The Therapeutic Effect Of ICAM-1 Modified MSCs On Inflammatory Bowel Disease

In recent years, mesenchymal stem cells(MSCs) based cell transplantation has emerged as a promising therapeutic strategy for the treatment of inflammatory bowel diseases(IBD). IBD is thought to be elicited by dysregulated immune responses toward communal and nonpathogenic bowel antigens in genetically susceptible individuals. Eventually, the excessive immune reactions lead to the defects in the intestinal epithelial barrier, thereafter, resulted in serious tissue destruction of bowels. MSCs posess the capability to modulate immune function and to promote tissue regeneration, which enable the application of MSCs for the treatment of autoimmune diseases. Previous reports have demonstrated that intravenously transplanted MSCs may home to injured intestinal tissues, promote intestinal cell regeneration, and ameliorate the clinical syndromes. In addition,MSC transplantation have been proved to be a safe treatment. Based on the promoting fingdings, MSC transplantation supplies a novel clinic choice for curing IBD, nonetheless, for severe refractory IBD cases. However, the clinic applications are confined by the low efficiency and un-stability of MSC transplantation. Thus, the further investigations will focus on the improvement of efficiency and stability of the therapy.The immunosuppressive effect that MSCs exert is mainly mediated by soluble factors and adhesion molecules. In addition, the MSC adhesion molecules and their ligands contribute to the contact-dependent MSC-immune cell interactions and control the MSC migration. ICAM-1 served as a crucial molecule in MSC-base cell functions. Physiologically, MSCs were found to constitutively express a low level of ICAM-1. In the inflammatory microenvironment, the expression of ICAM-1 by MSCs was significantly up-regulated. Further researches show that blockage of the function of adhesion molecules significantly reversed the immunosuppressive effect of MSCs in vitro and in vivo. The ICAM-1 overexpressing MSCs was prepared genetically as described in our previous reports. Interestingly, we found that the overexpression of ICAM-1 can significantly enhance the immunosupressive effect of MSCs in vitro. However, it remains unknown that whether the modification of ICAM-1 affects the immune regulation ability in vivo and the therapeutic effect of IBD.In the present study,(1) we firstly established a stable and reliable IBD animal model to investigate the therapeutic effect and mechanism of ICAM-1 modified MSCs in vivo. The classical colitis mouse models were induced by dextran sulfate sodium(DSS).(2) The primary MSCs and C3H10T1/2 cell lines were cultured in vitro. The expression of ICAM-1 in C3 cells were detected by flow cytometry. A large amount of cells were amplified and cryopreserved for subsequent experimental application.(3) Cell therapy. Briefly, the experimental groups include: Control group, PBS group, MSCs group, C group, C3-MIGRI group, C3-ICAM-1 group. At day 3 of oral up-taken of 5% DSS, mice were tail vein-injected with MSCs(2.5×106 in 500?lm per mouse). The MSC distribution in vivo was detected by frozen sectioning. In addition, the survival rate, body weight change, colon length and weight, ogical scores, and the number of regulatory T cells(Tregs) were also determined.We found that the mice developed colon ulcer at day 6 while drinking water with 3%, 5%, or 7% DSS. The model rate increased with the increasing concentration of DSS. In addition, the mortality of mice also increased. In general, drinking 5% DSS solution is helpful to establish IBD model in an efficient and economical manner. Moreover, the results of MSC distribution experiments showed that over-expressing ICAM-1 MSCs increases the delivery of MSCs into inflamed organs. Moreover, infusing over-expressing ICAM-1 MSCs improved the general condition of IBD mouse, increased survive rate, reduced pathological damage, modulated the differentiation of T cell subpopulation, and reduced the expression of IFN-? and IL-17, but increased the expression of Foxp3 in splenocytes.In conclusion, we successfully established the DSS induced colitis mice model. We found that ICAM-1 modified MSCs exerted better treat effects on IBD mice by targeting migration and enhanced immunosuppression. The findings reveal the novel role of ICAM-1 in MSC based cell therapy and broaden the application of MSC transplantation for IBD treatment.