Extracellular Matrix Orchestration of Tissue Remodeling in the Chronically Inflamed Mouse Colon

Abstract

Background & AimsChronic inflammatory illnesses are debilitating and recurrent conditions associated with significant co-morbidities, including an increased risk of developing cancer. Extensive tissue remodelling is a hallmark of such illnesses, and is both a consequence and a mediator of disease progression. Despite previous characterisation of epithelial and stromal remodelling during Inflammatory Bowel Disease, a complete understanding of its impact on disease progression is still lacking. MethodsA comprehensive proteomic pipeline using data-independent acquisition was applied to decellularized colon samples from the Muc2KO mouse model of colitis, for an in-depth characterisation of extracellular matrix remodelling. Unique proteomic profiles of the matrisomal landscape were extracted from pre- and pathological colitis. Integration of proteomics and transcriptomics datasets extracted from the same murine model produced network maps describing the orchestrating role of matrisomal proteins in tissue remodelling during the progression of colitis. ResultsThe in-depth proteomic workflow used here allowed the addition of 34 proteins to the known colon matrisomal signature. Protein signatures of pre- and pathological colitic states were extracted, differentiating the two states by expression of small leucine rich proteoglycans. We outlined the role of this class and other matrisomal proteins in tissue remodelling during colitis, as well as the potential for co-ordinated regulation of cell types by matrisomal ligands. ConclusionOur work highlights a central role for matrisomal proteins in tissue remodelling during colitis and defines orchestrating nodes that can be exploited in selection of therapeutic targets.