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Biliary Epithelial Senescence and Plasticity in Acute Cellular Rejection

Lookup NU author(s): Dr John Brain, Dr Helen Robertson, Dr Aaron Ions GardnerORCiD, Dr Trevor Booth, Professor Thomas von Zglinicki, Professor Alastair BurtORCiD, Professor John Kirby

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Abstract

Biliary epithelial cells (BEC) are important targets in some liver diseases, including acute allograft rejection. Although some injured BEC die, many can survive in function compromised states of senescence or phenotypic de-differentiation. This study was performed to examine changes in the phenotype of BEC during acute liver allograft rejection and the mechanism driving these changes. Liver allograft sections showed a positive correlation (p < 0.0013) between increasing T cell mediated acute rejection and the number of BEC expressing the senescence marker p21WAF1/Cip or the mesenchymal marker S100A4. This was modeled in vitro by examination of primary or immortalized BEC after acute oxidative stress. During the first 48 h, the expression of p21WAF1/Cip was increased transiently before returning to baseline. After this time BEC showed increased expression of mesenchymal proteins with a decrease in epithelial markers. Analysis of TGF-β expression at mRNA and protein levels also showed a rapid increase in TGF-β2 (p < 0.006) following oxidative stress. The epithelial de-differentiation observed in vitro was abrogated by pharmacological blockade of the ALK-5 component of the TGF-β receptor. These data suggest that stress induced production of TGF-β2 by BEC can modify liver allograft function by enhancing the de-differentiation of local epithelial cells.


Publication metadata

Author(s): Brain JG, Robertson H, Thompson EH, Humphreys E, Gardner A, Booth TA, Jones DEJ, Afford SC, von Zglinicki T, Burt AD, Kirby JA

Publication type: Article

Publication status: Published

Journal: American Journal of Transplantation

Year: 2013

Volume: 13

Issue: 7

Pages: 1688-1702

Print publication date: 10/06/2013

Online publication date: 10/06/2013

Acceptance date: 26/03/2013

Date deposited: 03/04/2013

ISSN (print): 1600-6135

ISSN (electronic): 1600-6143

Publisher: Wiley-Blackwell Publishing, Inc.

URL: http://dx.doi.org/10.1111/ajt.12271

DOI: 10.1111/ajt.12271


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