Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses.
OBJECTIVE
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.
González
Manuel A
MA
Cellerix SA, Tres Cantos (Madrid), Madrid, Spain; Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
Gonzalez-Rey
Elena
E
Rico
Laura
L
Büscher
Dirk
D
Delgado
Mario
M
D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D015551:Autoimmunity; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology