Introduction

Background

Yearly, 60,000 European citizens die due to liver failure, and at least ten times more are chronically affected and disabled by liver disorders. There is currently no curative treatment and nearly no new medications have been marketed for chronic liver diseases in the last decade. In fact, liver transplantation often becomes the ultimate solution. However, liver transplantation is only available to a small fraction of patients due to shortage of donors. The recently implemented MELD score (1) gives priority to the sickest patients, the consequence being that the medical condition of patients has to deteriorate until late stage disease to have access to a graft. The only curative therapy for acute or chronic liver failures is liver transplantation, which costs 100.000 € the first year, and 10.000 € yearly thereafter.


At present, orthotopic liver transplantation represents the benchmark therapy of terminal liver disease, but is limited by shortage of donor grafts, the need for lifelong immuno-suppression and the very demanding state-of-the-art surgery. Therefore, new therapies have been developed to restore liver function, primarily in the form of hepatocyte transplantation and artificial liver support devices. Recently, liver progenitor cells have shown a promise in cell therapy and they have gained interest as alternative or supportive tools for liver transplantation. These liver progenitor cells are quiescent in the healthy liver and become activated in certain liver diseases in which the regenerative capacity of mature hepatocytes and/or cholangiocytes is impaired. Reports describing liver progenitor cells are numerous but they have not led to a consensus on the identity of the liver progenitor cell. It is clear that isolation and characterization of liver progenitor cells will enable the development of drugs that could be used to treat patients with fulminant liver failure, or chronic liver diseases where, due to exhaustion of the ability of the mature hepatocytes to proliferate, maturation of the progenitor pool towards mature hepatocytes may postpone or eliminate liver failure.


To date there are no approved anti-fibrotic agents for the management of liver fibrosis. There is much debate regarding reversibility of liver fibrosis/cirrhosis stimulating the search for anti-fibrosis/cirrhosis drugs. Anti-fibrotic therapies must be aimed at inhibiting the activated hepatic stellate cell or inducing apoptosis or senescence of this cell. In animal models it has been shown that decreased levels TIMP1 and TIMP2 produced by HSCs, together with apoptosis or senescence of the hepatic stellate cells may result in reversal of fibrosis (2-5). Although a number of agents have proven useful in murine models of fibrosis, preliminary data from therapeutic trials have not demonstrated the efficiency of such inhibitors in human patients. Understanding the molecular mechanisms that induce the activation of the stellate cells will certainly contribute to the development of new anti-fibrotics.


Portal hypertension remains a very important complication of chronic liver disease, resulting in bleeding from esophageal varices, ascites, encepholopathy etc. These complications have a high morbidity and mortality, and are responsible for huge costs. Therefore, the search for new and better drugs to treat portal hypertension is ongoing. In order to select superior drugs, it is mandatory to better understand the pathophysiology of portal hypertension. We investigate the mechanisms of contraction of hepatic stellate cells, key cells in the regulation of intrahepatic vascular resistance.

References
1.Katoonizadeh, A. et al. Liver Int 27, 329-34 (2007) 2.Iredale, J. P., Benyon, R. C., Pickering, J. & al., e. J Clin Invest 102, 538-549 (1988) 3.Issa, R., Williams E. & N., N. T. Gut 48, 548-557 (2001) 4.Elsharkawy, M., Oakley, F. & Mann, D. A. Apoptosis 10, 927-39 (2005) 5. Le Bousse-Kerdilès, M. C., Martyré, M. C. & Samson, M. Eur Cytokine Netw. 19, 69-80 (2008)

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Hepatic Stellate Cells : short history

Stellate cells were discovered serendipitously by Karl von Kupffer in 1876 when he was investigating the micro-anatomy of the hepatic nervous system. He tried to stain the nerves by a goldchloride impregnation method, but instead stained star-shaped cells that he called "sternzellen". For nearly 100 years the cells remained enigmatic until Kenjiro Wake, Professor of Anatomy at the University of Tokyo, Japan, summarized all the available information and defined the stellate cell as a cell type in its own right.

Hepatic stellate cells have been studied intensively since 1975. There is overwhelming evidence that these cells play a prominent role in development of hepatic fibrosis and cirrhosis (endstage of fibrotic liver disease). In Belgium, approximately 1500 people per year die as a result of chronic liver disease that has developed into cirrhosis. In the different countries of the European Union, chronic liver disease is between the 4th and 8th cause of death.

