Abstract
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.
Highlights
Orthotopic liver transplantation is currently the only possible cure for patients with acute and end-stage liver diseases
An extensive deal of work with animal models has demonstrated the repopulation of injured livers after hepatocyte transplantation (HT) by percutaneous or transjugular infusion into the portal vein, or injecting into the splenic pulp or the peritoneal cavity, which is a less invasive procedure compared with liver transplantation
We have recently described that hepatocyte-specific IKKc/NEMO knockout (NEMODhepa) mice represent an excellent liver disease model as it reflects human liver pathogenesis with progression from chronic hepatitis to non-alcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma (HCC) [5,6]
Summary
Orthotopic liver transplantation is currently the only possible cure for patients with acute and end-stage liver diseases. Due to the complexity and associated morbidity and mortality, the scarcity of donor organs and the need for immunosuppression, other alternatives are being currently considered. The transplantation of isolated hepatocytes has arisen as a potential promising alternative. Multiple recipients can benefit from one donor liver, in contrast to whole liver transplant. A major problem in most HT studies to date has been the limited growth and engraftment of transplanted cells in the recipient organ. 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. We hypothesized that NEMODhepa mice may serve as an experimental model to study HT
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