Trps1 regulates biliary epithelial-mesenchymal transition and has roles during biliary fibrosis in liver grafts: a preliminary study.

Cheng Zhe,Shuguo Zheng,Ju Tian,Fan Yu,Makoto Sato

doi:10.1371/journal.pone.0123233

Cheng Zhe, Shuguo Zheng + Show 3 more

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https://doi.org/10.1371/journal.pone.0123233

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Journal: PloS one	Publication Date: Apr 17, 2015
Citations: 8	License type: CC BY 4.0

Affiliation: Army Medical University, Southwest Hospital

Abstract

ObjectiveTo investigate the role(s) of Trps1 in non-anastomotic biliary stricture (NABS) following liver transplantation.MethodsImmunohistochemical and histological techniques were used to detect Trps1, E-cadherin, CK19, vimentin, α-SMA, and collagen deposition. Human intrahepatic biliary epithelial cells (HIBECs) were infected with a Trps1 adenovirus, or transfected with Trps1 short-interfering RNAs (siRNAs). Reverse transcription polymerase chain reaction (RT-PCR) assays and western blotting were used to determine expression levels of epithelial and mesenchymal markers, and Trps1 in HIBECs.ResultsExpression of Trps1 and epithelial markers was down-regulated or absent in NABS liver samples. Mesenchymal markers were seen in biliary epithelial cells (BECs), with collagen deposited around the bile duct. Trps1 expression positively correlated with epithelial markers. Expression of epithelial marker mRNAs and proteins in HIBECs decreased with prolonged cold preservation (CP), while mesenchymal marker expression increased. A 12-h CP period led to increased Trps1 mRNA and protein levels. Expression of E-cadherin was increased in HIBECs following Trps1 adenovirus infection and CP/reperfusion injury (CPRI), with vimentin expression levels reduced and CPRI-mediated epithelial-mesenchymal transition (EMT) inhibited. Transfection of HIBECs with Trps1 siRNAs in conjunction with CPRI revealed that E-cadherin expression was decreased, vimentin expression was increased, and CPRI-mediated EMT was promoted.ConclusionTrps1 is involved in NABS pathogenesis following liver transplantation and negatively correlates with BEC EMT and biliary fibrosis in liver grafts. Trps1 demonstrates antagonistic effects that could reverse EMT.

Highlights

Non-anastomotic biliary stricture (NABS) is a major biliary complication after liver transplantation, and can result in biliary cirrhosis, graft failure, re-transplantation, or death
Mesenchymal markers were seen in biliary epithelial cells (BECs), with collagen deposited around the bile duct
A 12-h cold preservation (CP) period led to increased Trps1 mRNA and protein levels

Summary

Introduction

Non-anastomotic biliary stricture (NABS) is a major biliary complication after liver transplantation, and can result in biliary cirrhosis, graft failure, re-transplantation, or death. NABS progresses with biliary fibrosis of the graft, resulting in ineffective or excessive repair of the injured bile duct epithelium. Cold preservation/reperfusion injury (CPRI) is an independent factor of biliary fibrosis following liver transplantation, the mechanisms involved require clarification [1]. Previous studies into the mechanisms of biliary fibrosis in liver grafts have primarily focused upon the pathway of TGF-β-mediated hepatic stellate cell activation. Cells that synthesize matrix are derived from the inherent source (activated hepatic stellate cell) and other heterologous cell populations [2]. Hepatocyte or biliary epithelial cells (BECs) are the major matrix-synthesizing cells in liver and biliary tract fibrosis during epithelial-mesenchymal transition (EMT) [3]

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