- Dr. Jorge A. Bezerra, Principal Investigator
- Dr. David Witte
- University of Cincinnati, Cincinnati, USA
- Role of proteins to improve outcome of liver cell transplantation
Hepatocyte transplantation is an emerging treatment modality for patients with liver failure of hereditary metabolic diseases. In this technique, hepatocytes (the main liver cell) are injected into the vascular bed of patients with liver disease. Following injection, hepatocytes migrate to the liver, become part of the native liver cells, and function normally. Despite the pioneering use in patients with liver failure as a bridge to liver transplantation, the use of hepatocyte transplantation remains limited because only a small number of cells successfully populate the recipient liver. Although little is known about the factors which control the outcome of hepatocyte transplantation, recent studies in genetically modified mice demonstrated that in the appropriate biological setting transplanted cells can repopulate almost the entire liver. These mice produced an elevated amount of urokinase, a protein involved in the reorganisation of the structural scaffold of the liver and other organs. Data from our laboratory demonstrated that urokinase creates a microenvironment in the liver which is conducive to expansion of transplanted hepatocytes. In this grant, we propose to use mice with genetic modifications of urokinase and of other functionally related proteins in transplantation experiments to define their role in the outcome of hepatocyte transplantation. Our strategy will be to transplant hepatocytes from these mice into control mice. We will then use gene markers and morphological analysis to identify and count the number of transplanted hepatocytes in the recipient livers. We expect that the production of these proteins by donor hepatocytes will lead to improved outcome following transplantation. These experiments are likely to identify key molecules that can be used in the clinical setting to optimise the use of this technique in the support of patients awaiting liver transplantation and in the treatment of patients with liver disease.