Bi-directional Regulatory Mechnisms Of Bone Marrow Mesenchymal Stem Cells On Colitis Associated Colorectal Cancer

Background: Inflammatory bowel disease(IBD)is a kind of non-specificity chronic inflammation in gastrointestinal tract.In recent years,the incremental prevelance of IBD showed younger trend.Severe complications,such as colitis associated colorectal cancer(CAC),which result from raising course and recurrent attacks of inflammation,attracts more and more attention.Bone marrow mesenchymal stem cells(BMMSCs),a kind of bonemarrow-derived non-hematopoietic stem cells,have become the ideal cells in regeneration medicine because of their self-renewal,multi-directional differentiation,low immunogenicity and immunomodulation characteristics.Applications of MSC in IBD have always been the hotspot in basic and clinical research.But the detailed mechanism and safety problems still need to be explicit.Objectives: The study investigated the effects of h BMMSC on AOM/DSS induced colonic malignant model,AOM/DSS induced acute colitis and colorectal cancer cell lines in order to observe systematically the therapeutic value of BMMSC in the colonic non-resolving inflammatory malignant transition.Methods: 1.Murine colitis associated colorectal cancer model was established by AOM/DSS protocol.2.Tumors formation was detected after treated with h BMMSC in the AOM/DSS model.3.The protective effect of h BMMSC was checked in the early acute colitis phase of the AOM/DSS model compared with the effects of o ridonin derivative--HAO472.4.Colorectal cancer cell line--SW1116 were stimulated with conditional medium of h BMMSC and TNF-? activated h BMMSC,CCL5 and inhibitors of CCRs or Wnt pathway.MTT assay was applied to detect the proliferation of SW1116.Wound healing and transwell assay were applied to check the migra ted ability of SW1116.Real-Time PCR and Western Blot were applied to detect alteration of epithelial-mesenchymal transition(EMT)marker--Slug and the change of activation of Wnt pathway.Results: 1.h BMMSC administration in the earlier phase ameliorated the tumor formation both in the tumor loads and tumor size at the terminal time point.On the contrary,h BMMSC administration in the later phase seemed to enhance the tumor formation.2.In the early acute colitis phase of the AOM/DSS model,h BMMSC treated one day after DSS administration ameliorated the injury and loss of epithelium.3.h BMMSC prompted the growth and migration of colon cancer cells,which might be involved with the up-regulation of EMT transcript factors slug via CCL5/CCR1/Wnt pathway.Conclusion: Bone marrow MSC inhibited the inflammatory injury and tumor formation in the murine model at the earlier phase.O n the contrary,administration at the later phase was proved to promote the tumor formation.BMMSC also promoted proliferation and migration of the colon cancer cells,which may be involved with CCL5/CCR1/Wnt pathway.