title: 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-γ (IFN-γ). In this article, we assessed the effects of IFN-γ prestimulation of MSCs (IMSCs) on their immunosuppressive properties in vitro and in vivo. To this end, we pretreated MSCs with IFN-γ 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. IMSC-treated 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-γ enhances their capacity to inhibit Th1 inflammatory responses, resulting in diminished mucosal damage in experimental colitis. These data demonstrate that IFN-γ activation of MSCs increases their immunosuppresive capacities and importantly, their therapeutic efficacy in vivo.
authors: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands. m.duijvestein@lumc.nl
authors: Marjolijn
authors: M
authors: Duijvestein
authors: Manon E
authors: ME
authors: Wildenberg
authors: Mick M
authors: MM
authors: Welling
authors: Simone
authors: S
authors: Hennink
authors: Ilse
authors: I
authors: Molendijk
authors: Vanessa L
authors: VL
authors: van Zuylen
authors: Tjalling
authors: T
authors: Bosse
authors: Anne Christine W
authors: AC
authors: Vos
authors: Eveline S M
authors: ES
authors: de Jonge-Muller
authors: Helene
authors: H
authors: Roelofs
authors: Louise
authors: L
authors: van der Weerd
authors: Hein W
authors: HW
authors: Verspaget
authors: Willem E
authors: WE
authors: Fibbe
authors: Anje A
authors: AA
authors: te Velde
authors: Gijs R
authors: GR
authors: van den Brink
authors: Daniel W
authors: DW
authors: Hommes
mesh_terms: D000818:Animals; D001835:Body Weight; D002454:Cell Differentiation; D002465:Cell Movement; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D003106:Colon / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000032:analysis; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007165:Immunosuppression Therapy; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000685:Serum Amyloid A Protein / Q000032:analysis; D014302:Trinitrobenzenesulfonic Acid / Q000009:adverse effects
chemical_list: D016207:Cytokines; D000685:Serum Amyloid A Protein; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate