Dirk Büscher

Adipose-Derived Mesenchymal Stem Cells Alleviate Experimental Colitis by Inhibiting Inflammatory and Autoimmune Responses

BACKGROUND & AIMS Crohns 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 Crohns disease.

Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells

OBJECTIVE Rheumatoid arthritis (RA) is a chronic autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Adult mesenchymal stem cells (MSCs) were recently found to suppress effector T cell responses and to have beneficial effects in various immune disorders. The purpose of this study was to examine a new therapeutic strategy for RA based on the administration of human adipose-derived MSCs (AD-MSCs). METHODS DBA/1 mice with collagen-induced arthritis were treated with human AD-MSCs after disease onset, and clinical scores were determined. Inflammatory response was determined by measuring the levels of different mediators of inflammation in the joints and serum. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen. The number of Treg cells and the suppressive capacity on self-reactive Th1 cells were also determined. RESULTS Systemic infusion of human AD-MSCs significantly reduced the incidence and severity of experimental arthritis. This therapeutic effect was mediated by down-regulating the 2 deleterious disease components: the Th1-driven autoimmune and inflammatory responses. Human AD-MSCs decreased the production of various inflammatory cytokines and chemokines, decreased antigen-specific Th1/Th17 cell expansion, and induced the production of antiinflammatory interleukin-10 in lymph nodes and joints. Human AD-MSCs also induced de novo generation of antigen-specific CD4+CD25+FoxP3+ Treg cells with the capacity to suppress self-reactive T effector responses. CONCLUSION Human AD-MSCs emerge as key regulators of immune tolerance by inducing the generation/activation of Treg cells and are thus attractive candidates for a cell-based therapy for RA.

Human adipose-derived mesenchymal stem cells reduce inflammatory and T-cell responses and induce regulatory T cells in vitro in rheumatoid arthritis

Objectives: Adult mesenchymal stem cells were recently found to suppress effector T cell and inflammatory responses and have emerged as attractive therapeutic candidates for immune disorders. In rheumatoid arthritis (RA), a loss in the immunological self-tolerance causes the activation of autoreactive T cells against joint components and subsequent chronic inflammation. The aim of this study is to characterise the immunosuppressive activity of human adipose-derived mesenchymal stem cells (hASCs) on collagen-reactive T cells from patients with RA. Methods: The effects of hASCs on collagen-reactive RA human T cell proliferation and cytokine production were investigated, as well as effects on the production of inflammatory mediators by monocytes and fibroblast-like synoviocytes from patients with RA. Results: hASCs suppressed the antigen-specific response of T cells from patients with RA. hASCs inhibited the proliferative response and the production of inflammatory cytokines by collagen-activated CD4 and CD8 T cells. In contrast, the numbers of IL10-producing T cells and monocytes were significantly augmented upon hASC treatment. The suppressive activity of hASCs was cell-to-cell contact dependent and independent. hASCs also stimulated the generation of FoxP3 protein-expressing CD4+CD25+ regulatory T cells, with the capacity to suppress collagen-specific T cell responses. Finally, hASCs downregulated the inflammatory response and the production of matrix-degrading enzymes by synovial cells isolated from patients with RA. Conclusions: The present work identifies hASCs as key regulators of immune tolerance, with the capacity to suppress T cell and inflammatory responses and to induce the generation/activation of antigen-specific regulatory T cells.

Endoscopic submucosal injection of adipose-derived mesenchymal stem cells ameliorates TNBS-induced colitis in rats and prevents stenosis

BackgroundMesenchymal stem cells have potential applications in inflammatory bowel disease due to their immunomodulatory properties. Our aim was to evaluate the feasibility, safety and efficacy of endoscopic administration of adipose-derived mesenchymal stem cells (ASCs) in a colitis model in rats.MethodsColitis was induced in rats by rectal trinitrobenzenesulfonic acid (TNBS). After 24 h ASCs (107 cells) or saline vehicle were endoscopically injected into the distal colon. Rats were followed for 11 days. Daily weight, endoscopic score at days 1 and 11, macroscopic appearance at necropsy, colon length and mRNA expression of Foxp3 and IL-10 in mesenteric lymph nodes (MLN) were analyzed.ResultsEndoscopic injection was successful in all the animals. No significant adverse events or mortality due to the procedure occurred. Weight evolution was significantly better in the ASC group, recovering initial weight by day 11 (− 0.8% ± 10.1%, mean ± SD), whereas the vehicle group remained in weight loss (− 6.7% ± 9.2%, p = 0.024). The endoscopic score improved in the ASC group by 47.1% ± 5.3% vs. 21.8% ± 6.6% in the vehicle group (p < 0.01). Stenosis was less frequent in the ASC group (4.8% vs. 41.2%, p < 0.01). Colon length significantly recovered in the ASC group versus the vehicle group (222.6 ± 17.3 mm vs. 193.6 ± 17.9 mm, p < 0.001). The endoscopic score significantly correlated with weight change, macroscopic necropsy score and colon length. Foxp3 and IL-10 mRNA levels in MLN recovered with ASC treatment.ConclusionsASC submucosal endoscopic injection is feasible, safe and ameliorates TNBS-induced colitis in rats, especially stenosis.

Obtención de células madre inmortalizadas derivadas de lipoaspirado para su diferenciación hacia diferentes linajes

Adult stem cells are considered the present and the future in gene therapy. One of the sources for adult stem cells is adipose tissue where CMDL (lipoaspiration derived stem cells) are obtained, CMDL are well known for their autorenovation capacity, long term viability and potential to differentiate to diverse cellular types in vitro, like adipogenic, condrogenic, miogenic, osteogenic eventhough neurons.