Our work focuses on 4 aspects of hepatocyte transplantation research
- The development of alginate microbeads for hepatocyte encapsulation
Acute liver failure (ALF) carries a very high death rate without liver transplantation, which is limited by the availability of donor organs. However, when using a auxiliary liver transplantation – a temporary transplantation – up to 70% of patients achieve complete regeneration of their native liver. Earlier clinical experiences with human hepatocytes in ALF has been only partly successful when cells were injected either in the liver or the peritoneal cavity mainly because of rejection and use of immunosuppression in very sick patients, increasing the risks of infections. We have developed an in house novel technique where human hepatocytes are encapsulated in clinical grade alginate. This technique helps avoid the need of immunosuppression and the encapsulated cells could be safely deposited in the peritoneal cavity with relative ease. Our preliminary data is encouraging but is restricted by the limited availability of good quality cells and limited life span of even good quality cells
- The use of MSC to improve hepatocyte viability and function
Our in vitro experiments have shown that co-culture of human hepatocytes with umblical cord-derived MSCs prolongs the survival and the function of hepatocytes (Fitzpatrick et al. 2013). MSCs have also been shown to decrease inflammatory signalling in a number of models of inflammation. Their dual effects would therefore make MSCs the perfect partner cells to transplant with hepatocytes. Our team is currently investigating this hypothesis.
- The use of non-parenchymal cells and extra-cellular matrices to mimic the hepatocyte niche
Hepatocytes are the main cell of the liver but are embedded in a niche composed of extra-cellular matrix and a number of other support cell types (non-parenchymal cells). The composition and stiffness of the matrix, as well as the presence of support cells are necessary to maintain the viability and function of hepatocytes. Part of our research consequently focuses on analysing the potential of non-parenchymal cells to support hepatocytes. Overlapping our work on the alginate beads, we also investigate the effect of different matrix composition on cell survival and metabolism.
- Prevention of early cell loss after hepatocyte transplantation
The outcome of hepatocyte transplantation has been limited by the low efficiency of integration of transplanted cells into the host liver parenchyma. Most of the transplanted hepatocytes (>70 %) are lost within 24 hours. The main aim of this project is to investigate the mechanisms of this early cell loss in vitro and in vivo and to attempt to identify methods to prevent this occurring in order to increase hepatocyte engraftment. Preliminary studies performed on the instant blood-mediated inflammatory reaction (IBMIR) with hepatocytes showed rapid activation of coagulation and complement. In collaboration with Dr Richard Smith of the Protein Therapeutics Laboratory, MRC Centre for Transplantation at Guy’s we are investigating novel peptide agents with membrane-anchoring technology to allow retention on cell surfaces, which can control coagulation and protease-activated receptors and regulate complement. It is hoped that the findings of the project will be translated to clinical application in hepatocyte transplantation.
Over the years, our research has generously been funded by the following organisations: