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P015 Wnt10b promotes fibrosis in murine colitis

Ortiz-Masia D.*1,2, Salvador P.3, Macias-Ceja D.C.4, Gisbert-Ferrándiz L.3, Hernandez C.4, Calatayud S.3, Esplugues J.V.3,4, Barrachina D.3

1Universidad de Valencia-CIBERehd, Department of Pharmacology, Valencia, Spain 2Universidad de Valencia, Department of Medicine, Valencia, Spain 3Universidad de Valencia, Department of Pharmacology, Valencia, Spain 4FISABIO Hospital Peset, Department of Pharmacology, Valencia, Spain

Background

Intestinal fibrosis is a common complication of IBD. We have recently reported in STAT6 knockout mice treated with TNBS that intestinal fibrosis is associated with up-regulation of M2c macrophages which express high levels of Wnt10b. The aim of the present study is to analyze the direct effects of Wnt10b in fibrosis development in a murine model of colitis.

Methods

Balbc mice were given TNBs (0.5, 0.5 mg, intrarectally) or saline weekly and received a single administration of Wnt10b (1ug/mice) or its vehicle, daily until sacrifice, 2 weeks after the first TNBs administration. Body weight was recorded daily and the mRNA expression of collagens (Col1a, Col3a and Col4a), fibrosis markers (TIMP1, MMP2) and cellular markers (Vimentin, FSP1, E-Cadherin and αSMA) in the intestinal mucosa was analyzed by quantitative PCR. Results are expressed as fold induction vs control mice. Collagen deposition was quantified by the Sircol assay and the expression of β-catenin was analyzed by immunohistochemistry in the intestinal mucosa, 2 weeks after the first TNBs administration. Data are expressed as Mean ± SEM with n≥3 in all groups (*p<0.05 vs vehicle; #p<0.05 vs TNBS).

Results

The systemic administration of Wnt 10b: a) did not significantly alter the body weight loss in TNBS- or vehicle-treated mice; b) significantly increased the amount (μg/mg wet weight) of collagen in TNBS-treated mice (Sircol quantification; TNBS: 0.75±0.08 and TNBS+Wnt10b: 1.39±0.06*#) while it did not significantly modify it in vehicle treated mice (vehicle: 0.85±0.18 and vehicle+Wnt10b: 1.07±0.10); c) significantly increased the mRNA expression in collagen (Col1a and Col3a) and fibrosis markers (TIMP1, FSP1, αSMA and Vimentin)in TNBS-treated mice while it failed to induce a significant increase in the expression of these genes in vehicle-treated mice; d) increased the expression of nuclear β-catenin in cells located at the base of the crypt and cells in the lamina propria.

Figure 1. mRNA expression.

Conclusion

Wnt10b increase deposition of collagen and promotes intestinal fibrosis in TNBs-treated mice through the activation of myofibroblasts likely through canonical Wnt signaling pathway.