Recombinant soluble thrombomodulin accelerates epithelial stem cell proliferation in mouse intestinal organoids and promotes the mucosal healing in colitis.

BACKGROUND AND AIM Epithelial regeneration, a critical step for the mucosal healing in inflammatory bowel disease, is tightly regulated by stem cells. Therefore, identification of the specific factors that induce stem cell proliferation could contribute to the development of effective strategies for treating inflammatory bowel disease. Recombinant soluble thrombomodulin (rsTM) has previously been shown to promote cell proliferation in skin and corneal wound healing in murine models, but its effects on intestinal epithelial cell proliferation remains unclear. METHODS Mouse intestinal organoids and dextran sulfate sodium (DSS)-induced colitis mouse model were used to assess the effects of rsTM on proliferation of intestinal epithelial cells. The size and budding morphologies of organoids were studied by confocal microscopy. The gene expression levels were analyzed by quantitative real-time polymerase chain reaction and immunofluorescence analysis. The effects of rsTM on DSS-induced colitis were investigated by evaluating body weight changes, colon length, histological score, and survival rate. RESULTS The rsTM markedly stimulated the growth of intestinal organoids, thereby increasing the surface areas and budding phenotypes of the organoids. rsTM also significantly upregulated the gene expression of intestinal stem cell-specific and epithelial cell-specific markers in a dose-dependent manner. Furthermore, the treatment with high concentrations of rsTM significantly improved the recovery of body weight, histological outcomes, colon length shortening, and prolonged the survival of mice with colitis. CONCLUSIONS The rsTM promotes intestinal stem cell proliferation in intestinal organoids and enhances the mucosal healing during recovery phase in DSS-induced colitis.