Endosialin an Integral Cog in the Liver Fibrosis Machine

DISCOVERY of a new molecule on the surface of hepatic stellate cells has broadened knowledge of the underlying mechanisms that cause liver fibrosis, potentially paving the way for targeted treatments.

Liver fibrosis is a very serious problem today; it afflicts approximately 10% of the population alongside its corresponding later stage, liver cirrhosis, which itself increases the risk of liver cancer. Hepatic stellate cells, specialised cells present in the walls of blood vessels, are seen as initiators of liver fibrosis and, following liver damage, secrete key substances that stimulate scar tissue formation in the surrounding environment.

A research team led by Prof Hellmut Augustin, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Medical Faculty in Mannheim, Heidelberg University, Heidelberg, Germany, has revealed that a cell surface protein known as endosialin activates these cells, giving rise to the creation of scar tissue. The conclusion was reached when genetically modified mice, whose cells contained no endosialin, developed far less liver fibrosis following extended liver damage than the controls, whose cells were able to make endosialin.

Furthermore, the absence of endosialin not only reduced scar tissue formation and activation of hepatic stellate cells, but also boosted the regenerative capacity of the remaining liver cells while steering clear of proliferative growth; this underlines the crucial effect endosialin has on the balance between scar formation and liver regeneration. Upon examination of samples from healthy liver tissue, and from liver tissue at different stages of liver fibrosis through to cirrhosis, the team were able to determine the human subjects’ levels of endosialin and discovered that the protein likely catalyses early human liver fibrosis.

“Endosialin is produced at very elevated levels primarily in the early, active phase of liver fibrosis,” said Dr Carolin Mogler, Institute of Pathology, Heidelberg University, the 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.”

It will be a while until these findings can be tested in clinical trial settings. However, the team aims to investigate whether an antibody that inhibits endosialin, which is currently under clinical evaluation for treating particular types of tumours, can be used to treat other diseases including liver fibrosis.

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