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MCs-inTEST Report Summary

Project ID: 340217
Funded under: FP7-IDEAS-ERC
Country: Greece

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

Mesenchymal cells of the intestinal lamina propria (IMCs) 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 project, we put forward the challenging hypothesis that, especially during acute or chronic inflammatory and tumorigenic conditions, IMCs 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 posited that a unifying principle underlying such functions would be the innate character of IMCs, which we hypothesized 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.
To address our hypothesis we are using genetic approaches to target innate pathways in IMCs and state of the art phenotyping to discover the physiologically important signals orchestrating intestinal homeostasis in various animal models of intestinal pathophysiology. We also study IMC lineage relations and plasticity during disease and develop ways to interfere therapeutically with IMC physiology to achieve translational added value for intestinal diseases and a range of other pathologies sharing similar characteristics. These results were also validated in human samples indicating their relevance to human disease.
During the first period of the project we have made substantial progress towards our objectives. Initially we identified two kinases that act downstream of innate immune signals and play important roles in the regulation of intestinal homeostasis, inflammation and cancer. More specifically, we showed that the kinase Tpl2 participates in innate immune sensing pathways in IMCs and regulates the Cox-2/PGE2 pathway, subsequently affecting epithelial homeostatic responses. We also provided evidence that this pathway may underlie IBD susceptibility in humans (Roulis et al., 2014). We also showed that the kinase IKKβ, a major regulator of the NFκΒ transcription factor signaling pathway, functions in IMCs and is critically involved in colitis and colitis-associated cancer, through the regulation of pro-inflammatory and pro-tumorigenic mediator expression, including IL-6, revealing thus an important immunomodulatory role for IMCs in both intestinal inflammation and tumorigenesis (Koliaraki et al., 2015).
We have performed initial lineage tracing experiments and have revealed that cells targeted by the ColVI-cre mouse comprise a specific population of mesenchymal cells in the intestine with diverse functions in intestinal inflammation and tumorigenesis (Koliaraki et al., 2015). Part of this population includes pericytes, suggesting important roles in angiogenesis and vascularization of the intestine (Prados et al., 2016). Similar lineage tracing approaches also showed that the ColVI-cre mouse targets stromal cells in secondary and tertiary lymphoid organs in the intestine, but not in the spleen or lymph nodes and could therefore prove a useful new tool for the dissection of MRC- and FDC-specific functions and plasticity in the GALT (Prados et al., 2016).
These results have been already been published in peer-review international journals. We are continuing our efforts in further understanding the physiological roles of IMCs in health and disease and the molecular pathways that underlie their functions.

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