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.he 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.
Liver development starts after the formation of the endoderm during gastrulation, more specifically in the foregut. The first transcription factors that confer hepatic competence are forkhead-box protein A (FOXA) and Gata binding protein (GATA). Both factors are expressed in the ventral foregut endoderm even before albumin (ALB) is expressed. Fibroblast growth factor (FGF), BMP (Bone morphogenetic protein) and Wnt are expressed and secreted by the mesoderm adjacent to the ventral foregut endoderm (cardiac mesoderm and septum transversum) and are to date identified as the only early hepatic inducing signals.
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.
The liver is the largest internal organ of the body that weighs 1-1.5kg which represents 1.5-2.5% of the mean body mass. It serves as a chemical factory, excretory system, exocrine and endocrine gland. One of the major functions is its capacity to metabolize, detoxify and inactivate endo- and exogenous compounds.
HEPATOCYTE MEDIATED REGENERATION
Upon the loss or damage of a portion of the total amount of liver parenchymal tissue, remaining hepatocytes recover from their cell cycle arrest and replenish thus the liver, to improve normal homeostasis. It has been shown that hepatocytes are capable of dividing at least 69 times during a life time.
Liver fibrosis is caused by prolonged exposure to viruses, toxins, and environmental factors among others. Upon liver injury, hepatic stellate cells transdifferentiate into contractile myofibroblastlike cells that produce matrix proteins eventually leading to scar formation and liver fibrosis. Inhibition of this process is thus an important target for therapeutic intervention in liver fibrogenesis.