Grant: Team Grant: CEEHRC - Full application

There are over 100 types of liver disease and left untreated, these diseases can develop into liver cirrhosis and potentially into hepatocellular carcinoma (HCC). Thousands of Canadians die each year from liver cirrhosis causing liver failure. Currently the only treatment for liver failure is a transplant. However, treatment is hindered by a shortage of donor tissue. Thus, viable alternatives to donor liver transplant are required. Many researchers are trying to develop methods to make hepatocytes, the main functional cell of the liver, in the laboratory from cells which are pluripotent, meaning that they can make many different types of cells. Human pluripotent stem cells (hPSCs) are differentiated into hepatocytes by mimicking the step-wise signals that are used to make hepatocytes in embryos. Amazingly, HCC exhibits gene expression patterns that are similar to an embryonic hepatocyte suggesting that development of HCC is related to a reversal of differentiation. In this proposal, we will explore the similarities and differences between HCC and hepatocytes generated from hPSCs. We are particularly interested in factors that regulate DNA packaging and, thus, are able to regulate the expression of genes. We will use genome-wide techniques to map the similarities and differences in these factors between hepatocyte differentiation and HCC development. From this, we will be able to build a picture of how changes in DNA packing can regulate HCC formation, which can lead to better diagnostics and therapeutics. Moreover, our work can contribute to the development of better methods for generating hepatocytes in the laboratory that can be used for transplantation, gene therapy, drug testing and bioartifical livers for bypass machines.