Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.512022
Title: Glucocorticoid-mediated trans-differentiation of the pancreas to liver, in vitro and in vivo
Author: Wallace, Karen
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2010
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Abstract:
The AR42J B-13 (B-13) rat acinar cell line trans-differentiates into functional hepatocyte-like cells (B-13/H) in response to glucocorticoid without the need for any complex extracellular matrix or treatment with expensive recombinant proteins. B-13 cells expressed pluripotency markers but did not respond to factors associated with the embryonic development of the liver. B-13 cells were readily expanded in culture and could provide a potentially unlimited supply of quantitatively functional hepatocyte-like cells. The role of the WNT signalling pathway - specifically the activity of the proximal WNT regulated TCF/LEF transcription factors - was examined. Trans-differentiation was dependent on a transient suppression of TCF/LEF transcriptional activity leading to the expression of the liver-enriched transcription factors C/EBPβ and proteins. Trans-differentiation was associated with a decrease in total β-catenin and increased phospho-β-catenin expression; whilst recruitment to the plasma membrane, cytosolic degradation and nuclear exclusion of β-catenin was a hallmark of B-13/H cells. Silencing of β-catenin induced trans-differentiation and repression of TCF/LEF signalling in the absence of glucocorticoid whilst glucocorticoid mediated trans-differentiation was abrogated when mutant forms of β-catenin were over expressed or cells were pre-treated with a WNT agonist. Analysis of the in vivo response to glucocorticoid using an adult rat model, a transgenic mouse model of Cushing's disease and patients treated with glucocorticoid was made. Results showed that the B-13 cell response to glucocorticoid is physiologically relevant and related to a normal patho-physiological response of mature pancreatic acinar cells to elevated levels of circulatory glucocorticoid. Data suggest that the expression of liver genes in pancreatic acinar cells in vivo is the result of direct trans-differentiation of mature acinar cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.512022  DOI: Not available
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