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Characterization of epithelial wound repair at the molecular level for revealing epithelial aspects of inflammatory bowel disease

Final Report Summary - EPIREP (Characterization of epithelial wound repair at the molecular level for revealing epithelial aspects of inflammatory bowel disease)

Intestinal lumen is covered by single layered epithelium, which forms a physical barrier and protects our body from luminal contents such as pathogens. An intact barrier is crucial for our healthy lives. Inflammatory bowel disease (IBD) affects millions of people in worldwide and is characterised by prolonged inflammation of the lower gastrointestinal tract. Patients with IBD are broadly treated with anti-inflammatory medication for prolonged periods of time in order to achieve mucosal healing. Crucially, the socio-economical burdens as well as suppressed quality of life of the patients due to long-lasting medication are not negligible. In addition, groups of patients do not respond to standard therapy. Hence, we need to have additional approach to complement current treatment options to support the process of mucosal healing in these patients. Little is known about the process of regeneration after excessive injury or following excessive inflammation as in patients suffering from IBD. Lack of this knowledge limits our ability to ameliorate the regenerative process.

In this research project, we aimed to understand this process by mainly focusing on transitional cellular fate of intestinal epithelial cells during regeneration. By utilizing Dextran Sulfate Sodium (DSS) colitis model, which is widely accepted as a model of human colitis in rodents and presents ideal materials to analyse the process, we characterise the process of epithelial regeneration. We demonstrate that the repairing epithelium (RE) that appears during regeneration unique surface antigens, which allow their isolation. Comprehensive gene expression analysis reveals that the RE has a distinct transcriptional profile when compared to the homeostatic epithelium. Interestingly, the adaptive response reveal reprogramming into a more primitive state and identify a family of transcriptional regulators as the main driver of this process. Analysis of the upstream activators of the pathway shows strong evidence of activation of the entire signalling pathway uniquely to the repairing epithelium. Based on these in vivo observations we have recreated the cellular environment in vitro and demonstrate that the observed pathway is required and sufficient for reprogramming cells into the more primitive state. Crucially, we reveal that this adaptive response that lead to the formation of the RE is truly transitional and fully reversible.

This study firstly illustrates that the cellular reprogramming into a primitive state takes place during tissue regeneration. Our study also presents a simple model of this process, whereby define components act in synergy to evoke a transitional state responsible for tissue regeneration. This study describes the regenerative response in intestinal epithelium, however our finding may have broad impact to understand regenerative process in other types of epithelial tissue.