Induction of mucosal healing (MH) is an important treatment goal in
inflammatory bowel disease (IBD). Although the molecular mechanisms underlying MH in IBD is not fully explored, local
fibrosis would contribute to interfere mucosal repair.
Carbohydrate sulfotransferase 15 (CHST15), which catalyzes sulfation of
chondroitin sulfate to produce rare E-
disaccharide units, is a novel mediator to create local
fibrosis. Here we have used
siRNA-based approach of silencing CHST15 in
dextran sulfate sodium (DSS) induced
colitis in mice, human colon fibroblasts and
cancer cell lines. In a DSS-induced acute
colitis model, CHST15
siRNA reduced CHST15
mRNA in the colon, serum
IL-6, disease activity index (DAI) and accumulation of F4/80+ macrophages and ER-TR7+ fibroblasts, while increased Ki-67+ epithelial cells. In DSS-induced chronic
colitis models, CHST15
siRNA reduced CHST15
mRNA in the colon, DAI, alpha-smooth muscle actin+ fibroblasts and
collagen deposition, while enhanced MH as evidenced by reduced histological and endoscopic scores. We also found that endoscopic submucosal injection achieved effective pancolonic delivery of CHST15
siRNA in mice. In human CCD-18 Co cells, CHST15
siRNA inhibited the expression of CHST15
mRNA and selectively reduced E-units, a specific product biosynthesized by CHST15, in the culture supernatant. CHST15
siRNA significantly suppressed
vimentin in both TGF-ß-stimulated CCD18-Co cells and HCT116 cells while up-regulated BMP7 and
E-cadherin in HCT116 cells. The present study demonstrated that blockade CHST15 represses colonic
fibrosis and enhances MH partly though reversing EMT pathway, illustrating a novel therapeutic opportunity to refractory and fibrotic lesions in IBD.