Endocrine Abstracts

Stem cell therapy offers a far-sighted opportunity to cure Type 1 diabetes. To achieve this ambitious goal, an in depth understanding of how human beta cells normally develop is critical, as it provides the perfect model for the differentiation of stem cells down normal safe developmental pathways. Our data provide a framework of human pancreas development and islet formation, highlighting subtle differences from the parallel process in mouse. Key genes have been identified that regulate the pathway from precursor to beta cell. The early human pancreatic cells robustly express the gene SOX9, which is extinguished upon endocrine differentiation. Strikingly, islet structure is abnormal when SOX9 is mutated as part of the haploinsufficiency syndrome campomelic dysplasia, demonstrating a role for this critical developmental transcription factor. Given this importance, we have taken steps in determining its transcriptional regulation, hoping to identify pancreas-specific element(s) around the SOX9 locus. We hope to integrate these data with a range of models that interrogate the key inter-cellular signaling pathways that govern human beta cell differentiation, describing the negative influences of peri-pancreatic mesenchyme and positive effects of vascular endothelium. We have also generated an inducible expression model of the key 'pro-endocrine' gene, NGN3. This work has generated some interesting downstream candidates on the way to a beta cell fate. In summary, these studies, integrated with the wealth of knowledge of pancreas development in other species, hope to provide the information, by which stem cell therapy in Type 1 diabetes will be transformed from theoretical potential into reality.