The hepatic progenitor cell niche in man and dog

Abstract

Chronic progressive liver diseases occur frequently in humans and animals, and lead to severe dysfunction and cirrhosis. The only available treatment is liver transplantation. Due to donor liver shortage, alternatives for liver transplantation are needed. Several forms of hepatitis occurring in dogs present with histological and molecular reaction patterns highly similar to human hepatitis. The important cell types of the liver are hepatocytes (detoxification), cholangiocytes (transport of bile), stellate cells (lipid storage), endothelial cells, Kupffer cells (liver specific macrophages), and hepatic progenitor cells (HPCs, adult liver stem cells). HPCs become activated in liver diseases whit insufficient hepatocyte and/or cholangiocyte replication. The activation is often too little or too late to fully restore liver function. Detailed knowledge of the regulatory signals of HPC activation will be crucial to develop new HPC-based therapies. Furthermore, relevant clinical models are needed to assess safety and efficacy of new treatment strategies and translate fundamental rodent studies into clinical practice. In this thesis we (i) investigated signalling pathways involved in HPC activation in man and dog; and (ii) characterised the canine HPC niche in comparison to man, needed to evaluate its potential as translational model for clinical liver diseases. These studies were exerted in close collaboration with the Department of Morphology and Molecular Pathology (Prof Roskams, Leuven, Belgium). Immunohistochemical comparison of human and canine liver diseases extended the known similarities between these two species to the level of the HPC and its microenvironment (HPC niche). These studies further characterised a canine liver disease with extreme HPC activation unrivalled across species; lobular dissecting hepatitis (LDH). This canine disease offers unique and clinically relevant material for HPC research. Follow up gene-expression and cell culture studies revealed the involvement of Wnt and Notch signalling in proliferation, migration and differentiation of HPCs. Furthermore the well-known self-renewal factor Bmi1 was shown to play a role in HPC proliferation. However, high expression of Bmi1 in aggressive liver tumours highlights the potential risk of tumour formation associated with long standing HPC proliferation. Finally, microarray analysis of LDH revealed a strong involvement of fibrosis, extra cellular matrix (ECM) remodelling and cell-matrix interactions (mainly through integrins) in HPC behaviour during liver disease. Follow up studies should further elucidate the exact role of ECM components in HPC activation. Expression profiling by microarray analysis revealed numerous other new signalling cascades differentially expressed in liver diseases. In collaboration with UMC-Utrecht (Prof Medema) and EU-Rotterdam (Prof Peppelenbosch) two different high throughput screens are now used to discover signalling pathways functionally important in HPC proliferation. The studies document high similarity in histology and regulation of HPCs between man and dog. Therefore we propose clinical liver diseases of the dog as important models to evaluate and implement new HPC based treatment strategies in currently untreatable liver diseases. This work was supported by an NWO-AGIKO research grant and was the basis for the ZonMW grant on liver stem cells on which recently started a PhD-student and a post-doctoral researcher