| Description |
Type I diabetes is caused by selective loss of insulin-producing β-cells. Identifying and activating an endogenous source of new β-cells could be used to replenish those lost in this disease. The nature and existence of an adult pancreatic stem/progenitor cell population, however, is still controversial. Circumstantial evidence indicates that islet cells arise from embryonic ductal cells. In contrast, the majority of adult islet cells appear to regenerate via self-renewal during postnatal expansion and adult homeostasis. That ducts could also give rise to new beta-cells in the adult (neogenesis) was recently suggested in the context of pancreatic ductal ligation (PDL) injury. The Notch signaling pathway inhibits islet development and promotes progenitor cell maintenance during early pancreatic organogenesis, acting primarily through its target gene Hes1. While Hes1 is broadly expressed in the embryonic pancreas, only rare Hes1-expressing cells can be found in the adult organ, among mature ducts and centroacinar cells (CACs), the latter of which have been proposed to represent adult progenitors. This thesis aims to test directly the ability of duct cells to generate islet cells, and to determine the biological function of Hes1+ duct cells. For this, we performed lineage tracing and genetic manipulation using two novel Cre-lines, Muc1IC2, which marks exocrine cells, and Hes1C2, which marks Hes1+ cells. Our work has uncovered three major phases in the development of pancreatic islet cells: (i) initially, new islet cells originate from Notchresponsive exocrine cells, (ii) later in embryogenesis, Notch signaling needs to be downiv regulated in exocrine cells for islet neogenesis to proceed and (iii) from birth onwards, islet cells are maintained by replication of pre-existing cells with no detectable influx from neogenesis. Additionally, our findings demonstrated that early Hes1+ cells represent multipotent progenitors and that their immature state is maintained through active Notch signaling. Interestingly, later in development Notch promotes duct specification of Hes1-expressing bipotent exocrine progenitors. In the mature pancreas, Hes1 expression persists in Notch-sensitive centroacinar cells, which act as facultative exocrine-specific progenitor cells. Thus, the research described in this thesis determines the identity of embryonic and adult pancreatic progenitor cells, and demonstrates that these cells utilize Notch signaling for maintenance of their undifferentiated state. |
