Department of Gastroenterology, Chinese PLA General Hospital, Medical College of PLA, Beijing 100853, China.
World J Gastroenterol. 2013 Aug 7;19(29):4702-17. doi: 10.3748/wjg.v19.i29.4702.
To investigate the potential therapeutic effects of mesenchymal stem cells (MSCs) in inflammatory bowel disease (IBD), we transplanted MSCs into an experimental model of IBD.
A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg body weight) was administered to female BALB/c mice. Bone marrow mesenchymal stem cells (BMSCs) were derived from male green fluorescent protein (GFP) transgenic mice and were transplanted intravenously into the experimental animals after disease onset. Clinical activity scores and histological changes were evaluated. GFP and Sex determining region Y gene (SRY) expression were used for cell tracking. Ki67 positive cells and Lgr5-expressing cells were determined to measure proliferative activity. Inflammatory response was determined by measuring the levels of different inflammatory mediators in the colon and serum. The inflammatory cytokines included tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-6, IL-17, IL-4, IL-10, and transforming growth factor (TGF-β). Master regulators of Th1 cells (T-box expressed in T cells, T-bet), Th17 cells (retinoid related orphan receptor gamma(t), RORγt), Th2 cells (GATA family of transcription factors 3, GATA3) and regulatory T cells (forkhead box P3, Foxp3) were also determined.
Systemic infusion of GFP-BMSCs ameliorated the clinical and histopathologic severity of colitis, including body weight loss, diarrhea and inflammation, and increased survival (P < 0.05). The cell tracking study showed that MSCs homed to the injured colon. MSCs promoted proliferation of intestinal epithelial cells and differentiation of intestinal stem cells (P < 0.01). This therapeutic effect was mainly mediated by down-regulation of both Th1-Th17-driven autoimmune and inflammatory responses (IL-2, TNF-α, IFN-γ, T-bet; IL-6, IL-17, RORγt), and by up-regulation of Th2 activities (IL-4, IL-10, GATA-3) (P < 0.05). MSCs also induced activated CD4(+)CD25(+)Foxp3(+) regulatory T cells (TGF-β, IL-10, Foxp3) with a suppressive capacity on Th1-Th17 effecter responses and promoted Th2 differentiation in vivo (P < 0.05).
MSCs are key regulators of immune and inflammatory responses and may be an attractive candidate for cell-based therapy of IBD.
通过将间充质干细胞（MSCs）移植到实验性炎症性肠病（IBD）模型中，来探究其在炎症性肠病中的潜在治疗效果。
采用三硝基苯磺酸（TNBS）（100mg/kg 体重）直肠内给药的方法构建雌性 BALB/c 小鼠 IBD 模型。从雄性绿色荧光蛋白（GFP）转基因小鼠中提取骨髓间充质干细胞（BMSCs），在疾病发病后经静脉移植入实验动物体内。评估临床活动评分和组织学变化。使用 GFP 和性别决定区 Y 基因（SRY）表达进行细胞追踪。测定 Ki67 阳性细胞和 Lgr5 表达细胞以测量增殖活性。通过测量结肠和血清中不同炎症介质的水平来确定炎症反应。炎症细胞因子包括肿瘤坏死因子-α（TNF-α）、干扰素-γ（IFN-γ）、白细胞介素-2（IL-2）、IL-6、IL-17、IL-4、IL-10 和转化生长因子（TGF-β）。还测定了 Th1 细胞（T 细胞表达的 T 盒，T-bet）、Th17 细胞（维甲酸相关孤儿受体γ（t），RORγt）、Th2 细胞（GATA 家族转录因子 3，GATA3）和调节性 T 细胞（叉头框 P3，Foxp3）的主要调节因子。
系统输注 GFP-BMSCs 可改善结肠炎的临床和组织病理学严重程度，包括体重减轻、腹泻和炎症，并提高存活率（P<0.05）。细胞追踪研究表明，MSCs 归巢至受损的结肠。MSCs 促进肠上皮细胞的增殖和肠干细胞的分化（P<0.01）。这种治疗效果主要是通过下调 Th1-Th17 驱动的自身免疫和炎症反应（IL-2、TNF-α、IFN-γ、T-bet；IL-6、IL-17、RORγt），以及上调 Th2 活性（IL-4、IL-10、GATA-3）来实现的（P<0.05）。MSCs 还诱导了具有抑制 Th1-Th17 效应器反应能力的活化 CD4+CD25+Foxp3+调节性 T 细胞（TGF-β、IL-10、Foxp3），并在体内促进了 Th2 分化（P<0.05）。
MSCs 是免疫和炎症反应的关键调节因子，可能是 IBD 细胞治疗的有吸引力的候选者。
