Liver transplantation offers hope to children born with metabolic diseases, to people suffering from acute liver failure, and to those who have long term liver disease such as that caused by the worldwide epidemic of Hepatitis C. Unfortunately the demand for healthy liver tissue for transplantation far exceeds the available supply. A renewable source of human liver cells would also make the development of safe new medicines faster and more reliable. Many drugs are metabolized in the liver, but this metabolism can result in the conversion of a safe medicine into a toxin, or can convert an active compound into an inactive and ineffective substance. Tests in animals do not always predict how the human liver will metabolize drugs. Thus, during the drug development process, many compounds drop out late because of unpredictable results of human metabolism, adding greatly to the cost of
Human embryonic stem cells, or pluripotent stem cells made by reprogramming adult cells, could in principle provide a renewable source of liver cells for transplantation and drug testing. Previous work has shown that it is possible to convert embryonic stem cells into cells resembling liver cells, but the methods described are inefficient and do not yield pure populations of functionally mature cells. While most work to date has attempted to isolate mature liver cells directly, research in several laboratories has recently identified a stem cell population in the fetal and adult liver capable of extensive growth and regeneration. Our preliminary work shows that it is possible to convert embryonic stem cells into cells that resemble these stem cells found in fetal or adult human liver. This project will focus on identifying the most efficient way to convert stem cells in liver progenitors, to grow these progenitors in the laboratory, and to convert them into mature liver cells. We will test their ability to engraft and function in animal models of liver repair. By producing pure, well characterized populations of liver stem cells on a large scale from embryonic stem cells, we will overcome a major bottleneck to the application of stem cell technology to liver disease.
End stage liver disease is one of the leading causes of death in California. Minority populations including Native Americans, Hispanics, and African Americans are particularly affected. There is an acute shortage of liver tissue for transplantation; it is estimated that 15% of patients die on the waiting lists. The development of cell replacement therapy for liver disease could greatly enhance the therapeutic options for treatment of children with metabolic disorders, or adults with acute liver failure in the near term future. In the long run, it may be possible to use such approaches for the treatment of chronic liver disease such as that caused by Hepatitis C, if transplanted cells could be engineered to resist viral infection. Thus, a novel source of healthy tissue could impact strongly on the treatment of liver disease. Production of human liver cells in the laboratory also could greatly accelerate the process of drug development. Since the liver accounts for most drug metabolism, and animal models do not necessarily predict how the human body will handle drugs, many compounds fail in the final stages of testing at a great economic cost when it becomes apparent that the human liver inactivates the drug or worse converts it to a toxic compound. Human cell culture models of liver metabolism have the potential to address this hurdle in the drug development process and would be of great economic value. This proposal addresses both the clinical problems of liver cell transplantation and the practical laboratory use of human liver cells in the pharmaceutical industry. It has the potential to impact on human health and to provide significant economic benefit to the State.