Type 1 diabetes (T1D) is a chronic disease, characterised by the destruction of pancreatic beta cells, which results in lack of insulin expression. Most current therapies rely on the exogenous administration of recombinant insulin. Islet transplantation has been shown to be a more effective alternative treatment, but it is also limited by the lack of available islets for transplantation. The recently awarded work of Yamanaka and colleagues has shown that fully differentiated cells can be reprogrammed towards their pluripotent, undifferentiated state, through overexpression of a simple combination of four key transcritption factors (TFs). The studies presented in this thesis sought to investigate whether a combination of a small group of key pancreatic TFs would be able to drive both mouse embryonic stem cells (mES) and fully differentiated rat and human acinar cells of the pancreas towards insulin-producing cells. When administered in a timely manner to mES cells, the pancreatic TFs Pdx1 and MafA were able to induce the formation of cells that synthesised insulin de novo. Further studies aimed at investigating if a small number of TFs would be able to reprogramme the exocrine pancreatic cells towards insulin expressing cells, since, unlike endocrine cells, exocrine cells are highly abundant in the pancreas. Studies performed in both a rat exocrine cell line (AR42J-B13) and in human exocrine cells demonstrated that the combination of the TFs Pdx1, MafA, Ngn3 and Pax4 was able to generate glucose responsive β-like cells in both models. In addition, Pax4 was found to be determinant for the functionality of the generated β-cells. The functionality of these cells was further demonstrated by their ability to prevent the onset of hyperglycemia upon transplantation into a diabetic mouse model. The work presented in this thesis has shown that cultured exocrine cells may be a promising alternative for generating a replenishable supply of β-cells for transplantation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:600094 |
| Date | January 2013 |
| Creators | Marques de Lima, Maria João |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=203785 |
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