Pretreatment with Interferon-γ Enhances the Therapeutic Activity of Mesenchymal Stromal Cells in Animal Models of Colitis

Abstract

Mesenchymal stromal cells (MSCs) are currently under investigation for the treatment of inflammatory disorders, including Crohn's disease. MSCs are pluripotent cells with immunosuppressive properties. Recent data suggest that resting MSCs do not have significant immunomodulatory activity, but that the immunosuppressive function of MSCs has to be elicited by interferon-c (IFN-c). In this article, we assessed the effects of IFN-c prestimulation of MSCs (IMSCs) on their immunosuppressive properties in vitro and in vivo. To this end, we pretreated MSCs with IFN-c and assessed their therapeutic effects in dextran sodium sulfate (DSS)-and trinitrobenzene sulfonate (TNBS)-induced colitis in mice. We found that mice treated with IMSCs (but not MSCs) showed a significantly attenuated development of DSS-induced colitis. Furthermore, IMSCs alleviated symptoms of TNBS-induced colitis. IMSCtreated mice displayed an increase in body weight, lower colitis scores, and better survival rates compared with untreated mice. In addition, serum amyloid A protein levels and local proinflammatory cytokine levels in colonic tissues were significantly suppressed after administration of IMSC. We also observed that IMSCs showed greater migration potential than unstimulated MSCs to sites within the inflamed intestine. In conclusion, we show that prestimulation of MSCs with IFN-c enhances their capacity to inhibit Th1 inflammatory responses, resulting in diminished mucosal damage in experimental colitis. These data demonstrate that IFN-c activation of MSCs increases their immunosuppresive capacities and importantly, their therapeutic efficacy in vivo. STEM CELLS 2011;

Mesenchymal Stem Cell treatment for autoimmune diseases: a critical review

“…Sun et al reported similar fi ndings with UC-MSCs transplantation in patients with refractory SLE 3 months after treatment, also suggesting a polarization toward the Th1 phenotype, that was associated with clinical improvement . In gastrointestinal models of disease, pretreatment of MSCs with IFN-γ markedly inhibited dextran sodium sulfate (DSS) induced colitis in mice, leading to improvement of body weight, colitis scores and better survival rates compared to untreated mice (Duijvestein et al, 2011). Recent studies have suggested that Toll Like Receptor (TLR) signaling regulates the proliferation, diff erentiation and immune function of MSCs.…”

Stem Cell Therapy in the Treatment of Inflammatory Bowel Disease

“…Preclinical studies on the models of necrotizing colitis as well as experimental colitis induced by DSS and 2,4,6-TNBA showed positive effect of systemic and local use of MSC derived from the bone marrow, amniotic fluid, cord blood, adipose tissue on the course of colitis and stimulation of reparation [15,16,19,26]. CT was shown to increase survival and stimulate reparation of the damaged mucous membranes of the large intestine of newborn rats with necrotizing colitis.…”

Strategies to improve the migration of mesenchymal stromal cells in cell therapy

“…Prestimulation with a cocktail of five cytokines containing fms-like tyrosine kinase 3 (Flt-3) ligand, stem cell factor (SCF), interleukin (IL)-6, HGF, and IL-3 promotes the migration of FLK(+) MSCs to the bone marrow through up-regulation of both cell surface and intracellular CXCR4 [71] . Other factors, such as IGF-1 [72,73] , IL 1β [74] , interferon γ (IFNγ) [4,75] , basic fibroblast growth factor (bFGF), PDGF [41] , nitric oxide donor [76] , or complement 1q (C1q) [77] have also been shown to improve MSC homing in different disease models possibly as a result of increased CXCR4 or MMP expression. Pretreating MSCs with a combination of hematopoietic growth factors erythropoietin (EPO) and granulocyte colony stimulating factor (G-CSF) can enhance their motility by increasing the MMP expression [78] .…”