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Human liver disease: Study of the hepatic stem cells and their niche, and development of novel model systems (HEPRO-2)

Research project P7/47 (Research action P7)

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Description :

In human liver, adult progenitor cells are present in specialized dynamic micro-environments, the so-called stem or progenitor cell niches. When hepatocytes are damaged by developing disease or chemical injury, they undergo apoptotic and/or necrotic cell death and are unable to replicate to restore liver tissue. Repopulation of the damaged liver with functional liver cells, however, may occur in part by proliferation and differentiation of these local progenitor cells and this process is triggered by a variety of signals, growth factors and supportive scaffold provided by the stem cell niche. Liver progenitor cells (LPCs) are therefore an attractive source for liver cell therapy and a target for in vivo induction of hepatic recovery. However, to achieve this, it is crucial to identify and understand the key cellular and molecular mechanisms that control the activation and differentiation of LPCs and their participation in the onset, progress and recovery of liver pathology/injury. Furthermore, the interplay with their niche is also thought to be of major importance.

Building further on the results of the successful HEPRO-1 project, which was focussed on LPCs in healthy liver, in the HEPRO-2 project investigation will be concentrated on LPCs and their niche in human liver disease/injury. The translational aspect will play a major role in this project. Namely the results obtained for the molecular characterization of the LPCs and their niche in human liver samples of disease/injury, obtained via Laser Capture Microdisssection technology of samples stored in a large human liver tissue bank, will be the starting point. By continuous challenging of these results with observations done under in vivo and in vitro experimental conditions, the clinical relevance will be guaranteed throughout the project. The research involved is condensed in 5 work packages and will be carried out by intensive collaboration and networking between 4 national and 2 international partners. The main objectives of the HEPRO-2 project can therefore be summarized as follows :

1. Molecular characterization of progenitor cells in pathological versus normal conditions : to identify and understand the key molecular players and required conditions (transcription factors, growth factors, microRNAs) that determine the hepatic/cholangiocytic differentiation capacity of LPCs and their participation in the onset, progress and recovery of liver pathologies/injuries. Hereto, LPCs from various rodent liver models will, through in vivo and in vitro experiments, be compared at the molecular level with LPCs from human diseased liver using the isolation techniques (side population-and aldehyde dehydrogenase-based methods) and lineage tracking methods (CK19-Cre;Rosa26R-YFP and Sox9-Cre;Rosa26R-YFP mice) collaboratively developed in the HEPRO-1 project. In addition, a third system to track LPC cell fate will be evaluated, namely Osteopontin-CreER;Rosa26R-YFP transgenic mice. Liver pathologies envisaged are chronic viral hepatitis B and C, hepatic cirrhosis, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, hepato/cholangiocarcinoma and polycystic liver. Further optimization of the in vitro maturation process of extra-hepatic (i.e. human skin-derived) progenitors to hepatocyte-like cells as an alternative cell source for recovery of liver injury as well as human hepatocytes for in vitro pharmaco-toxicological applications, is also envisaged.

2. Dynamics of the progenitor cell niche : the LPCs' environment regulates the maintenance and activation of the cells. Characterizing how the stem cell niche is structured and maintained and how it affects LPC activation is a prerequisite to develop therapies that promote harmonious liver repair in conditions of injury. Using the aforementioned transgenic mouse models, liposome¬mediated and viral delivery of compounds and siRNA/microRNA, and Laser Capture Microdissection, the molecular interplay that maintains the progenitor cell niche will be further characterized and the role of the different cell types within the niche (e.g. stellate cells, Küpffer cells) in the activation of the LPCs will be identified. The architecture of the niche in mouse models of disease and in chronic human liver diseases will be established by three-dimensional reconstruction using cell type specific markers/tracing.

3. Development of novel model systems to study liver disease/injury : since current rodent models of liver disease usually target only mature hepatocytes, there is a clear need to develop new model systems in which progenitor cells are targeted.

3.1. In vivo model systems : The repopulation efficiency of the isolated LPCs (rodent/human; normal/diseased) will be studied in a novel immune deficient FRG mouse model of hypertyronisemia (fumarylacetoacetate-hydrolase (FAH)-/-Rag2-/-), allowing induction of liver injury on demand, in comparison to the benchmark uPA+/+-SCID (urokinase-type plasminogen activator – severe combined immune deficient) model, which has been successfully used within the HEPRO-1 project to study the regenerative character of LPCs. In addition, the novel NemoΔhepa conditional knockout mouse model will be further characterized and used as an alternative transplantation model but also to study LPC activation under conditions reflecting chronic liver disease progression as found in humans.

3.2. In vitro model systems : -At present, no robust long-term hepatic cell culture model is available. This hampers in vitro
research on long-term effects caused by xenobiotics (e.g. carcinogenicity) or after viral infections. Here, two novel human(ized) three-dimensional liver models will be explored, respectively, i.e. (i) a naturally-derived decellularized liver scaffold that will be recellularized with different (normal/diseased) liver cells (progenitors, committed cells, hepatocytes,…), and (ii) a new human three-dimensional liver model with both hepatocytes and non-parenchymal liver cells cultured on synthetic nylon scaffolds. -Although evidence is accumulating that tumours may arise from progenitor cells, little is known whether they also are direct targets of genotoxic carcinogens or tumour promoters. By using rat liver progenitors that were also studied during HEPRO-1, it will be investigated whether these cells when exposed to genotoxic carcinogens express biomarkers with in vivo relevance for liver carcinogenesis.

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