Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling

Hepatology Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling Bart Spee1, Guido Carpino2, Baukje A Schotanus3, Azeam Katoonizadeh1, Sara Vander Borght1, Eugenio Gaudio4, Tania Roskams1 + Author Affiliations 1Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium 2Department of Health Sciences, University of Rome ‘Foro Italico’, Rome, Italy 3Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands 4Department of Human Anatomy, Sapienza University of Rome, Rome, Italy Correspondence to Dr B Spee, Department of Morphology and Molecular Pathology, University Hospitals Leuven, Minderbroederstraat 12, Leuven B3000, Belgium; b.spee@uu.nl Revised 18 September 2009 Accepted 8 October 2009 Published Online First 1 November 2009 Abstract 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