Pre-clinical study of hepatocyte transplantation using human embryonic stem cell-derived hepatocytes

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In the UK liver disease is the fifth most common cause of death, and it is rising dramatically. Whole organ liver transplantation is limited in its availability, it is not capable of meeting the clinical need. Other options include infusing suspensions of liver cells into patients with liver disease, but this is again limited by a lack of livers. Thus, there is a clear need to expand functional liver cells for clinical applications such as liver cell transplantation. In collaboration with Geron, we have generated highly efficient methods to direct human embryonic stem cells down the liver cell lineage resulting in 90% purity. There are two main issues to be overcome before these cells can be used clinically. (1) The delivery of these cells within the liver needs to be improved as at present we can only deliver small numbers of cells. (2) There are concerns that cells derived from embryonic stem cells can form tumours after transplantation.We will identify the molecules which control the entry of infused liver cells into the liver, and augment their activity, thus improving the number of cells entering. Initially we will do this with liver cells in a complex multi-cellular culture model which mimics what happens in a living organ. Having identified which molecules are most important in improving the engraftment of liver cells in tissue culture we will then proceed to a mouse model where we can test the effects of stimulating these molecules in a living organism. Of note we will use a mouse which has a metabolic liver disorder, which means that as well as being able to quantify the number of human liver cells which have engrafted within the mouse liver we can also see what impact they have had on the metabolic defect. This is timely, as it is likely that the first clinical studies with such cells will occur in patients with metabolic liver disease.By purifying the population of liver cells we infuse as well as limiting the route of administration we intend to demonstrate that we can completely abrogate the risk of tumour development. There is however a theoretical risk that transplanting human embryonic stem liver cells into a mouse will not adequately assess the risk of tumour development. As a fail-safe therefore we will also perform experiments in which we infuse mouse embryonic stem liver cells into the mouse to exclude this possibility.