Background Hepatic progenitor cells (HPCs) hold a great potential for therapeutic intervention for currently untreatable liver diseases. However, in human diseases molecular mechanisms involved in proliferation and differentiation of HPCs are poorly understood.
Methods and results In the present study activated HPCs and their microenvironment (niche) were investigated in acute and chronic human liver disease by gene-expression analysis and immunohistochemistry/immunofluorescence. Cryopreserved liver tissues were used from patients with parenchymal versus biliary diseases: acute necrotising hepatitis (AH), cirrhosis after hepatitis C infection, and primary biliary cirrhosis in order to study differentiation of HPCs towards hepatocytic versus biliary lineage. Keratin 7 positive HPCs/reactive ductules were captured by means of laser capture microdissection and gene-expression profiles were obtained by using a customised PCR array. Gene expression results were confirmed by immunohistochemistry and immunofluorescence double staining. In all disease groups, microdissected HPCs expressed progenitor cell markers such as KRT7, KRT19, NCAM, ABCG2, LIF, KIT, OCT4, CD44 and TERT. In AH, HPCs were most activated and showed a high expression of prominin-1 (CD133) and α-fetoprotein, and a strong activation of the Wnt pathway. In contrast to parenchymal diseases, HPCs in primary biliary cirrhosis (biliary differentiation) showed a high activation of Notch signalling.
Conclusion A distinct pattern of HPC surface markers was found between acute and chronic liver diseases. Similar to what is known from animal experiments, strong evidence has been found signifying the role of Wnt signalling in proliferation of human HPCs whereas Notch signalling is involved in biliary differentiation. These pathways can be targeted in future therapies.
- Stem cells
- laser microdissection
- acute hepatitis
- chronic hepatitis
- primary biliary cirrhosis
- molecular biology
- molecular mechanism
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Supplementary files and a figure are published online only at http://gut.bmj.com/content/vol59/issue2
BS and GC contributed equally to this study.
Funding This study was partially funded by the Funds for Scientific Research Flanders (FWO).
Competing interests None.
Ethics approval The use of the tissues in this research is allowed by Belgian law (19-12-2008 articles 2 and 20). This study was conducted with the approval of the Local Commission for Medical Ethics and Clinical Studies of the University of Leuven given on 7 November 2003.
Provenance and peer review Not commissioned; externally peer reviewed.