Final Report Summary - MORPHOSTASIS (Morphostasis of the intestinal mucosa and it's deregulation in cancer and inflammation)
The intestinal mucosa is home to a powerful immune system that is in a basal state of tolerance and covered by an epithelium with an astonishing rate of renewal. Mesenchymal cells such as myofibroblasts are in close contact with the intestinal epithelium and were for a long time believed to act mainly as support cells for the rapidly regenerating epithelium. The research funded by the ERC grant has allowed us to show that Indian Hedgehog (Ihh) is a signal produced by the functional differentiated epithelial cells that is uniquely perceived by the underlying myofibroblasts. We found that Ihh plays a critical role as a negative feedback signal from the differentiated cells to their rapidly proliferating precursors by inducing negative regulators of intestinal stem cells in the myofibroblasts. In addition to these epithelial-mesenchymal interactions we have found that mesenchymal cells are key intermediates between epithelial cells and the mucosal immune system as mice in which we specifically deleted Indian Hedgehog from the intestinal epithelium develop a chronic inflammatory bowel disease. Despite the importance of Ihh as a negative feedback regulator of intestinal epithelial renewal we observed an absolute requirement of Ihh signaling the development of intestinal adenomas (polyps), the precursors to colorectal cancer. Apparently Ihh is required to induce signals in the myofibroblasts that are required to allow adenoma development. Our research is currently focusing on identifying how myofibroblasts regulate the intestinal immune system and adenoma development.