Original Article
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Aug 7, 2013; 19(29): 4702-4717
Published online Aug 7, 2013. doi: 10.3748/wjg.v19.i29.4702
Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses
Qian-Qian Chen, Li Yan, Chang-Zheng Wang, Wei-Hua Wang, Hui Shi, Bin-Bin Su, Qing-Huan Zeng, Hai-Tao Du, Jun Wan
Qian-Qian Chen, Li Yan, Chang-Zheng Wang, Wei-Hua Wang, Hui Shi, Bin-Bin Su, Qing-Huan Zeng, Hai-Tao Du, Department of Gastroenterology, Chinese PLA General Hospital, Medical College of PLA, Beijing 100853, China
Jun Wan, Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
Author contributions: Chen QQ and Yan L done this study and wrote the paper; Wang CZ and Wang WH gave experimental instructions; Shi H and Su BB collected data; Zeng QH and Du HT analyzed and interpreted data; Wan J designed this study.
Supported by The National Natural Science Foundation of China, No. 81050027
Correspondence to: Jun Wan, MD, Professor, Department of Gastroenterology, Chinese PLA General Hospital, No. 28, Fu Xing Road, Haidian District, Beijing 100853, China. wanjun301@126.com
Telephone: +86-10-66876266 Fax: +86-404-68295664
Received: February 1, 2013
Revised: June 12, 2013
Accepted: June 19, 2013
Published online: August 7, 2013

AIM: 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.

METHODS: 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.

RESULTS: 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).

CONCLUSION: MSCs are key regulators of immune and inflammatory responses and may be an attractive candidate for cell-based therapy of IBD.

Keywords: Mesenchymal stem cells, Transplantation, Inflammatory bowel disease, Inflammatory response, Immunomodulation, Trinitrobenzene sulfonic acid colitis, Therapy

Core tip: In this study, the following factors were identified: (1) The differentiation of intestinal stem cells in injured gut was determined by detecting Lgr5+ cells; (2) Th1-Th2-Th17-Tregs-related inflammatory and immune cytokine expressions in serum and local intestinal tissues were determined; (3) A Th2 shift and correction of the imbalanced Th17/Tregs were found; (4) Master regulators of Th1, Th2, Th17 and Tregs were detected in bone marrow mesenchymal stem cells -treated trinitrobenzene sulfonic acid-induced colitis; and (5) The passways of Th1-T-bet, Th2-GATA family of transcription factors 3, Th17-retinoid related orphan receptor gamma(t) and Tregs-Foxp3 which serve as important immunoregulators in the correction of immune disorders and enhance the healing of injured intestinal mucosa were identified.