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Mesenchymal Cells of the Lamina Propria in Intestinal Epithelial and Immunological Homeostasis

Final Report Summary - MCS-INTEST (Mesenchymal Cells of the Lamina Propria in Intestinal Epithelial and Immunological Homeostasis.)

In this project, we sought to define the physiological significance of mesenchymal cells (MCs) in epithelial and immunological homeostasis and the pathophysiology of chronic intestinal inflammatory and neoplastic disease. Our hypothesis was that mesenchymal cells play important physiological roles in intestinal homeostasis regulating key processes such as epithelial damage, regeneration and tumorigenesis, intestinal inflammation and lymphoid tissue formation, while we further proposed that a unifying principle underlying such functions was the innate character of MCs, meaning their ability to directly sense and metabolize innate signals from microbiota or cytokines in order to exert homeostatic epithelial and immunological regulatory functions in the intestine. To address this hypothesis, we used genetic approaches and state of the art phenotyping to discover the physiologically important signals orchestrating intestinal homeostasis in various animal models. We also studied MC lineage relations and plasticity during homeostasis and disease and developed ways to interfere with MC physiology.

In relation to the pathophysiological role of IMCs, we have identified several intrinsic signaling pathways and effector molecules that regulate mesenchymal cell function and their communication with other cell types during homeostasis, inflammation and cancer. Such molecules include the kinases Tpl2, MK2 and IKKβ. Briefly, we found that Tpl2 via its regulation of Cox2/PGE2 production plays an important role on the maintenance of intestinal homeostasis. The mesenchymal MK2/Hsp27 axis and NFkB activation in a subset of IMCs also showed an important pathogenic role in intestinal tumorigenesis through the production of inflammatory and tumorigenic mediators, such as IL-6, with a dominant effect on epithelial/cancer cell function. In addition to intracellular pathways, we have analyzed the role of mesenchymal-specific innate and cytokine receptors during chronic inflammation and cancer. Most importantly, we have identified that innate TLR4/MyD88 signals activate IMCs and cancer -associated fibroblasts to promote intestinal carcinogenesis through the production of cytokines, chemokines and ECM-modulating enzymes, which provides a direct proof of our initial hypothesis. Comparisons with human samples and publicly available human data has offered the necessary validation for the importance of similar mechanisms also in human disease.

In conclusion, we have addressed the unexplored hypothesis that brings into focus innate activation of mesenchymal cells as an early mechanism with dominant contribution in the initiation and progression of intestinal disease. This deep understanding of the biology of chronic innate activation of the intestinal mesenchymal compartment at the level of biochemical, molecular and cellular regulation has provided novel mechanistic insights and the potential for prognostic or therapeutic procedures that could be also relevant for a multitude of chronic diseases, such as chronic inflammatory or fibrotic mucosal pathologies, mainly of the skin and lung, and the pathogenesis of a variety of solid tumors, where MCs are also considered to play major pathogenic roles.