Glucocorticoid-induced pancreatic-hepatic trans-differentiation in a human cell line in vitro.
| Title: | Glucocorticoid-induced pancreatic-hepatic trans-differentiation in a human cell line in vitro. |
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| Authors: | Fairhall EA; Institute of Cellular Medicine, Newcastle University, Level 4 William Leech Building, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK.; Leitch AC; Institute of Cellular Medicine, Newcastle University, Level 4 William Leech Building, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK.; Lakey AF; Institute of Cellular Medicine, Newcastle University, Level 4 William Leech Building, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK.; Probert PME; Institute of Cellular Medicine, Newcastle University, Level 4 William Leech Building, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK.; Richardson G; Institute of Cellular Medicine, Newcastle University, Level 4 William Leech Building, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK.; De Santis C; Institute of Cellular Medicine, Newcastle University, Level 4 William Leech Building, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK.; Wright MC; Institute of Cellular Medicine, Newcastle University, Level 4 William Leech Building, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK. Electronic address: M.C.Wright@ncl.ac.uk. |
| Source: | Differentiation; research in biological diversity [Differentiation] 2018 Jul - Aug; Vol. 102, pp. 10-18. Date of Electronic Publication: 2018 May 22. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: England NLM ID: 0401650 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0436 (Electronic) Linking ISSN: 03014681 NLM ISO Abbreviation: Differentiation Subsets: MEDLINE |
| Imprint Name(s): | Publication: London : Elsevier; Original Publication: London, Macmillan Journals. |
| MeSH Terms: | Cell Differentiation/*drug effects ; Glucocorticoids/*pharmacology ; Hepatocytes/*drug effects ; Pancreas/*cytology; Dexamethasone/pharmacology ; Hepatocytes/cytology ; Liver/metabolism ; Pancreatic Neoplasms/drug therapy ; Receptors, Glucocorticoid/drug effects ; Cell Line ; Humans |
| 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 1-10 µM 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 signalling 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.; (Copyright © 2018 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.) |
| Grant Information: | NC/K500471/1 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research |
| Contributed Indexing: | Keywords: AR42J; AR42J-B13; B-13; HPAC; Liver; NR3C1; Pancreas |
| Substance Nomenclature: | 0 (Glucocorticoids); 0 (Receptors, Glucocorticoid); 7S5I7G3JQL (Dexamethasone) |
| Entry Date(s): | Date Created: 20180602 Date Completed: 20181121 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.diff.2018.05.003 |
| PMID: | 29857331 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't