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P014. Pretreatment with interferon-gamma enhances the therapeutic activity of mesenchymal stromal cells in dextran sodium sulfate (DSS) induced colitis

M. Duijvestein1, M.E. Wildenberg1, M.M. Welling1, A.C.W. Vos1, S. Hennink1, T. Bosse1, E.S.M. de Jonge-Muller1, H. Roelofs1, H.W. Verspaget1, W.E. Fibbe1, A.A. te Velde2, G.R. van den Brink1, D.W. Hommes1

1Leiden University Medical Center (LUMC), Leiden, The Netherlands; 2Academic Medical Center (AMC), Amsterdam, The Netherlands

Aim: Mesenchymal stromal cells (MSCs) are pluripotent cells with immunosuppressive properties, currently studied as a potential treatment for inflammatory bowel diseases (IBD). Recent data suggest that MSCs, when activated by IFNγ, have greater immunosuppressive potential. Therefore, we assessed the effects of interferon-gamma (IFNγ) prestimulation of MSCs (IMSCs) in the dextran sodium sulfate (DSS) induced colitis model. Furthermore, the effects of IFNγ on the migration capacities of MSCs was examined.

Materials and Methods: The effect of IFNγ stimulation on MSC function was analyzed in vitro and in the DSS induced colitis model. C57BL/6 mice were supplied with drinking water supplemented with 2.25% (w/v) DSS for seven days. On day 0, mice were injected intraperitoneally with 0.5×106 human MSCs diluted in 100 μL PBS, 0.5×106 human IMSCs diluted in 100 μL PBS or a vehicle control (PBS alone). All mice were sacrificed on day 9 after the start of the experiment. Colonic inflammation was examined both symptomatically and histologically, and proinflammatory cytokine levels were determined. To analyze the biodistribution and compare homing of MSCs and IMSCs, (I)MSCs were labeled with technetium-99m (99mTc) and intraperitoneally injected into different groups of animals on day 7. Animals were sacrificed 24 hrs after injection of radiolabeled (I)MSCs in established colitis models, and relevant organs and tissues were excised, weighed, and measured for radioactivity using a dose calibrator.

Results: MSC suppress lymphocyte proliferation in vitro, and this effect was markedly enhanced by IFNg pre-stimulation of MSC, indicating a potentiation of their immunosuppressive capacity. To further test this potentiation in vivo, the effect of (I)MSC treatment was evaluated in the DSS model of experimental colitis. Strikingly, IMSCs (but not MSCs) significantly attenuated the development of DSS-induced colitis. IMSC-treated mice showed improved body weight gain as well as lower colitis scores compared to MSC-treated mice. In addition, serum amyloid A protein levels and local proinflammatory cytokine levels in colonic tissues were significantly suppressed. Next, we examined the migration of IMSC and MSC under steady state and inflammatory conditions. Interestingly, IMSCs showed greater potential to migrate to sites within the inflamed instestine than did unstimulated MSC, suggesting a possible contribution of migration to the attenuation of colitis.

Conclusion: These data demonstrate that MSCs prestimulated with IFNγ increases therapeutic efficacy in experimental models of colitis by altering local cytokine levels and enhancing cell migration to sites within the diseased intestine.