The HEPRO Project (project leader VUB-LIVR: Laurent Dollé, PhD)

HEPRO I (2007-2011): The hepatic progenitor cell niche under experimental conditions and in human liver disease

HEPRO II (10/2012-09/2017): Human liver disease: study of the hepatic stem cells and their niche, and development of novel model systems

http://www.iap-hepro.be

 

Project coordinator :
Prof. Albert Geerts, VUB (01/01/2007-24/01/2009)
Prof. Vera Rogiers, VUB (25/01/2009-31/12/2011 + 10/2012-09/2017)

Co-Promotors
Prof.Leo van Grunsven, VUB
Prof. Geert Leroux-Roels and Prof. Philip Meuleman, UGent
Prof. Isabelle Leclercq and Prof. Frédéric Lemaigre, UCL
Prof. Tania Roskams, K.U.Leuven

European Partners
Prof. Malcolm Alison, QMUL, London, UK
Prof. Christian Trautwein, UKA, Aachen, Germany

Funding:
BELSPO (IAP VI+VII programme)

 

HEPRO I: This project will add significantly to our basic understanding of the structure and functions of the hepatic progenitor cell niche. This highly specialized cellular environment constitutes the cradle in which progenitor cells can reside for nearly unlimited periods of time. Better insight into the basic biology of the local hepatic progenitor cell niche will improve our understanding of the pathogenesis of liver diseases, and lead the way to strategies to repopulate the liver with functional cells in the event the original cells have vanished as a result of disease. Two possibilities for repopulation are conceivable : cell transplantation of autologous or allogeneic progenitor cells in patients with impaired liver, or stimulation of proliferation and differentiation of remaining local hepatic progenitor cells.

Working hypothesis :

In adult liver, adult somatic progenitor cells (ASPCs) have at least partially retained their embryonic plasticity. Some of these cells are of endodermal origin. These cells are bipotential : they can give rise to hepatocytes or to bile duct epithelial cells (1-2). Other cells are of mesodermal origin and could possibly give rise to stellate cells and possibly to sinusoidal fenestrated endothelial cells (3). To which extent the endodermal and mesenchymal cell compartments are strictly separated, or whether transdifferentiation is possible, is an important question we will address. The ASPCs stand in close contact with TACs (oval cells, small hepatocyte-like cells, committed mesenchymal cells), non-stem niche cells (possibly periductular fibroblasts and stellate cells), parasympathetic nerve endings and with extracellular matrix. This intact micro-environment inhibits proliferation and differentiation of ASPCs. Alterations in the micro-environment discontinue this inhibition. Apart from recruitment of liver cells from local niches, we will also investigate whether some progenitors derive from extrahepatic sources, and if so, where they engraft into the liver and to which cell types they give rise to.
The capacity of ASPCs and extrahepatic progenitor cells to proliferate and differentiate into liver cells makes these cells new targets for therapeutic intervention in liver disease. Theoretically, the existing local compartment of progenitors could be stimulated to repopulate the liver. The isolation of progenitors, and their propagation and differentiation ex vivo, opens new possibilities for autologous or allogeneic cell transplantation.

1. Roskams TA, Libbrecht L, Desmet VJ. Progenitor cells in diseased human liver. Semin Liver Dis 2003 Nov;23(4):385-396.
2. Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 2004 Jun;39(6):1477-1487.
3. Roskams T. Different types of liver progenitor cells and their niches. J Hepatol 2006;45:1-4.

HEPRO II:

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 underin vivo and in vitro experimental conditions, the clinical relevance will be guaranteed throughout the project.


 

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