Regulation of pancreas organoid plasticity: new strategies for diabetes

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Since the discovery of insulin almost a century ago, there has been an alarming increase in new diabetes cases, but the only treatment for diabetes is still based on delivering insulin via injections or pumps. While insulin administration can successfully control diabetic symptoms, the risk of complications is very high, and the continual blood sugar management required can be a real burden in patients' lives. Regenerative medicine offers new hopes of a curative treatment for diabetes by replacing lost beta cells, which respond to blood glucose levels and produce insulin. However, the source of replacement cells, the efficiency with which they can be produced and how well they work in the body are all still under investigation. Recent evidence suggests that the ductal cells of the pancreas, which are not damaged in diabetes, can change into other cell types when given the right trigger. Ductal cells can be grown long term outside the body as "organoids" in 3D culture. We and others have shown that when grown in special conditions or genetically modified to produce three key proteins responsible for making beta cells in the embryo (Ngn3/Pdx1/MafA), ductal cells change to beta-like cells. In our lab, we have exciting evidence that the reason the efficiency of conversion and functionality of the generated cells does not match "real" mature beta cells is firstly, because not all cells are equally responsive to the signals to become beta-cells, and secondly, because of the strong degradation mechanisms that operate on Ngn3, Pdx1 and MafA, inactivating them before they have a chance to work. We believe that by identifying the cells that can convert into beta-cells, and discovering how to stabilise Ngn3, Pdx1 and MafA we will be able to improve the chances of curing diabetes. In this proposal, we want to address these questions: What are the proteasomal mechanisms regulating proendocrine factors stability? How does the lysosome regulate the proendocrine factors? Can the variation of such mechanisms at a single cell level explain the heterogeneity of the ductal organoids? Altogether this research proposal will substantially increase our knowledge of beta cell generation from ductal cells. We hope that our findings pave the way for the development of new, more efficient strategies to replenish lost beta cells in diabetes patients, in order to achieve the ultimate therapy goal for diabetes: a "diabetes free" life.