Hepatocyte growth factor/c-Met signalling is important for the selection of transplanted hepatocytes
- Michaela Kaldenbach1,
- Arne Giebeler1,2,
- Darjus F Tschaharganeh3,
- Stephanie Erschfeld1,
- Hermann E Wasmuth1,
- Laurent Dolle4,
- Juergen Floege5,
- Christian Trautwein1,
- Konrad L Streetz1
- 1Department of Medicine III, RWTH Aachen University, Aachen, Germany
- 2Department of Surgery, RWTH Aachen University, Aachen, Germany
- 3Department of Pathology, University of Heidelberg, Heidelberg, Germany
- 4Faculty of Medicine and Pharmacy, Free University of Brussels, Brussels, Belgium
- 5Department of Medicine II, RWTH Aachen University, Aachen, Germany
- Correspondence to Dr Konrad Streetz, Department of Medicine III, University Hospital Aachen, Pauwelsstr 30, 52074 Aachen, Germany;
Contributors MK, AG, DFT, SE, HEW, JF and LD performed experiments. MK, CT and KLS wrote the paper. MK and KLS designed experiments.
- Revised 19 December 2011
- Accepted 20 December 2011
- Published Online First 27 January 2012
Background At present hepatocyte transplantation is a promising option for cellular therapy of end-stage liver diseases. However, the underlying molecular mechanisms need to be better defined in order to translate this technique into clinical use. This study investigated the cursiv relevance of hepatocyte growth factor (HGF)/c-Met signalling for hepatocyte repopulation after transplantion.
Methods Wild-type mice (c-MetloxP/loxP) and hepatocyte-specific conditional c-Met (HGF receptor) knockout (c-MetΔhepa) mice were used as donors and recipients for hepatocyte transplantation.
Results Transplantation experiments revealed two major findings. First it was demonstrated that c-Met is indispensable in donor cells, as c-MetΔhepa cells did not repopulate recipient livers after transplantation. Second, genetic deletion of c-Met in recipient hepatocytes resulted in enhanced expansion of unmodified donor cells in host livers (up to 250-fold after 12 weeks). The relevant mechanisms for this observation in c-MetΔhepa host hepatocytes could be defined. c-MetΔhepa hepatocytes showed enhanced apoptosis, reduced cellular proliferation and a lack of AKT-kinase and STAT3 activation. In addition, tissue remodelling was changed in c-MetΔhepa recipient livers. Therefore, the lack of pro-proliferative transcription factors, increased apoptosis and changes in matrix-remodelling inhibit host cell proliferation in c-MetΔhepa recipient livers and thus favour repopulation of transplanted hepatocytes. Therapeutically liver repopulation could be increased through adenoviral expression of NK-4—an inhibitor of HGF signalling—in host hepatocytes.
Conclusion 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.
- Biliary cirrhosis
- cell biology
- cell signalling
- chronic liver disease
- hepatobiliary cancer
- hepatocyte transplantation
- immunology in hepatology
- liver cirrhosis
- liver immunology
- liver regeneration
- liver repopulation
- liver transplantation
- molecular linkage analysis
- stem cells
Funding This study was supported by the following grant: KLS: DFG 661/4-1.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.