Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.

<h4>Background</h4>Hepatocyte transplantation (HT) is a promising alternative treatment strategy for end-stage liver diseases compared with orthotopic liver transplantation. A limitation for this approach is the low engraftment of donor cells. The deletion of the I-kappa B kinase-regulat...

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Autores principales:	Michaela Kaldenbach, Francisco Javier Cubero, Stephanie Erschfeld, Christian Liedtke, Christian Trautwein, Konrad Streetz
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cf13c5d8db0b4c8e96ae8372ec730c55
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spelling	oai:doaj.org-article:cf13c5d8db0b4c8e96ae8372ec730c552021-11-25T06:10:14ZHepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.1932-620310.1371/journal.pone.0100786https://doaj.org/article/cf13c5d8db0b4c8e96ae8372ec730c552014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24979756/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Hepatocyte transplantation (HT) is a promising alternative treatment strategy for end-stage liver diseases compared with orthotopic liver transplantation. A limitation for this approach is the low engraftment of donor cells. The deletion of the I-kappa B kinase-regulatory subunit IKKγ/NEMO in hepatocytes prevents nuclear factor (NF)-kB activation and triggers spontaneous liver apoptosis, chronic hepatitis and the development of liver fibrosis and hepatocellular carcinoma. We hypothesized that NEMOΔhepa mice may therefore serve as an experimental model to study HT.<h4>Methods</h4>Pre-conditioned NEMOΔhepa mice were transplanted with donor-hepatocytes from wildtype (WT) and mice deficient for the pro-apoptotic mediator Caspase-8 (Casp8Δhepa).<h4>Results</h4>Transplantation of isolated WT-hepatocytes into pre-conditioned NEMOΔhepa mice resulted in a 6-7 fold increase of donor cells 12 weeks after HT, while WT-recipients showed no liver repopulation. The use of apoptosis-resistant Casp8Δhepa-derived donor cells further enhanced the selection 3-fold after 12-weeks and up to 10-fold increase after 52 weeks compared with WT donors. While analysis of NEMOΔhepa mice revealed strong liver injury, HT-recipient NEMOΔhepa mice showed improved liver morphology and decrease in serum transaminases. Concomitant with these findings, the histological examination elicited an improved liver tissue architecture associated with significantly lower levels of apoptosis, decreased proliferation and a lesser amount of liver fibrogenesis. Altogether, our data clearly support the therapeutic benefit of the HT procedure into NEMOΔhepa mice.<h4>Conclusion</h4>This study demonstrates the feasibility of the NEMOΔhepa mouse as an in vivo tool to study liver repopulation after HT. The improvement of the characteristic phenotype of chronic liver injury in NEMOΔhepa mice after HT suggests the therapeutic potential of HT in liver diseases with a chronic inflammatory phenotype and opens a new door for the applicability of this technique to combat liver disease in the human clinic.Michaela KaldenbachFrancisco Javier CuberoStephanie ErschfeldChristian LiedtkeChristian TrautweinKonrad StreetzPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 6, p e100786 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michaela Kaldenbach Francisco Javier Cubero Stephanie Erschfeld Christian Liedtke Christian Trautwein Konrad Streetz Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.
description	<h4>Background</h4>Hepatocyte transplantation (HT) is a promising alternative treatment strategy for end-stage liver diseases compared with orthotopic liver transplantation. A limitation for this approach is the low engraftment of donor cells. The deletion of the I-kappa B kinase-regulatory subunit IKKγ/NEMO in hepatocytes prevents nuclear factor (NF)-kB activation and triggers spontaneous liver apoptosis, chronic hepatitis and the development of liver fibrosis and hepatocellular carcinoma. We hypothesized that NEMOΔhepa mice may therefore serve as an experimental model to study HT.<h4>Methods</h4>Pre-conditioned NEMOΔhepa mice were transplanted with donor-hepatocytes from wildtype (WT) and mice deficient for the pro-apoptotic mediator Caspase-8 (Casp8Δhepa).<h4>Results</h4>Transplantation of isolated WT-hepatocytes into pre-conditioned NEMOΔhepa mice resulted in a 6-7 fold increase of donor cells 12 weeks after HT, while WT-recipients showed no liver repopulation. The use of apoptosis-resistant Casp8Δhepa-derived donor cells further enhanced the selection 3-fold after 12-weeks and up to 10-fold increase after 52 weeks compared with WT donors. While analysis of NEMOΔhepa mice revealed strong liver injury, HT-recipient NEMOΔhepa mice showed improved liver morphology and decrease in serum transaminases. Concomitant with these findings, the histological examination elicited an improved liver tissue architecture associated with significantly lower levels of apoptosis, decreased proliferation and a lesser amount of liver fibrogenesis. Altogether, our data clearly support the therapeutic benefit of the HT procedure into NEMOΔhepa mice.<h4>Conclusion</h4>This study demonstrates the feasibility of the NEMOΔhepa mouse as an in vivo tool to study liver repopulation after HT. The improvement of the characteristic phenotype of chronic liver injury in NEMOΔhepa mice after HT suggests the therapeutic potential of HT in liver diseases with a chronic inflammatory phenotype and opens a new door for the applicability of this technique to combat liver disease in the human clinic.
format	article
author	Michaela Kaldenbach Francisco Javier Cubero Stephanie Erschfeld Christian Liedtke Christian Trautwein Konrad Streetz
author_facet	Michaela Kaldenbach Francisco Javier Cubero Stephanie Erschfeld Christian Liedtke Christian Trautwein Konrad Streetz
author_sort	Michaela Kaldenbach
title	Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.
title_short	Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.
title_full	Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.
title_fullStr	Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.
title_full_unstemmed	Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.
title_sort	hepatic tissue environment in nemo-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/cf13c5d8db0b4c8e96ae8372ec730c55
work_keys_str_mv	AT michaelakaldenbach hepatictissueenvironmentinnemodeficientmicecriticallyregulatespositiveselectionofdonorcellsafterhepatocytetransplantation AT franciscojaviercubero hepatictissueenvironmentinnemodeficientmicecriticallyregulatespositiveselectionofdonorcellsafterhepatocytetransplantation AT stephanieerschfeld hepatictissueenvironmentinnemodeficientmicecriticallyregulatespositiveselectionofdonorcellsafterhepatocytetransplantation AT christianliedtke hepatictissueenvironmentinnemodeficientmicecriticallyregulatespositiveselectionofdonorcellsafterhepatocytetransplantation AT christiantrautwein hepatictissueenvironmentinnemodeficientmicecriticallyregulatespositiveselectionofdonorcellsafterhepatocytetransplantation AT konradstreetz hepatictissueenvironmentinnemodeficientmicecriticallyregulatespositiveselectionofdonorcellsafterhepatocytetransplantation
_version_	1718414130856067072

Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.

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