Since 1998, pancreatic stellate cells have come into the picture. The available evidence indicates that pancreatic stellate cells play a cardinal role in pancreatic fibrosis which develops as a result of chronic pancreatitis or of diabetes type II.

Stellate cells have also been found in many other organs as is summarized in the table underneath.

Organ system
Organ/tissue
GI tract
salivary gland, oesophagus, gastric fundus, duodenum, liver, pancreas, ileum, rectum
Eye
lacrimal gland
Respiratory tract
vocal fold, lung
Urinary tract
kidney, prostate
Endocrine system
adrenal, pituitary
Female reproductive system
uterus
Male reproductive system
ductus deferens
Lymphoid organs
spleen, lymphe node, tonsil
Hematopoietic system
bone marrow

Exception made for the liver and the pancreas, stellate cells in other organs have not been thoroughly studied. However, these cells may be involved in important pathologies such as emphysema in the lung, interstitial and glomerular fibrosis in the kidney, inflammatory bowel diseases and Sjögren´s syndrome in the salivary glands. As is the case for cirrhosis and pancreatic fibrosis, the above diseases are characterized by development of significant amounts of fibrotic tissue that replaces functional tissue of the affected organ.

In primary as well as in metastatic liver tumors, activated stellate cells act as stromal cells. These stromal cells produce extracellular matrix required for neo-angiogenesis, allowing the tumor to expand. These stromal cells also produce matrix metalloproteinases allowing tumor cells to metastazise.

Besides the classical functions that are attributed to hepatic stellate cells (vitamin A storage, ECM synthesis, contraction, secretion of growth factors and cytokines, neural signal propagation), it appears that a subpopulation of these cells plays a role in formation of the progenitor cell niches.

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The Hepatic Stem / Progenitor Cell Niche

Many adult mammalian tissues contain adult somatic progenitor cells (ASPCs) located in specialized micro-environments (local adult progenitor cell niches[1,2]), that contain several cell types (ASPCs, 'transit amplifying' cells, non-stem niche cells) in contact with a specialized extracellular matrix [3,4].
In the liver, canals of Hering (CoH), that connect to the terminal bile ducts (TBD) act as microscopic progenitor cell niches [5-8]. CoH and TBD originate in the embryo from the endodermal cell layer of the ductal plates[9,10]. These plates contain mesenchymal cells at both sides[11,12]. Some of these endodermal and mesenchymal cells retain progenitor cell features throughout the embryonal and postnatal development.
In chronic human liver diseases as well as in many experimental animal models of liver disease, hepatocytes are in a condition of replicative senescence [13,14]. Progenitor cells try to compensate by proliferation and differentiation into new hepatocytes [15]. The enhanced and prolonged stimulation of liver progenitor cells increases the probability for malignancy[16]. Insight into the liver progenitor cell compartment will improve our understanding of the pathogenesis of many liver diseases and the ontogenesis of liver cancers. At the therapeutical level, better knowledge of the liver progenitor cell compartiment could lead to autologous or allogeneic cell transplantation, and to treatment of chronic liver diseases via stimulation of proliferation of local progenitor cells.

References
1. Diaz-Flores L, et al. Histol Histopathol 2006;21:995-1027. 2. Alison MR, et al.. Markers of adult tissue-based stem cells. Handb Exp Pharmacol 2006;185-227.3.Blanpain C, et al. Genes Dev 2006;20:3022-3035. 4. Blanpain C, Fuchs E. Annu Rev Cell Dev Biol 2006;22:339-373. 5. Roskams TA, et al. Hepatology 2004;39:1739-1745. 6. Saxena R, Theise N. Semin Liver Dis 2004;24:43-48. 7. Gaudio E, et al. Gastroenterology 2006;130:1270-1282. 8. Glaser S, et al. World J Gastroenterol 2006;12:3523-3536. 9. Calmont A, et al. Dev Cell 2006;11:339-348. 10. Desmet V. In: McIntyre N, et al, eds. Oxford Textbook of Clinical Hepatology.Oxford: Oxford University Press, 1991. 497-519. 11. Sell S, Ilic Z. Liver Stem cells. Austin, Texas, USA: R.G. Landes Company, 1997. 12. Roskams T. J Hepatol 2006. 13. Wiemann SU, et al. FASEB J 2002;16:935-942. 14. Roskams TA, et al. Semin Liver Dis 2003;23:385-396. 15. Yang S, et al. Hepatology 2004;39:403-411. 16. Roskams T. Oncogene 2006;25:3818-3822.

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