IBD is a chronic condition without a medical cure, and patients with IBD disease require a lifetime of care. The prevalence of IBD is currently highest in the Western world and affects 2.5-3.0 million patients in Europe, with an estimated annual cost for European health systems in excess of €5.0bn excluding the added socioeconomic burden. The current standard of care involves immunomodulatory drugs either alone or in combination with biologics such as inhibitors of specific signalling pathways. Due to failure of the palliative care, many IBD patients will have to undergo bowel resection and subsequently deal with the physiological and psychological complications related to a life without parts of the small or large intestine. To decrease the large socio-economic burden, alternative treatment strategies are required. We propose that IBD patients will benefit from epithelial transplants initially in combination with immunosuppressive therapies, or alternative strategies for promoting mucosal healing based on activation of endogenous stem cells. This requires the availability of an appropriate and sustainable source of cells for autologous transplantation, as well as better insight in the intestinal epithelium. Notably, the development of cell culture methods for primary epithelial cells from human small intestine and colon and the encouraging transplantation results from rodents bring promise to this approach.
The objective of the proposed research programme has been twofold. Firstly, we aimed to characterise and investigate the suitability of current sources of epithelial intestinal stem cells for transplantation. Secondly, we wished to define the transcriptional regulatory networks that control the differences observed between an immature foetal state and its adult state in the intestinal epithelium.
Via support from the European Research Council, we have been able to make significant progress towards the identified objectives. Most notably, we have utilized insight into how normal tissue regeneration proceeds using experimental animal models and in patient samples. This has enabled us to direct intestinal epithelial cells isolated from the adult epithelium into a fetal state both via genetically manipulating the cells and via using clinically compliant cell culture components. Importantly, cells in this fetal state efficiently engraft into an injured intestine. Importantly, we went on to show that epithelial cells in this fetal state were inherently more potent than cells in the adult state explaining both why they emerge during tissue regeneration and why these cells efficiently engraft upon transplantation. Collectively, we believe that this insight is critical and will have significant potential for moving cellular therapies into the clinic.
