The role of adhesion molecule interactions in the engraftment of transplanted hepatocytes into host liver

摘要

Orthotopic liver transplantation (OLT) remains the only proven treatment for end-stage liver disease. However the waiting list for OLT far exceeds the supply of donor organs. Hepatocyte transplantation may offer an alternative for these patients either as a bridge to OLT or replacing OLT altogether. Unfortunately efforts so far have failed to result in long term benefit despite initial promising results. The mechanisms regulating engraftment of transplanted hepatocytes into host liver, in particular the nature of their interaction with hepatic sinusoidal endothelial cells (HSEC), remain poorly understood. I have significantly improved the outcome of human hepatocyte isolation from liver tissue and shown that human hepatocytes express a range of adhesion molecules including β1-integrin. Rather than reducing adhesion, β1-integrin blockade significantly improves hepatocyte adhesion to HSEC under flow, increases transmigration across HSEC and leads to greater engraftment in a murine model of hepatocyte transplantation. Furthermore, I have shown that blocking β1-integrin on human hepatocytes leads to activation of the PKB/Akt signalling pathway, resulting in suppression of anoikis and improved viability, and promotion of cytoskeletal reorganisation that may lead to a more migratory phenotype. This work therefore demonstrates a possible target to improve hepatocyte engraftment and thus the outcome of hepatocyte transplantation.