Gastroenterology

Gastroenterology

Volume 136, Issue 3, March 2009, Pages 978-989
Gastroenterology

Basic—Alimentary Tract
Adipose-Derived Mesenchymal Stem Cells Alleviate Experimental Colitis by Inhibiting Inflammatory and Autoimmune Responses

https://doi.org/10.1053/j.gastro.2008.11.041Get rights and content

Background & Aims

Crohn's disease is a chronic disease characterized by severe T-helper (Th)1 cell–driven inflammation of the colon partially caused by a loss of immune tolerance against mucosal antigens. Mesenchymal stem cells were recently described to suppress effector T-cell responses and have therapeutic effects in some immune disorders. Here, we investigated the potential therapeutic effects of human adipose-derived mesenchymal stem cells (hASCs) in a model of inflammatory bowel disease.

Methods

Mice with trinitrobenzene sulfonic acid–induced colitis were treated with hASCs after onset of disease and clinical scores were evaluated. Inflammatory response was determined by measuring the levels of different inflammatory mediators in colon and serum. Th1-mediated effector responses were evaluated by determining the proliferation and cytokine profile of activated mesenteric lymph node cells. The number of regulatory T cells and the suppressive capacity on Th1 cell responses was determined.

Results

Systemic infusion of hASCs or murine ASCs ameliorated the clinical and histopathologic severity of colitis, abrogating body weight loss, diarrhea, and inflammation and increasing survival (P < .001). This therapeutic effect was mediated by down-regulating both Th1-driven autoimmune and inflammatory responses. ASCs decreased a wide panel of inflammatory cytokines and chemokines and increased interleukin-10 levels (P < .001), directly acting on activated macrophages. hASCs also impaired Th1 cell expansion and induced/activated CD4+CD25+FoxP3+ regulatory T cells with suppressive capacity on Th1 effector responses in vitro and in vivo (P < .001).

Conclusions

hASCs emerge as key regulators of immune tolerance and as attractive candidates for a cell-based therapy for Crohn's disease.

Section snippets

Cell Preparation

hASCs and mASCs were obtained and characterized as described in Supplementary Methods and Supplementary Figure 1 (see supplemental material online at www.gastrojournal.org).3, 12

Induction of Colitis and Study Design

To induce colitis, trinitrobenzene sulfonic acid (TNBS, 3 or 5 mg; Sigma, St Louis, MO) in 50% ethanol (100 μL) was administered intrarectally in BALB/c mice. Control mice received 50% ethanol alone. Animals were treated intraperitoneally with medium or with different numbers (105–106 cells/mouse) of hASCs, allogeneic

hASC Injection Protects Against TNBS-Induced Colitis

Recent studies have characterized the immunoregulatory activity of hASCs on T cells.3, 12, 13, 16 Therefore, we first investigated the potential therapeutic action of hASCs in an experimental model of colitis induced by intrarectal infusion of TNBS, which displays human CD-like clinical, histopathologic, and immunologic features.15 TNBS-treated mice developed a severe illness characterized by bloody diarrhea, rectal prolapse, pancolitis accompanied by extensive wasting syndrome, and profound

Discussion

In the present study, we showed that hASCs are able to suppress xenogeneic immune responses and provide a highly effective treatment for TNBS-induced colitis, a murine experimental model of CD. A single systemic injection of hASCs at the onset of the disease ameliorated the clinical and histopathologic severity of the wasting disease, abrogating body weight loss, diarrhea, and intestinal inflammation, and reducing the high mortality caused by this syndrome. Of obvious therapeutic importance is

Acknowledgements

The authors thank Dr Antonio Bernad and the research and development team at Cellerix for their critical reading of the manuscript.

References (29)

  • G. Ren et al.

    Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide

    Cell Stem Cell

    (2008)
  • P.N. Khalil et al.

    Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease

    Gastroenterology

    (2007)
  • G. Bouma et al.

    The immunological and genetic basis of inflammatory bowel disease

    Nat Rev Immunol

    (2003)
  • M.F. Pittenger et al.

    Multilineage potential of adult human mesenchymal stem cells

    Science

    (1999)
  • Cited by (0)

    M.A.G. and E.G.-R. contributed equally to this report.

    Conflicts of interest The authors disclose the following: The results presented in this report are part of patent applications by Cellerix. M.A.G., D.B., and M.D. are inventors. Because Cellerix SA and/or the inventors and/or their institutes stand to profit from this work, the authors have a conflict of interest, which hereby has been officially disclosed to the public.

    Funding Supported by Ministry of Health, Ministry of Education and Science (PETRI), Cellerix SA, Junta de Andalucia, and RETICS. D.B. is the recipient of a Marie Curie International Integration Grant.

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