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.
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