Endocrine Abstracts

One possible route for treating type 1 diabetes is through an induced augmentation of beta cell mass. Some success has been achieved in recent years using islet grafts into the liver but at present the main limitation to the wider application of this technique is the limited supply of islets from human organ donors. To overcome this problem, alternative sources of β-cells need to be found. One approach is via transdifferentiation, or the conversion of one cell type to another. The liver and pancreas arise from neighbouring regions of the endoderm in embryonic development, and it is possible that the two tissues are initially distinguished by the expression of one or two transcription factors. We have therefore been investigating methods for generating pancreatic cell types (including beta-cells), by the introduction of pancreatic transcription factors into liver. Most of the work has been performed with a modified transcription factor: Pdx1-VP16. In Xenopus tadpoles we have found that early developing liver can be reproducibly reprogrammed to pancreas by expression of the Pdx1-VP16 transgene. In the human hepatoma cell line HepG2 we find Pdx1-VP16 can generate beta-like cells, but the proportion of these among the transfected cells is small. We have now devised a culture system for the long term maintenance of differentiated hepatocytes. In this system, introduction of adenoviral vectors activates pancreatic gene expression but does not reprogram the cell types completely. We are currently testing combinations of pancreatic transcription factors in this system. In addition we have found that normal mouse bile duct contains some pancreatic endocrine cells. This suggests that the biliary epithelium may be closer to pancreas in terms of transcription factor expression than are hepatocytes, and so may be an appropriate source of tissue for the preparation of beta cells.