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The B-13 hepatocyte progenitor cell resists pluripotency induction and differentiation to non-hepatocyte cells.

Lookup NU author(s): Dr Emma Fairhall, Dr Michelle Charles, Karen Wallace, Claire Schwab, Professor Christine Harrison, Professor Matthew Wright

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

The rat pancreatic “B-13” acinar cell is a stable progenitor cell line that differentiates into hepatocyte-like cells (B-13/H cells) in 2D un-coated plastic culture with simple culture media in response to glucocorticoid exposure. Examination of cytochrome P450 indicated that the expression of a range of genes were similar to freshly isolated hepatocytes and that these gene products were functional on the basis of spectrophotometrically-detectable reduced carbon-monoxide haemoprotein and metabolism of several drugs. Since normal hepatocytes readily de-differentiate under similar conditions, we hypothesized that B-13 cells have undergone a variety of alterations that stabilise a progenitor phenotype and restrict differentiation to hepatocytes only (which if capitulated in human cells, could generate a readily accessible supply of functional human hepatocytes in vitro). To examine this hypothesis, the B-13 karyotype; pluripotency-inducing transcription factor expression and forced over-expression of these factors in B-13 cells were examined. B-13 cells were also injected into NOD/SCID mice and engraftment and differentiation assessed by RT-PCR, Western blotting, immunohistochemistry and fluorescent in situ hybridization (FISH). B-13 cells expressed four pluripotency-inducing transcription factors c-Myc, Klf4, Oct4 and Sox2 with only c-Myc expression maintained after glucocorticoid treatment. Over-expression of the pluripotency-inducing transcription factors blocked B-13/H formation in response to glucocorticoid. Injection of B-13 cells into NOD/SCID mice resulted in their engraftment to the pancreas and liver, with restricted differentiation to hepatocytes in the liver. The cells did not engraft to any other tissues examined. The ability of B-13 cells to specifically generate functional hepatocytes in vitro in response to glucocorticoid is therefore associated with genetic rearrangements that may facilitate expression of genes associated with plasticity (without leading to pluripotency), which are repressed by glucocorticoid treatment


Publication metadata

Author(s): Fairhall EA, Charles MA, Wallace K, Schwab CJ, Harrison CJ, Richter M, Hoffmann SA, Charlton KA, Zeilinger K, Wright MC

Publication type: Article

Publication status: Published

Journal: Toxicology Research

Year: 2013

Volume: 2

Issue: 5

Pages: 308-320

Print publication date: 01/09/2013

Online publication date: 24/06/2013

Acceptance date: 21/06/2013

Date deposited: 05/11/2015

ISSN (print): 2045-452X

ISSN (electronic): 2045-4538

Publisher: RSC Publications

URL: http://dx.doi.org/10.1039/c3tx50030f

DOI: 10.1039/c3tx50030f


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