Organ switching - can we make beta cells from the liver?

S Thowfeequ, J R Dutton, N L Chillingworth, D Eberhard, D Tosh, J M W Slack

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The technique of islet transplanation would be transformed if there were available a plentiful source of autologous beta cells. We have been investigating the possibility of making beta cells starting from cell types of theliver. In the mature individual, the liver and pancreas are very different but the two organs are formed from neighboring regions of the endoderm during embryonic development, and their precursor cells are initially distinguished by the expression of just a small number of transcription factors. It may therefore be possible to reprogram liver cells to a pancreatic, or specifically, to a beta cell phenotype, by altering the expression of those few transcription factors.
Most of our work has been performed with a modified version of the Pdx1 transcription factor which incorporates VP16, a transcription activation domain from herpesvirus . In Xenopus tadpoles we have found that liver can reproducibly be reprogrammed to pancreas by expression of the Pdx1-VP16transgene, but as the liver matures it becomes refractory to reprogramming. In the human hepatoma cell line HepG2 we find that Pdx1-VP16 can generate beta-like cells, but the proportion of these among transfected cells is small. In primary rat hepatocytes introduction of Pdx1-VP16 using adenovirus will activate pancreatic genes but not reprogram the cell types completely. We are currently testing combinations of pancreatic transcription factors in this system to improve the outcome, and have found that media provoking de-differentiation are necessary for their activity.
In addition, we have found that normal mouse extahepatic bile ducts contain 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 also be an appropriate source tissue for the preparation of beta cells.
If a suitable protocol can be found then it would be possible to remove a small biopsy from a diabetic patient, expand the cells in vitro, transform them to a beta cell phenotype in vitro, and then reinfuse the cells as for an islet graft.
Original languageEnglish
Article number201.1
Pages (from-to)394
Number of pages1
JournalXenotransplantation
Volume14
Issue number5
DOIs
Publication statusPublished - Sep 2007
EventJoint Meeting of the International Xenotransplantation Association (IXA), the International Pancreas and Islet Transplant Association (IPITA), and the Cell Transplant Society (CTS) - Minneapolis, USA United States
Duration: 15 Sep 200720 Sep 2007

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