Cholangiocyte Epithelial to Mesenchymal Transition (EMT) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.

Cholangiocyte Epithelial to Mesenchymal Transition (EMT) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.

Donation after circulatory death (DCD) has expanded the donor pool for liver transplantation. However, ischemic cholangiopathy (IC) after DCD liver transplantation causes inferior outcomes. The molecular mechanisms of IC are currently unknown but may depend on ischemia-induced genetic reprograming o...

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Autores principales: Niluka Wickramaratne, Ru Li, Tao Tian, Jad Khoraki, Hae Sung Kang, Courtney Chmielewski, Jerry Maitland, Loren K Liebrecht, Ria Fyffe-Freil, Susanne Lyra Lindell, Martin J Mangino
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Publicado: Public Library of Science (PLoS) 2021
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Acceso en línea:https://doaj.org/article/ad2d841d6af04276be94b19b9fed7529
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spelling oai:doaj.org-article:ad2d841d6af04276be94b19b9fed75292021-12-02T20:05:11ZCholangiocyte Epithelial to Mesenchymal Transition (EMT) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.1932-620310.1371/journal.pone.0246978https://doaj.org/article/ad2d841d6af04276be94b19b9fed75292021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0246978https://doaj.org/toc/1932-6203Donation after circulatory death (DCD) has expanded the donor pool for liver transplantation. However, ischemic cholangiopathy (IC) after DCD liver transplantation causes inferior outcomes. The molecular mechanisms of IC are currently unknown but may depend on ischemia-induced genetic reprograming of the biliary epithelium to mesenchymal-like cells. The main objective of this study was to determine if cholangiocytes undergo epithelial to mesenchymal transition (EMT) after exposure to DCD conditions and if this causally contributes to the phenotype of IC. Human cholangiocyte cultures were exposed to periods of warm and cold ischemia to mimic DCD liver donation. EMT was tested by assays of cell migration, cell morphology, and differential gene expression. Transplantation of syngeneic rat livers recovered under DCD conditions were evaluated for EMT changes by immunohistochemistry. Human cholangiocytes exposed to DCD conditions displayed migratory behavior and gene expression patterns consistent with EMT. E-cadherin and CK-7 expressions fell while N-cadherin, vimentin, TGFβ, and SNAIL rose, starting 24 hours and peaking 1-3 weeks after exposure. Cholangiocyte morphology changed from cuboidal (epithelial) before to spindle shaped (mesenchymal) a week after ischemia. These changes were blocked by pretreating cells with the Transforming Growth Factor beta (TGFβ) receptor antagonist Galunisertib (1 μM). Finally, rats with liver isografts cold stored for 20 hours in UW solution and exposed to warm ischemia (30 minutes) at recovery had elevated plasma bilirubin 1 week after transplantation and the liver tissue showed immunohistochemical evidence of early cholangiocyte EMT. Our findings show EMT occurs after exposure of human cholangiocytes to DCD conditions, which may be initiated by upstream signaling from autocrine derived TGFβ to cause mesenchymal specific morphological and migratory changes.Niluka WickramaratneRu LiTao TianJad KhorakiHae Sung KangCourtney ChmielewskiJerry MaitlandLoren K LiebrechtRia Fyffe-FreilSusanne Lyra LindellMartin J ManginoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0246978 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Niluka Wickramaratne
Ru Li
Tao Tian
Jad Khoraki
Hae Sung Kang
Courtney Chmielewski
Jerry Maitland
Loren K Liebrecht
Ria Fyffe-Freil
Susanne Lyra Lindell
Martin J Mangino
Cholangiocyte Epithelial to Mesenchymal Transition (EMT) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.
description Donation after circulatory death (DCD) has expanded the donor pool for liver transplantation. However, ischemic cholangiopathy (IC) after DCD liver transplantation causes inferior outcomes. The molecular mechanisms of IC are currently unknown but may depend on ischemia-induced genetic reprograming of the biliary epithelium to mesenchymal-like cells. The main objective of this study was to determine if cholangiocytes undergo epithelial to mesenchymal transition (EMT) after exposure to DCD conditions and if this causally contributes to the phenotype of IC. Human cholangiocyte cultures were exposed to periods of warm and cold ischemia to mimic DCD liver donation. EMT was tested by assays of cell migration, cell morphology, and differential gene expression. Transplantation of syngeneic rat livers recovered under DCD conditions were evaluated for EMT changes by immunohistochemistry. Human cholangiocytes exposed to DCD conditions displayed migratory behavior and gene expression patterns consistent with EMT. E-cadherin and CK-7 expressions fell while N-cadherin, vimentin, TGFβ, and SNAIL rose, starting 24 hours and peaking 1-3 weeks after exposure. Cholangiocyte morphology changed from cuboidal (epithelial) before to spindle shaped (mesenchymal) a week after ischemia. These changes were blocked by pretreating cells with the Transforming Growth Factor beta (TGFβ) receptor antagonist Galunisertib (1 μM). Finally, rats with liver isografts cold stored for 20 hours in UW solution and exposed to warm ischemia (30 minutes) at recovery had elevated plasma bilirubin 1 week after transplantation and the liver tissue showed immunohistochemical evidence of early cholangiocyte EMT. Our findings show EMT occurs after exposure of human cholangiocytes to DCD conditions, which may be initiated by upstream signaling from autocrine derived TGFβ to cause mesenchymal specific morphological and migratory changes.
format article
author Niluka Wickramaratne
Ru Li
Tao Tian
Jad Khoraki
Hae Sung Kang
Courtney Chmielewski
Jerry Maitland
Loren K Liebrecht
Ria Fyffe-Freil
Susanne Lyra Lindell
Martin J Mangino
author_facet Niluka Wickramaratne
Ru Li
Tao Tian
Jad Khoraki
Hae Sung Kang
Courtney Chmielewski
Jerry Maitland
Loren K Liebrecht
Ria Fyffe-Freil
Susanne Lyra Lindell
Martin J Mangino
author_sort Niluka Wickramaratne
title Cholangiocyte Epithelial to Mesenchymal Transition (EMT) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.
title_short Cholangiocyte Epithelial to Mesenchymal Transition (EMT) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.
title_full Cholangiocyte Epithelial to Mesenchymal Transition (EMT) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.
title_fullStr Cholangiocyte Epithelial to Mesenchymal Transition (EMT) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.
title_full_unstemmed Cholangiocyte Epithelial to Mesenchymal Transition (EMT) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.
title_sort cholangiocyte epithelial to mesenchymal transition (emt) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.
publisher Public Library of Science (PLoS)
publishDate 2021
url https://doaj.org/article/ad2d841d6af04276be94b19b9fed7529
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