Smad4 Loss in the Mouse Intestinal EpitheliumAlleviates the Pathological Fibrotic Response to Injury in the Colon
Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel diseases (IBDs). Unresolved injury and inflammation, on the other hand, increases pathological fibrosis and the predisposition to cancer. Loss of Smad4, a tumor suppressor, is known to increase colitis-associated cancer in mouse models of chronic IBD. Since common biological processes are involved in both injury repair and tumor growth, we sought to investigate the effect of Smad4 loss on the response to epithelial injury.  To study the injury response, an IBD mouse model of acute inflammation using dextran sulphate sodium (DSS) was used. Smad4 was knocked out only in the mouse intestinal epithelium, treated with DSS, and the early molecular and morphological response compared to its wildtype counterpart.   We find that Smad4 loss alleviates pathological fibrosis and enhances mucosal repair. Transcriptomic changes specific to the epithelium indicate molecular changes that affect peri-crypt epithelial extracellular matrix (ECM), that might contribute to the enhanced mucosal repair, and in preventing the fibrotic response.  We find that biological processes that promote tumor progression might facilitate the wound healing response and reduce the pathological fibrotic response to DSS. Therefore, these repair processes could be exploited, if uncoupled from the tumorigenic effect, to develop therapies that promote non-pathological wound healing and to prevent fibrosis. Overall design: Gene expression prolifiling was performed on wildtype and Smad4 knockout colon epithelium of mice of C57/BL6 enriched background, with or without three days of DSS in drinking water consumed ad libitum.