoblasts,adipocytes,and chondrocytes.Their reparative,regenerative,and immunomodulatory properties make them good candidates for cell therapy and tissue regeneration.An increasing number of experiments and clinical trials have demonstrated the safety,feasibility,and efficacy of mesenchymal stem cells(MSCs)-based therapies for the treatment of various diseases.The main drawbacks of MSC therapy are the lack of specific homing after systemic infusion and early death of injected cells because of the injury microenvironment,that can reduce the therapeutic effect of MSCs.Application of pretreated or modified MSCs is a novel strategy to enhance MSCs’ capacity to migrate and promote tissue repair for the treatment of kidney injury.We pretreated bone mesenchymal stem cells(BMSCs)with erythropoietin(EPO)to investigate their positive effect on cyclosporine A(CsA)-induced nephrotoxicity.BMSCs were incubated with different concentrations of EPO(10,100,500,and 1000 IU/ml)for 24 and 48 h,and their proliferation rate,cytoskeletal morphology,migration ability,and the expression of CXCR4 were evaluated to determine the optimal pretreatment conditions.To investigate the therapeutic effects of BMSCs pretreated with EPO in CsA-induced nephrotoxicity,we established CsA-induced in vitro and in vivo toxicity models.In our in vitro study,preconditioning of BMSCs with 500 IU/ml EPO for 48 h induced a marked increase in their proliferation rate,cytoskeletal rearrangement,migration in the scrape-healing assay,and migration towards injured HK2 cells.Analysis revealed that the EPO-BMSCs group had significant anti-apoptotic effect on HK2 cells following stimulation with CsA at 24 h.The treatment with EPO-BMSCs significantly reduced IL-1β or TGF-β1 upregulation and promoted the expression of E-cadherin,HO-1,and VEGF,and the levels of the Bcl-2 increased and those of caspase-3 reduced in EPO-BMSC group.In vivo,EPO-BMSCs showed higher ability to improve renal function than BMSCs,and in CsA-induced rats treated with EPO-BMSCs,interstitial lymphocyte infiltration,tubular swelling,necrosis,and interstitial fibrosis decreased.We demonstrated that pretreatment with 500 IU/ml EPO before infusion markedly increased the homing ability and healing ability of BMSCs.It can significantly inhibit the apoptosis of HK2 cells in the toxicity of CsA.Moreover,the infusion treatment of one-time EPO-BMSCs significantly improved the renal function of CsA induced chronic toxic renal injury,and promoted the repair of renal fibrosis in rats. |
