Mesenchymal cells (MCs) of the intestinal lamina propria refer to a variety of cell types, most commonly intestinal myofibroblasts, fibroblasts, pericytes, and mesenchymal stromal cells, which show many similarities in terms of origin, function and molecular markers. Understanding the physiological significance of MCs in epithelial and immunological homeostasis and the pathophysiology of chronic intestinal inflammatory and neoplastic disease remains a great challenge.In this proposal, we put forward the challenging hypothesis that, especially during acute or chronic inflammatory and tumorigenic conditions, MCs play important physiological roles in intestinal homeostasis regulating key processes such as epithelial damage, regeneration and tumorigenesis, intestinal inflammation and lymphoid tissue formation. We further posit that a unifying principle underlying such functions would be the innate character of MCs, which we hypothesize are capable of directly sensing and metabolizing innate signals from microbiota or cytokines in order to exert homeostatic epithelial and immunological regulatory functions in the intestine.We will be using genetic approaches to target innate pathways in MCs and state of the art phenotyping to discover the physiologically important signals orchestrating intestinal homeostasis in various animal models of intestinal pathophysiology. We will also study MC lineage relations and plasticity during disease and develop ways to interfere therapeutically with MC physiology to achieve translational added value for intestinal diseases, as well as for a range of other pathologies sharing similar characteristics.