Characterization of the role of hepatic stellate cells in liver regeneration

• Applicant: Dr. Young-Min Anna Lee
• Subject Area: Gastroenterology
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 193437902

Chronic liver disease is a leading cause of morbidity and mortality worldwide. Despite the remarkable regenerative capacity of the liver, liver fibrosis and cirrhosis are common and often lead to liver failure and increased risk for hepatocellular carcinoma. Hepatic stellate cells (HSCs) are the primary source of extracellular matrix deposition in fibrosis. Their role in adult liver regeneration is suggested by their secretion of a number of hepatocyte mitogens, but has not been clearly established. Moreover, it is unclear during liver injury whether HSCs attenuate or worsen hepatocyte damage, and/or enhance hepatocellular regeneration. Also, the contribution of HSCs to the termination of the growth response once the liver mass is reconstituted is not fully understood. We are developing a novel mouse model in which HSCs transgenically express the herpes simplex virus thymidine kinase (HSV-tk) gene under the control of the mouse GFAP promoter, rendering them susceptible to cell-specific killing by administration of the drug ganciclovir when HSCs proliferate following transient liver injury due to thioacetamide administration (a standard fibrogenic stimulus). This approach ensures that extra-hepatic GFAP-expressing cells (especially astrocytes and enteric glial cells) will not be affected due to their very low proliferation rate. The role of HSCs in liver regeneration will be analyzed by ablating them with ganciclovir in mouse models after partial hepatectomy. Our hypothesis is that HSCs promote hepatocyte proliferation following partial hepatectomy. The selective ablation of HSCs will be confirmed and toxic collateral side effects to resident liver cells excluded by using immunohistological techniques and well established molecular biological and biochemical methods. We will then analyze the contribution of HSCs in different phases of liver regeneration and explore the role of HSCs in the revascularization process of newly formed hepatic lobules.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Scott L. Friedman