Induction of fibrolytic activity in hepatic stellate cells by T cell derived microparticles in vitro and in vivo

• Applicant: Privatdozent Dr. Miroslaw Kornek
• Subject Area: Gastroenterology
• Term: from 2010 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 182582722

Cirrhosis is the consequence of many forms of chronic liver diseases. Currently, there is no clinically validated antifibrotic therapy for liver fibrosis. The most important fibrogenic effector cells in the liver are activated hepatic stellate cells and myofibroblasts (collectively termed HSC). Other, mainly immunology relevant cells, have the potential to induce fibrolysis, but HSC can also develop a fibrolytic potential. Induction of a fibrolytic phenotype in HSC would open attractive therapeutic options for hepatic fibrosis. The applicant could show that 1) microparticles (MP) derived from membranes of activated/apoptotic T cells induce the expression of fibrolytic matrix metalloproteinases; 2) the uptake of MP is receptor-mediated; 3) the cell-membrane molecule CD147, which induces fibrolytic signal transduction in HSC, is a major effector of the observed fibrolytic effect. The aims of this research proposal are 1) to identify and the functionally characterize other relevant membrane proteins that induce fibrolytic activation of HSC; 2) to analyze on a functional and molecular level the MP from various T cell subpopulations (and macrophages); and 3) the application and in vivo generation of fibrolytically active MP in a murine model of liver fibrosis. In summary, the proposal will further explore this novel mechanism of (hepatic) fibrolysis on a molecular level. The translational goal of the proposed study is the development of a novel antifibrotic therapy based on the induction of T cell microparticles for patients with hepatic fibrosis.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Nezam H. Afdhal