Background Exosomes as the main therapeutic vectors of mesenchymal stem cells (MSC) for inflammatory bowel disease (IBD) treatment and its mechanism remain unexplored. Tumor necrosis factor-α stimulated gene 6 (TSG-6) is a glycoprotein secreted by MSC with the capacities of tissue repair and immune regulation. This study aimed to explore whether TSG-6 is a potential molecular target of exosomes derived from MSCs (MSCs-Exo) exerting its therapeutic effect against colon inflammation and repairing mucosal tissue. Methods Two separate dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced IBD mouse models were intraperitoneally administered MSCs-Exo extracted from human umbilical cord MSC (hUC-MSC) culture supernatant. Effects of MSCs-Exo on intestinal inflammation, colon barrier function, and proportion of T cells were investigated. We explored the effects of MSCs-Exo on the intestinal barrier and immune response with TSG-6 knockdown. Moreover, recombinant human TSG-6 (rhTSG-6) was administered exogenously and colon inflammation severity in mice was evaluated. Results Intraperitoneal injection of MSCs-Exo significantly ameliorated IBD symptoms and reduced mortality rate. The protective effect of MSCs-Exo on intestinal barrier was demonstrated evidenced by the loss of goblet cells and intestinal mucosa permeability, thereby improving the destruction of tight junctions (TJ) structures and microvilli, as well as increasing the expression of TJ proteins. Microarray analysis revealed that MSCs-Exo administration downregulated the level of pro-inflammatory cytokines and upregulated the anti-inflammatory cytokine in colon tissue. MSCs-Exo also modulated the response of Th2 and Th17 cells in the mesenteric lymph nodes (MLN). Reversely, knockdown of TSG-6 abrogated the therapeutic effect of MSCs-Exo on mucosal barrier maintenance and immune regulation, whereas rhTSG-6 administration showed similar efficacy to that of MSCs-Exo. Conclusions Our findings suggested that MSCs-Exo protected against IBD through restoring mucosal barrier repair and intestinal immune homeostasis via TSG-6 in mice.
Background Inflammatory bowel diseases (IBD) is a chronic intestinal disease characterized by persistent intestinal inflammation and mucosal damage. Mesenchymal stem cells (MSCs) transplantation is a promising therapy in IBD and other autoimmune diseases. Recent studies indicated that exosomes are the main therapeutic vectors of MSCs in treatment of IBD, but the therapeutic mechanism of exosomes derived from MSCs (MSCs-EXO) remains to be explored. The aims of our research is to explore whether MSCs-EXO have a protective effect on the intestinal barrier. Methods The serum-free cell culture supernatant of Human umbilical cord MSCs (hUC-MSCs) cultured for 48 hours was collected to extract exosomes. Two separate mouse models of IBD induced by dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS) were administered MSCs-EXO intraperitoneally. The effects of MSCs-EXO on intestinal inflammation, colon barrier function and proportion of T cells were investigated. Results Intraperitoneal injection of MSCs-EXO significantly ameliorated colitis, especially reduced disease activity index and mortality, and inhibited inflammatory cells infiltration. The protective effect of MSCs-EXO on intestinal barrier was demonstrated by reducing the loss of goblet cells and the intestinal mucosa permeability, improving the destruction of tight junctions (TJs) structures and microvilli, and increasing the expression of TJs proteins ZO-1, Claudin-1, and Occludin. MSCs-EXO administration downregulated the level of proinflammatory cytokines, including CXCL14, IL-1β, IL-11, and IL-12 and upregulated the anti-inflammatory cytokine IL-4 and TGF-β in colon tissue. MSCs-EXO also modulated the response of Th2 cells and Th17 cells in mesenteric lymph nodes (MLN). Conclusion Our findings suggested that MSCs-EXO promoted mucosal barrier repair and maintained intestinal immune homeostasis in murine colitis model.
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