Generation of safe and therapeutically effective human induced hepatocyte-like cells

Although the liver can regenerate itself, chronic or overwhelming damage can cause life-threatening liver failure. Currently, the only therapy for liver failure is liver transplantation. Because the supply of cadaveric livers or liver tissue from living donors far exceeds the demand, physicians and researchers seek to develop new therapies to save the lives of patients with liver failure. One promising strategy is transplantation of hepatocytes, the cells of the liver that provide most of its functions and that are defective in liver failure. To make hepatocyte transplantation available to all patients who could benefit, a cell source other than scarce donor livers has to be established. In contrast to hepatocytes, skin cells can be readily obtained and expanded in culture. Therefore, the recent discovery that skin cells can be converted into hepatocytes by transfer of a few genes suggests a promising new source of hepatocytes. To develop transplantation of such cells as a therapy for liver failure, we aim to identify which readily available human cell type—skin, blood or fat cells—can be most efficiently converted into hepatocytes using methods of temporary gene transfer. Importantly, the therapeutic efficacy and safety of these induced hepatocytes will be rigorously tested in animal models of human liver failure. If successful, our project will establish the feasibility of therapy of liver failure with cells derived from a patient’s own readily available non-liver cells.