HEPRO

A research network in the Interuniversity Attraction Pole (IAP) programme

of the Belgian Science Policy Office (BELSPO)

HEPRO is active since IAP phase VI (2007-2011) and is contuing in IAP phase VII (2012-2017)


IAP programme

 

HEPRO II (2012-2017): network n° P7/47

Human liver disease: study of the hepatic stem cells and their niche,
and development of novel model systems

 

ABSTRACT

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 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, 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.

MAIN OBJECTIVES

1) MOLECULAR CHARACTERIZATION OF LPC IN LIVER DISEASE / INJURY VERSUS NORMAL CONDITIONS

Samples:
- human liver bank
- in vivo experiments in rodent liver disease models
- in vitro experiments with adult human skin-derived progenitors

2) DYNAMICS OF LPC NICHE

- molecular characterization of interplay between LPC and their micro-environment (e.g. cells, matrix)
- 3D-architecture of the niche

3) DEVELOPMENT OF NOVEL MODEL SYSTEMS FOR LIVER DISEASE / INJURY STUDIES

- in vivo: transgenic mouse models + transplantation mouse model
- in vitro: long term cultures (natural & synthetic scaffolds) + progenitor cell cultures for genotoxicity testing

 

PREVIOUS PROJECT IN IAP PHASE VI

HEPRO I (2007-2011): network n° P6/36

The hepatic progenitor cell niche under experimental conditions and in human liver disease

The purpose of this project was to study the morphology, function and cellular physiology of the progenitor cell niche in the normal and diseased liver.

Local adult progenitor cell niches are special microenvironments that contain somatic progenitor cells (ASPCs). The latter are generally slow-cycling cells which give rise to transit amplifying cells (TACs) that leave the niche. TACs cycle faster than progenitor cells but have a limited proliferation potential. The niche also contains non-stem niche cells, axonal processes of neurons and specialized extracellular matrix. A complex molecular crosstalk between the progenitor cells and the non-stem niche cells ensures that progenitor cells divide asymmetrically, producing one daughter progenitor cell and one daughter cell that becomes a TAC. In the liver, canals of Hering and bile ductuli function as minute progenitor cell niches which contain both endodermal and mesenchymal ASPCs. Cells of endodermal origin are at least bipotent: they can give rise to hepatocytes and to bile duct epithelial cells. Mesenchymal ASPCs could give rise to mature stellate cells, sinusoidal endothelial cells or other hepatic mesenchymal cells, but formal proof for such differentiation is lacking. Apart from their presence in the hepatic niche, progenitor cells may also be recruited to the liver from more distant locations such as the bone marrow. This project will add significantly to our understanding of the structure and functions of the highly specialized cellular environment that constitutes the hepatic progenitor cell niche. New possibilities for autologous and allogeneic cell transplantation, and novel strategies for the treatment of chronic liver diseases, aiming at stimulating the proliferation of local progenitor cells, may stem from this research.

 




















 
    Last page update: 19.10.2016