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Glucocorticoid-induced pancreatic-hepatic trans-differentiation in a human cell line in vitro

Lookup NU author(s): Dr Emma Fairhall, Dr Alistair Leitch, Anne Lakey, Dr Phillip Probert, Carol De Santis, Professor Matthew Wright

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Abstract

The rodent pancreatic AR42J-B13 (B-13) cell line differentiates into non-replicative hepatocyte-like cells in response to glucocorticoid mediated via the glucocorticoid receptor (GR). The aims of this study were to identify a human cell line that responds similarly and investigate the mechanisms underpinning any alteration in differentiation. Exposing the human pancreatic adenocarcinoma (HPAC) cell line to 1 - 10µM concentrations of dexamethasone (DEX) resulted an inhibition of proliferation, suppressed carcinoembryonic antigen expression, limited expression of pancreatic acinar and hepatic gene expression and significant induction of the constitutively-expressed hepatic CYP3A5 mRNA transcript. These changes were associated with a pulse of genomic DNA methylation and suppressed notch signalling activity. HPAC cells expressed high levels of GR transcript in contrast to other nuclear receptors - such as the glucocorticoid-activated pregnane X receptor (PXR) - and GR transcriptional function was activated by DEX in HPAC cells. Expression of selected hepatocyte transcripts in response to DEX was blocked by co-treatment with the GR antagonist RU486. These data indicate that the HPAC response to glucocorticoid exposure includes an inhibition in proliferation, alterations in notch signaling and a limited change in the expression of genes associated with an acinar and hepatic phenotype. This is the first demonstration of a human cell responding to similarly to the rodent B-13 cell regarding formation of hepatocyte-like cells in response to glucocorticoid. Identifying and modulating the ablating factor(s) may enhance the hepatocyte-like forming capacity of HPAC cells after exposure to glucocorticoid and generate an unlimited in vitro supply of human hepatocytes for toxicology studies and a variety of clinical applications.

Publication metadata

Author(s): Fairhall EA, Leitch AC, Lakey AF, Probert PM, Richardson G, DeSantis C, Wright MC

Publication type: Article

Publication status: Published

Journal: Differentiation

Year: 2018

Volume: 102

Pages: 10-18

Print publication date: 01/07/2018

Online publication date: 22/05/2018

Acceptance date: 21/05/2018

Date deposited: 21/05/2018

ISSN (print): 0301-4681

ISSN (electronic): 1432-0436

Publisher: Elsevier

URL: https://doi.org/10.1016/j.diff.2018.05.003

DOI: 10.1016/j.diff.2018.05.003

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