Hepatocyte growth factor/c-Met signalling is important for the selection of transplanted hepatocytes

Kaldenbach, M.; Giebeler, A.; Tschaharganeh, Darjus F.; Erschfeld, S.; Wasmuth, Hermann E.; Dollé, Laurent; Floege, Juergen; Streetz, Konrad L.

doi:10.1136/gutjnl-2011-301345

Cited by 18 publications

(14 citation statements)

References 26 publications

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“…Hepatocyte transplantation is currently considered as a promising alternative, especially once the yield and outcome of this technique can be improved. In our previous studies we demonstrated the feasibility of HT and identified responsible factors for donor cell selection in this model [13], [19].…”

Section: Discussionmentioning

confidence: 89%

“…For the generation of donor mice, Casp8 Δhepa and Casp8 loxP/loxP mice were crossed with human-α1-antitrypsin (hAAT) transgenic mice (C57/Bl6) (Casp8 Δhepa /hAAT(+); Casp8 loxP/loxP /hAAT(+)). The expression of the marker protein hAAT is controlled by a α1-antitrypsin-specific promoter to ensure hepatocyte-specific gene expression [13], [16]. At least four mice per group were treated and analysed in parallel for all experiments – that were repeated at least twice.…”

Section: Methodsmentioning

confidence: 99%

“…Because of the spontaneous development of chronic liver injury, NEMO Δhepa mice have been regarded as an ideal model for the study of the molecular mechanisms governing hepatocyte transplantation. Thus, we aimed to apply our established model of hepatocyte transplantation [13] in NEMO Δhepa mice. In these animals, activation of TNFα-mediated apoptosis in hepatocytes is a known major key player for the development of chronic liver failure.…”

Section: Introductionmentioning

confidence: 99%

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Hepatic Tissue Environment in NEMO-Deficient Mice Critically Regulates Positive Selection of Donor Cells after Hepatocyte Transplantation

et al. 2014

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BackgroundHepatocyte 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.MethodsPre-conditioned NEMOΔhepa mice were transplanted with donor-hepatocytes from wildtype (WT) and mice deficient for the pro-apoptotic mediator Caspase-8 (Casp8Δhepa).ResultsTransplantation 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.ConclusionThis 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.

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Section: Discussionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatic Tissue Environment in NEMO-Deficient Mice Critically Regulates Positive Selection of Donor Cells after Hepatocyte Transplantation

et al. 2014

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“…Despite clinical improvements in patients, significant problems have arisen because of inefficient engraftment, death or ectopic distribution of cells that did not engraft in the target tissue, emboli formation, immunological rejection, and transient effects of transplanted cells [34][35][36]. A number of preconditioning regimens including irradiation or chemicals have been tried but discontinued for various reasons such as senescence, radiation hazards, or an increased risk of cancer [37,38].…”

Section: Discussionmentioning

confidence: 99%

Chemokine-Mediated Robust Augmentation of Liver Engraftment: A Novel Approach

Joshi

Oltean

Patil

et al. 2014

Stem Cells Translational Medicine

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Effective repopulation of the liver is essential for successful clinical hepatocyte transplantation. The objective was to improve repopulation of the liver with human hepatocytes using chemokines. We used flow cytometry and immunohistochemistry assays to identify commonly expressed chemokine receptors on human fetal and adult hepatocytes. The migratory capacity of the cells to various chemokines was tested. For in vivo studies, we used a nude mouse model of partial hepatectomy followed by intraparenchymal injections of chemokine ligands at various concentrations. Human fetal liver cells transformed with human telomerase reverse transcriptase were used for intrasplenic cell transplantation. Repopulation and functionality were assessed 4 weeks after transplantation. The receptor CXCR3 was commonly expressed on both fetal and adult hepatocytes. Both cell types migrated efficiently toward corresponding CXC chemokine ligands 9, 10, and 11. In vivo, animals injected with recombinant chemokines showed the highest cell engraftment compared with controls (p < .05). The engrafted cells expressed several human hepatic markers such as cytokeratin 8 and 18 and albumin as well as transferrin, UGT1A1, hepatocyte nuclear factor (1a, 1b, and 4a), cytochrome CYP3A1, CCAAT/enhancer binding protein (a and b), and human albumin compared with controls. No inflammatory cells were detected in the livers at 4 weeks after transplantation. The improved repopulation of transplanted cells is likely a function of the chemokines to mediate cell homing and retention in the injured liver and might be an attractive strategy to augment repopulation of transplanted hepatocytes in vivo. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:21-30

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“…The work by Kaldenbach et al 4 in the current issue of Gut begins to address these issues by investigating the relevance of hepatocyte growth factor (HGF)/c-Met signalling in vivo for hepatocyte repopulation after transplantation. The authors employed an experimental system that made use of c-Met (loxP/loxP) and hepatocyte-specific conditional c-Met knockout (c-Met−/−) mice as donors and/or recipients for hepatocyte transplantation.…”

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confidence: 99%

The central role of the c-Met pathway in rebuilding the liver

Thorgeirsson

2012

Gut

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Hepatocyte growth factor/c-Met signalling is important for the selection of transplanted hepatocytes

Abstract: HGF/c-Met plays a crucial role in host and donor cells of the liver for the cursiv selection of transplanted hepatocytes. Modulating HGF-dependent signalling seems a promising therapeutic option to favour expansion of transplanted hepatocytes.

Cited by 18 publications

References 26 publications

Hepatic Tissue Environment in NEMO-Deficient Mice Critically Regulates Positive Selection of Donor Cells after Hepatocyte Transplantation

Hepatic Tissue Environment in NEMO-Deficient Mice Critically Regulates Positive Selection of Donor Cells after Hepatocyte Transplantation

Chemokine-Mediated Robust Augmentation of Liver Engraftment: A Novel Approach

The central role of the c-Met pathway in rebuilding the liver

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