DKFZ. Germany: Scientists from the German Cancer Research Center (DKFZ) and the Medical Faculty in Mannheim at Heidelberg University are searching for new approaches to prevent liver fibrosis. They have identified a surface molecule on special liver cells called stellate cells as a potential target for interfering with this process. When the researchers turned off the receptor, this led to reduced liver fibrosis and improved regeneration of hepatic cells.
Liver fibrosis, which is the
progressive formation of scar tissue in the liver, is a massive medical
problem. An estimated ten percent of the population is affected by liver
fibrosis or its corresponding later stage, liver cirrhosis. A variety
of causes can lead to liver fibrosis, the most widely recognized ones
being alcohol consumption and virus-induced chronic liver inflammation.
Other factors that can lead to scarring in the liver include the use of
certain drugs, fatty liver disease and genetic disorders such as iron
overload disease. As fibrosis progresses, the liver tissue becomes
increasingly nodular, and the disease turns into liver cirrhosis, a
dangerous condition that also drastically increases the risk of
developing liver cancer.
The working group of Professor Hellmut
Augustin at the German Cancer Research Center (Deutsches
Krebsforschungszentrum, DKFZ) and the Medical Faculty in Mannheim at
Heidelberg University has now detected a new molecule on the surface of
hepatic stellate cells that is a major contributor to the development of
liver fibrosis. Hepatic stellate cells are a type of specialized cell
in the walls of blood vessels. Their functions in the liver include
storing vitamin A and regulating blood flow. They are considered to be
initiators of liver fibrosis: In the wake of liver damage, these cells
produce key substances for the formation of scar tissue and release them
into the surrounding environment. If the liver damage cannot be
completely repaired by dividing liver cells, this scar tissue stays put,
giving rise to liver fibrosis.
The scientists in Augustin’s group have now
discovered a protein called endosialin on the surface of hepatic
stellate cells that activates these cells and, thus, also promotes the
production of scar tissue. Genetically modified mice whose cells had no
endosialin developed considerably less liver fibrosis after prolonged
liver damage than normal animals whose cells were able to produce
endosialin.
Surprisingly, the absence of endosialin not only
reduced scarring and the activation of hepatic stellate cells but also
improved the regenerative capacity of the remaining liver cells without
leading to proliferative growth of the liver. Hence, endosialin can
influence the critical balance between scar formation and liver
regeneration.
Endosialin also appears to play a role in human
liver fibrosis: The scientists examined samples from healthy liver
tissue and from liver tissue at various stages of liver fibrosis,
through to cirrhosis, to determine their levels of endosialin.
“Endosialin is produced at very elevated levels
primarily in the early, active phase of liver fibrosis,” explains
Carolin Mogler, first author of the publication. “Many molecules are
produced at different levels after liver damage, but we were very
surprised by the extent to which the stellate cells increase the
production of endosialin. These findings help us better understand how
liver fibrosis develops.”
These findings, obtained in a basic research
setting, are still a long way from potential clinical application.
However, an antibody that blocks endosialin is already being tested in
clinical trials with the goal of treating specific types of tumors. The
scientists now plan to investigate whether this antibody might also be
useful for treating other diseases such as liver fibrosis.
Carolin Mogler, Matthias Wieland, Courtney König,
Junhao Hu, Anja Runge, Claudia Korn, Eva Besemfelder, Katja
Breitkopf-Heinlein, Dorde Komljenovic, Steven Dooley, Peter Schirmacher,
Thomas Longerich, Hellmut G. Augustin: Hepatic stellate cell expressed
Endosialin balances fibrogenesis and hepatocyte proliferation during
liver damage.
EMBO Mol Med 2015, DOI: 10.15252/emmm.201404246
A picture for this press release is available at: http://www.dkfz.de/de/presse/pressemitteilungen/2015/bilder/Fibrosis-Man.jpg