Paper

Characterisation of the activated liver progenitor cell niche, potential involvement of Wnt and Notch signalling

Bart Spee^1,*, Guido Carpino², Baukje A Schotanus³, Aezam Katoonizadeh¹, Sara Vander Borght¹, Eugenio Gaudio⁴, Tania Roskams¹

¹ University Hospitals Leuven, Belgium;
² University of Rome "Foro Italico", Italy;
³ Utrecht University, Netherlands;
⁴ Sapienza University of Rome, Belgium

Correspondence to: Bart Spee, Utrecht University, Yalelaan 104, Utrecht, 3584CM, Netherlands; b.spee{at}uu.nl

Accepted 8 October 2009

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 its microenvironment (niche) were investigated in acute and chronic human liver disease by gene-expression analysis and immuno-histochemistry/-fluorescence. Cryopreserved liver tissues were used from patients with parenchymal versus biliary diseases: acute necrotising hepatitis (AH), cirrhosis after hepatitis C infection (HCV), and primary biliary cirrhosis (PBC) in order to study differentiation of HPCs towards hepatocytic versus biliary lineage. Keratin 7 (K7) positive HPCs/reactive ductules were captured by means of Laser Capture Microdissection (LCM) and gene-expression profiles were obtained by using a customized 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 alpha-fetoprotein (AFP), and a strong activation of the Wnt-pathway. In contrast to parenchymal diseases, HPCs in PBC (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.

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