Accumulating evidence has established the use of mesenchymal stem cells (MSCs) as candidate cells for immunosuppressive therapy. Experimental studies have suggested that MSCs exert their immunomodulatory effects through the induction of regulatory T cells (Tregs) in vitro and in vivo. However, the interactions between MSCs and Tregs in inflammatory bowel disease (IBD) and whether MSCs can be used for the treatment of IBD remains to be elucidated. In this study, we aimed to investigate whether MSCs can be used for the treatment of IBD through the induction of Tregs. MSCs were isolated and identified by flow cytometry. The MSCs were transduced with a replication-defective recombinant lentiviral vector carrying GFP in order to be able to trace the injected cells in vivo. Prepared MSCs (1x106) were injected into rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)‑induced colitis via the tail vein; the control rats received phosphate-buffered saline (PBS) alone. Two weeks after the intravenous infusion, the frequency of CD4+CD25+Foxp3 cells in the peripheral blood was examined by flow cytometry. The colon was sectioned and analyzed for histopathological changes. Foxp3 mRNA expression was determined by real-time reverse-transcription polymerase chain reaction (qRT-PCR). In our study, the systemic infusion of MSCs significantly ameliorated the clinical and histopathologic severity of TNBS-induced colitis in contrast to the controls. There was an inverse regulation of mucosal and peripheral Foxp3 expression, suggesting that the MSCs redistributed the Tregs from the mucosa to the blood. Thus, MSCs exhibit immunomodulatory functions and may be used to ameliorate or treat IBD by redistributing regulatory T cells. Therefore, the interactions between transplanted bone marrow-derived MSCs and Tregs should be further investigated; MSCs have tremendous potential for use in the treatment of IBD.

Mesenchymal stem cells (MSCs) inhibit the immune response in vitro and prevent the induction of disease in certain experimental models. As a result, MSC‑mediated therapy is a rapidly growing field of research. However, the efficacy of MSCs in the treatment of inflammatory bowel disease (IBD) has remained to be determined. In the present study, rats with 2,4,6‑trinitrobenzene sulfonic acid (TNBS)‑induced colitis were injected with prepared MSCs (1x106) into the tail vein. Two weeks following intravenous MSC administration, the concentration of tumor necrosis factor‑α (TNF‑α) in the serum was measured by an ELISA. The protein expression of nuclear factor‑κB (NF‑κBp65) in the colonic mucosa was assessed by western blot analysis. mRNA expression of TNF‑α and NF‑κBp65 was determined by reverse‑transcription quantitative polymerase chain reaction. MSCs were shown to exert an immunomodulatory effect on TNBS‑induced colitis and may be of use in the treatment of IBD. In addition, modulation of the NF‑κB‑mediated pro‑inflammatory response may contribute to the underlying mechanism by which MSCs ameliorate the clinical and histological changes associated with IBD.

Objectives: Bone marrow-derived mesenchymal stem cells (BMSCs) show promise in treating inflammatory bowel disease. We tested if BMSCs improve Trinitro-benzene-sulfonic acid (TNBS)-induced colitis by inducing Treg differentiation by modulating programmed cell death 1 ligand 1(PD-L1). Results: BMSCs were isolated and transfected with PD-L1 siRNA. Sprague–Dawley rats were randomly divided into 4 groups: normal, model, BMSC control, and PD-L1 siRNA BMSC. Colitis was induced by TNBS, except in the normal group. On d4, the BMSC control and PD-L1 siRNA BMSC groups were intravenously injected with BMSCs at a dose of 5 × 10⁶ cells in phosphate-buffered saline (PBS; volume matched). BMSCs were later verified to have reached the colon tissue. BMSC control showed significantly better clinical symptoms and reduced histopathological colitis severity; PD-L1 siRNA BMSC group showed no difference. PD-L1 siRNA reduced: spleen and mesenteric lymph node Tregs, PD-L1, interleukin-10 (IL10), phosphate and tension homology deleted on chromosome ten (PTEN); colon p-Akt and p-mTOR were increased. Conclusions: We found that BMSCs can induce Treg differentiation by inhibiting the Akt/mTOR pathway via PD-L1; this significantly improved symptoms and pathology in our ulcerative colitis rat models.

Objective. Ulcerative colitis (UC) is closely related to immune response, in which Treg cells (Tregs) suppress the autoimmune response of effector T cells to maintain homeostasis. As a marker of endoplasmic reticulum stress (ERS), HSPA5 was highly expressed in the colon tissue of UC patients. This study is aimed at evaluating the therapeutic effect of HSPA5 inhibitor (HA15) on dextran sulfate sodium- (DSS-) induced ulcerative colitis in mice and explored the effect and related mechanism of HSPA5 inhibitor on the differentiation and function of Tregs. Methods. Thirty-two C57BL/6 mice were randomly divided into four groups (8 mice per group): normal control group, DSS model group, HSPA5 inhibitor (HA15) group (intraperitoneal injection), and dexamethasone (DXM) group (intraperitoneal injection). Except for the blank control group, the other groups were induced with 3 DSS for 7 days and then given corresponding intervention therapy for 7 days. Results. The disease activity index (DAI) score, colon length, histopathological changes, and scores of DSS-induced mice show that HA15 could significantly improve the degree of inflammation in ulcerative colitis. Moreover, HA15 can better inhibit the expression of HSPA5, HSPA1A, and CHIP in the colon and increase the level of FOXP3 mRNA. Finally, the content of Treg cells and the levels of IL-10 and TGF-β1 were significantly increased, and the levels of IL-6 were significantly reduced. Conclusions. HA15 can improve the differentiation and function of Treg cells by inhibiting the HSPA1A/CHIP pathway, thereby improving ulcerative colitis. Therefore, inhibiting the expression of HSPA5 may serve as a new approach to treat ulcerative colitis.

目的: 比较乌梅丸与西药柳氮磺胺吡啶SASP组对溃疡性结肠炎大鼠结肠组织NF-κB p65疗效的大小, 并分析其作用机制. 方法: 应用2, 4-二硝基氯苯(DNCB)免疫加醋酸局部灌肠法建立UC大鼠模型, 将56只健康SD大鼠(雌雄各半), 按雌雄随机分4组, 分别为乌梅丸组、SASP组、模型组和正常组, 分别观察治疗后大鼠结肠黏膜组织匀浆NF-κB p65的变化. 结果: 在正常结肠组织中NF-κB p65无或仅有弱阳性表达, 模型组结肠黏膜组织NF-κB p65阳性细胞表达率明显高于正常组(45.67%±4.25% vs 10.45%±5.20%, P<0.05), 乌梅丸(26.32%±9.65%)和SASP(31.23%±5.18%)组阳性细胞率则明显低于模型组, 乌梅丸组阳性细胞率较SASP组更低. 结论: NF-κB与UC发病关系密切, 乌梅丸可能通过抑制NF-κB p65活性调节免疫功能达到治疗的目的.