Characterizing and reversing ß-cell senescence and proliferation quiescence in monogenic diabetes

Cell senescence is defined as a permanent exit from cell cycle. Pancreatic ß-cells undergo rapid postnatal senescence and subsequent proliferative quiescence. Yet, in certain conditions, ß-cells are able to retain/regain a juvenile status and maintain their proliferative capacity. We recently described one such situation following total ß-cell ablation in juvenile mice. Naturally regenerated ß-like cells express ß-cell maturity markers and respond to glucose, yet even long time after ablation they still preserve low levels of senescence factors, manifesting a massive proliferation potential. These results and others suggest that the senescence program is not permanently reinforced and ß-cell senescence is potentially reversible. Here we will assess the role of ß-cell senescence and subsequent proliferative quiescence on MODY3 (Maturity Onset Diabetes of the Young type 3) monogenic disorder onset. We postulate that ß-cell decay results from a synergetic combination of a single gene defect and an age-related, potentially reversible, senescence mechanism. The goal of this proposal is to elucidate and reverse the molecular age-switch controlling the homeostatic gradual impairment and proliferation quiescence in ß-cells. In order to achieve this, we raised the following questions: what are the age-related molecular changes leading to ß-cell decay? what is the impact of ß-cell senescence and proliferation halt on MODY3 onset? which rejuvenation strategies can reverse the senescence-switch and delay MODY3 onset? are these findings translatable in humans? To reply to these questions we generate two different murine models of MODY3 disorder and cross them with genetic ß-cell tracing. This study will provide the first systematic cellular and molecular timeline of ß-cell decay in the context of MODY3 disorder with emphasis on the role of cellular senescence and proliferation in the age-related monogenic disease initiation.