|
Approximately 150 million people worldwide currently suffer from diabetes and that number is expected to rise to 300 million over the next 20 years. Although current treatment strategies are able to alleviate some symptoms, diabetics continue to have long term complications, including nephropathy, retinopathy and cardiovascular disease that arise from improper management of glucose levels. Much research is directed towards generating replacement cells that can mimic the exquisite glucose-responsiveness of the normal pancreatic beta cell. One possibility currently being explored is to use stem cells to produce beta cells in vitro for transplantation. An alternative strategy is to generate pancreatic tissue from some other tissue already present in the body, which would provide for an abundance of tissue and eliminate the risk of organ transplant complications related to immunosuppressive drug treatment.
The presence of pancreatic tissue in the liver has been found to occur in human patients with hepatic cirrhosis and can also be induced in rats and fish by various chemicals. These results that the liver may be one possible source of pancreatic tissue. As the liver and pancreas arise from adjacent regions in the developing embryo, it has been proposed that their specification differs by a single developmental decision, affecting the expression of a relatively small number of genes. The ability to direct either liver stem cells or differentiated cells down the pancreatic lineage however, requires an understanding of the molecular events underlying normal pancreas development. If these genes can be identified then it should be possible to cause transdifferentiation between the two tissues.
Top panel: Elastase-GFP transgenic tadpoles
Bottom panel: TTR-Pdx1-VP16:Elas-GFP transgenic tadpoles The Horb lab is interested in identifying these master switch genes that can convert or reprogram liver cells into pancreatic cells. To this end, we have recently shown that overexpression of a super active form of Pdx1 (Pdx1-VP16) in the liver in transgenic Xenopus tadpoles causes a conversion of liver to pancreatic tissue containing both endocrine and exocrine cell types (Curr Bio 13, 105-115). This result is not limited to the tadpole, since overexpression of Pdx1-VP16 in the human HepG2 hepatoma cell line also results in conversion to pancreatic cells. This result demonstrates that it is possible to switch one cell type to another by overexpression of a single transcription factor, and suggests a novel approach for the treatment of diabetes.
Ongoing projects related to transdifferentiation include:
- Determining the transdifferentiation potential of other pancreatic transcription factors
- Identifying the mechanism of Pdx1 action
- Examining the developmental plasticity of other endodermal organs
- Genetic regulation of dorsal versus ventral pancreas
|