Stimulation of beta-cell progenitors in diabetic pancreas (FWOAL549)

Diabetes Mellitus is a metabolic disease with worldwide a high and rising prevalence. In Belgium 314.10³ people suffered from diabetes in 2000 and by 2030 it is expected that about 461.10³ people will be affected by this disease (source: www.who.int/diabetes). The disease is characterized by an absolute (Type-1) or relative (Type-2) lack of functional beta cells. Patients that have become insulin-dependent often suffer from secondary complications associated with the long-term disease progression (retinopathy, nephropathy, neuropathy, cardiovascular complications). Transplantation of donor-derived beta cells can render patients insulin-independent and arrest disease progression but relapse occurs in the majority of patients after one year following transplantation (1). Moreover, cell replacement therapy is only available to a limited amount of people, due to the shortage in donor material. Regenerative therapy, based on the administration of pharmacological agents that stimulate beta cell regeneration, represents an interesting alternative. However, our knowledge on the mechanisms of beta cell regeneration is incomplete. Our project aims at a better understanding of beta cell regeneration in the pancreas, and on the possibility to stimulate it with pharmacological agents like growth factors.

Several experimental models exist wherein regeneration of the beta cell mass can be stimulated in animals. The mechanism of beta cell regeneration is controversial with respect to the relative importance of beta cells mitosis and neogenesis from stem cells (reviewed in: 2). This may be explained by the use of different experimental models. We have originally proposed the partial pancreatic duct ligation model (PDL) wherein tissue injury is caused by occlusion of part of the exocrine ductal system (3). Recently, we showed with this model that adult mice contain dormant pogenitors in their pancreas that can be activated by PDL (4). For this,we made use of Ngn3-GFP transgenic reporter mice; Ngn3 is an embryonic transcription factor that is only expressed in the progenitors of the endocrine islet cells. By in vivo lentiviral RNA-interference we showed that the induced reexpression of Ngn3 is necessary for the observed beta cell regeneration after PDL. We could isolate the Ngn3+ progenitors from the pancreas based on their GFP-expression and demonstrate ex vivo thatthey act as multipotent islet progenitors. These adult Ngn3+ cells are phenotypically very similar with embryonic Ngn3+ progenitors as seen by transcriptome analysis (Xu et al, unpublished observations). This discovery of Ngn3+ progenitors in adult pancreas caused a paradigm shift in the field of beta cell regeneration (5). In addition, we showed in our previous research that exocrine acinar cells can transdifferentiate in vitro to functional beta cells (6). Others have shown that this can also be obtained in vivo, namely by transducing acinar cells with three different transcription factors (7). We want to find out if this can also be obtained with extracellular factors in vivo. The following questions form the subject of this application: - can the progenitors be activated with extracellular agents like growth factors? - can progenitor activation cause beta cell regeneration and restore glycemic control in diabetic animals? - what is the relation (origin) of the progenitors with acinar, ductal or beta cells?

Keywords:Immunocytochemistry, Apoptosis, Endocrine Pancreatic Tumors, Pancreas, Zollinger Ellison Syndrome, Development, Endocrine, Cancer, Diabetes, Cell Biology, Histology, Morphogenesis Of Endocrine Pancreas, Morphology, Microscopy, Cell Growth And Differentiation, Men-I, Islet Cell Transplantation

Disciplines:Basic sciences, Biological sciences