| BACKGROUND:Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract in association with tissue damage. The pathogenesis of IBD is due to a dysfunctional interaction between bacterial microflora of the gut and the mucosal immune system. Until today, effective therapeutic strategy is still lacking. The advancement of stem cell technology brings about prospectives in the treatment of these disorders. Mesenchymal stem cells, which are poorly immunogenic and have potent immunosuppressive activities, have emerged as a promising candidate for cellular therapeutics for the treatment of disorders caused by abnormal immune responses. In this study we investigated in a TNBS-induced mouse colitis model whether human umbilical cord-derived mesenchymal stem cells (hUC-MSC) could ameliorate colitis.OBJECTION:This study was designed to determine if UC-MSC transplantion could promote the recovery of acute TNBS-induced colitis in BALB/c mice, and in the meantime to analyze the potential mechanisms.METHODS:TNBS-treated colitic mice were infused with hUC-MSC or vehicle control. The mice were sacrificed on day 1,3 and 5 after infusion, and their clinical and pathological conditions were evaluated by body weight, colon length and histological analysis. The expression levels of pro-inflammatory cytokine proteins such as IL-17, IL-23, IFN-γ, IL-6, IL-10 and TGF-p in colon and serum were examined by ELISA. The homing of hUC-MSC was studied by live in vivo imaging and immunofluorescent microscopy. In vitro experiments, the suppression of hUC-MSC were analyzed by co-culturing hUC-MSC and splenocytes/lamina propia mononuclear cells (LPMCs) from colitic mice. Further studies of the inhibition of hUC-MSC were carried out by co-culturing hUC-MSC and splenocytes/lamina propia mononuclear cells from normal healthy mice with stimulated by IL-12 or IL-23. the transwell experiments were carried out for analyzing the contact necessary. The expression of RORyt werer measured in colon sample or lamina propia mononuclear cells by Real-time PCR.RESULTS:hUC-MSC were found to migrate to the inflamed colon and effectively treated the mice suffering from colitis with improved clinical and pathological signs. The levels of IFN-y, IL-6, IL-17 and IL-23 were significantly lower in the colon tissues and serum of the hUC-MSC-treated mice in comparison with the vehicle treated mice. Co-culture experiments showed that hUC-MSC could significantly inhibit 1L-17 and IFN-γproduction by splenocytes and lamina propia mononuclear cells of the colitic mice or by those isolated from normal animals and simulated with IL-23 and IL-12. The inhibiton of hUC-MSC was dose and time dependent, and cell-cell contact was not necessary. The expression of transcript factor RORyt was inhibited in hUC-MSC treated mice or in lamina propia mononuclear cells after co-culturing with hUC-MSC with IL-23 stimulation.CONCLUSION:Systemically infused hUC-MSC could home to the TNBS-induced inflammatory colon and effectively ameliorate colitis. One of the mechanisms of action of hUC-MSC may be the suppression of the IL-23/IL-17 regulated inflammatory reactions involved in the pathogenesis. hUC-MSC could suppress IFN-y expressing by Thl cell and IL-17 expressing by Th17 cell. hUC-MSC could suppress Th17 cell by inhibiting the expression of transcript factor RORγt.
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