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TWEAK/Fn14 Signaling Is Required for Liver Regeneration after Partial Hepatectomy in Mice

BACKGROUND & AIMS: Pro-inflammatory cytokines are important for liver regeneration after partial hepatectomy (PH). Expression of Fibroblast growth factor-inducible 14 (Fn14), the receptor for TNF-like weak inducer of apoptosis (TWEAK), is induced rapidly after PH and remains elevated throughout...

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Autores principales: Karaca, Gamze, Swiderska-Syn, Marzena, Xie, Guanhua, Syn, Wing-Kin, Krüger, Leandi, Machado, Mariana Verdelho, Garman, Katherine, Choi, Steve S., Michelotti, Gregory A., Burkly, Linda C., Ochoa, Begoña, Diehl, Anna Mae
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886973/
https://www.ncbi.nlm.nih.gov/pubmed/24416188
http://dx.doi.org/10.1371/journal.pone.0083987
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author Karaca, Gamze
Swiderska-Syn, Marzena
Xie, Guanhua
Syn, Wing-Kin
Krüger, Leandi
Machado, Mariana Verdelho
Garman, Katherine
Choi, Steve S.
Michelotti, Gregory A.
Burkly, Linda C.
Ochoa, Begoña
Diehl, Anna Mae
author_facet Karaca, Gamze
Swiderska-Syn, Marzena
Xie, Guanhua
Syn, Wing-Kin
Krüger, Leandi
Machado, Mariana Verdelho
Garman, Katherine
Choi, Steve S.
Michelotti, Gregory A.
Burkly, Linda C.
Ochoa, Begoña
Diehl, Anna Mae
author_sort Karaca, Gamze
collection PubMed
description BACKGROUND & AIMS: Pro-inflammatory cytokines are important for liver regeneration after partial hepatectomy (PH). Expression of Fibroblast growth factor-inducible 14 (Fn14), the receptor for TNF-like weak inducer of apoptosis (TWEAK), is induced rapidly after PH and remains elevated throughout the period of peak hepatocyte replication. The role of Fn14 in post-PH liver regeneration is uncertain because Fn14 is expressed by liver progenitors and TWEAK-Fn14 interactions stimulate progenitor growth, but replication of mature hepatocytes is thought to drive liver regeneration after PH. METHODS: To clarify the role of TWEAK-Fn14 after PH, we compared post-PH regenerative responses in wild type (WT) mice, Fn14 knockout (KO) mice, TWEAK KO mice, and WT mice treated with anti-TWEAK antibodies. RESULTS: In WT mice, rare Fn14(+) cells localized with other progenitor markers in peri-portal areas before PH. PH rapidly increased proliferation of Fn14(+) cells; hepatocytic cells that expressed Fn14 and other progenitor markers, such as Lgr5, progressively accumulated from 12–8 h post-PH and then declined to baseline by 96 h. When TWEAK/Fn14 signaling was disrupted, progenitor accumulation, induction of pro-regenerative cytokines, hepatocyte and cholangiocyte proliferation, and over-all survival were inhibited, while post-PH liver damage and bilirubin levels were increased. TWEAK stimulated proliferation and increased Lgr5 expression in cultured liver progenitors, but had no effect on either parameter in cultured primary hepatocytes. CONCLUSIONS: TWEAK-FN14 signaling is necessary for the healthy adult liver to regenerate normally after acute partial hepatectomy.
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spelling pubmed-38869732014-01-10 TWEAK/Fn14 Signaling Is Required for Liver Regeneration after Partial Hepatectomy in Mice Karaca, Gamze Swiderska-Syn, Marzena Xie, Guanhua Syn, Wing-Kin Krüger, Leandi Machado, Mariana Verdelho Garman, Katherine Choi, Steve S. Michelotti, Gregory A. Burkly, Linda C. Ochoa, Begoña Diehl, Anna Mae PLoS One Research Article BACKGROUND & AIMS: Pro-inflammatory cytokines are important for liver regeneration after partial hepatectomy (PH). Expression of Fibroblast growth factor-inducible 14 (Fn14), the receptor for TNF-like weak inducer of apoptosis (TWEAK), is induced rapidly after PH and remains elevated throughout the period of peak hepatocyte replication. The role of Fn14 in post-PH liver regeneration is uncertain because Fn14 is expressed by liver progenitors and TWEAK-Fn14 interactions stimulate progenitor growth, but replication of mature hepatocytes is thought to drive liver regeneration after PH. METHODS: To clarify the role of TWEAK-Fn14 after PH, we compared post-PH regenerative responses in wild type (WT) mice, Fn14 knockout (KO) mice, TWEAK KO mice, and WT mice treated with anti-TWEAK antibodies. RESULTS: In WT mice, rare Fn14(+) cells localized with other progenitor markers in peri-portal areas before PH. PH rapidly increased proliferation of Fn14(+) cells; hepatocytic cells that expressed Fn14 and other progenitor markers, such as Lgr5, progressively accumulated from 12–8 h post-PH and then declined to baseline by 96 h. When TWEAK/Fn14 signaling was disrupted, progenitor accumulation, induction of pro-regenerative cytokines, hepatocyte and cholangiocyte proliferation, and over-all survival were inhibited, while post-PH liver damage and bilirubin levels were increased. TWEAK stimulated proliferation and increased Lgr5 expression in cultured liver progenitors, but had no effect on either parameter in cultured primary hepatocytes. CONCLUSIONS: TWEAK-FN14 signaling is necessary for the healthy adult liver to regenerate normally after acute partial hepatectomy. Public Library of Science 2014-01-09 /pmc/articles/PMC3886973/ /pubmed/24416188 http://dx.doi.org/10.1371/journal.pone.0083987 Text en © 2014 Karaca et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Karaca, Gamze
Swiderska-Syn, Marzena
Xie, Guanhua
Syn, Wing-Kin
Krüger, Leandi
Machado, Mariana Verdelho
Garman, Katherine
Choi, Steve S.
Michelotti, Gregory A.
Burkly, Linda C.
Ochoa, Begoña
Diehl, Anna Mae
TWEAK/Fn14 Signaling Is Required for Liver Regeneration after Partial Hepatectomy in Mice
title TWEAK/Fn14 Signaling Is Required for Liver Regeneration after Partial Hepatectomy in Mice
title_full TWEAK/Fn14 Signaling Is Required for Liver Regeneration after Partial Hepatectomy in Mice
title_fullStr TWEAK/Fn14 Signaling Is Required for Liver Regeneration after Partial Hepatectomy in Mice
title_full_unstemmed TWEAK/Fn14 Signaling Is Required for Liver Regeneration after Partial Hepatectomy in Mice
title_short TWEAK/Fn14 Signaling Is Required for Liver Regeneration after Partial Hepatectomy in Mice
title_sort tweak/fn14 signaling is required for liver regeneration after partial hepatectomy in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886973/
https://www.ncbi.nlm.nih.gov/pubmed/24416188
http://dx.doi.org/10.1371/journal.pone.0083987
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