Scientists of the HepatoSys consortium, the network for the systems biology study of the liver cell (hepatocyte), have gained new insights into the processes of liver cirrhosis.
They found that hepatocytes affected by damage to the liver undergo a mutation and contribute actively to the chronic cicatrisation of the tissue. The findings of researchers working under Prof. Dr. Steven Dooley, Medical School in Mannheim, University of Heidelberg, pave the way to new perspectives regarding the treatment of the hitherto incurable liver disease.
Of all the body's organs, the liver has the unique ability to regenerate completely after having suffered damage either through injuries, toxic substances such as alcohol, certain medication or other liver damaging substances, provided the causes are eliminated. Alcoholism or infections with hepatitis B or C viruses do result in a lasting malfunction of the liver tissue, which impedes the regeneration process. The growth factor TGF-beta plays an important role both in the healing process and in the continuing chronic damage.
After the organ has been damaged, TGF-beta becomes active and triggers signal transmission paths which eventually lead to the closing of the wound. However, if the damage is of a chronic nature, the growth factor changes from being a helper to being a harmful agent: its permanent activation and the excessive healing process lead to a changed architecture of the liver tissue. In place of functional hepatocytes there is an increasing occurrence of fibroblast-like cells which can be classified as connective tissue. Furthermore, there is an increased production of extracellular matrix, a form of grout, so to speak, for the intercellular space. The organ "scars over".
"With the help of Systems Biology, we want to find out what impact the excessive TGF-beta signal effect has on the hepatocyte", says Dooley, head of the Section for Molecular Alcohol Research in the Gastroenterology Department of the II. Medicinal Clinic in Mannheim. For this purpose, he and his team chose the co-called top-down approach: they cultivated primary (recently isolated) hepatocytes, stimulated them with TGF-beta and then examined which genes had been activated by this treatment. In doing so, they found that primarily the genes typical for fibroblasts became active. "The modelling of the experimental results and the subsequent testing of the predictions with laboratory animals showed that the lasting effect of TGF-beta leads to the hepatocytes losing their typical appearance and metamorphosing to fibroblast-like cells", explains the scientist.
The findings of the Mannheim HepatoSys-team come as a surprise and shine a completely new light onto liver cirrhosis. So far, scientists had assumed that only one cell type in the liver, the hepatic stellate cells, change into fibroblast-like tissue while the hepatocytes die off. These new insights allow a search for new ways of treating liver cirrhosis. At this point, the advancing disease is incurable and eventually leads to liver failure. At present, liver transplantation is the last resort.
Prof. Steven Dooley will speak on saturday, May 24nd, during the SBMC in Dresden about his work on TGF-beta induced signal paths in liver cells. The complete conference program and an online registration form can be found at http://www.sbmc08.de
Journalists are invited to attend the conference.About the SBMC and HepatoSys
* Word formation consisting of Hepatocyte - liver cell - and Systems Biology
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