Complex differentiation and facultative regenerative abilities are hallmarks of hepatocytes, the cells of the liver that provide its manifold functions. We are interested in identifying key regulators of these programs in order to direct the functional differentiation of immature cells from abundant cell sources which could then be used for therapy of diseases impairing hepatocyte function. In addition, this knowledge may provide a means to restore or unlock the functional and regenerative capabilities of ailing hepatocytes or other differentiated cell types, respectively. Hepatocytes derive from liver progenitors which expand and commit to one of two possible cell fates during late embryonic development. We aim to obtain a detailed understanding of these processes which we believe is essential for their recapitulation in cells intended for transplantation.
Intriguingly, hepatocyte progenitor cell characteristics could explain why liver cancers are refractory to therapy and we are therefore interested in identifying and isolating the cells that give rise to liver cancer. The ability to track the emergence and development of these cells in vivo will facilitate specific analyses of the molecular mechanisms involved in liver cancer formation. Understanding the biology of liver cancer initiation would potentially enable early detection and effective eradication.
Intrahepatic bile duct cancer, a rare and deadly form of cancer, known formally as cholangiocarcinoma, has been assumed to derive from cells in the bile ducts of the liver. However, an international team, led by Holger F. Willenbring, M.D., Ph.D., Associate Professor of Developmental and Stem Cell Biology in the Division of Transplant Surgery, Xin Chen, Ph.D.,and other prominent researchers, has shown that the disease actually may develop when hepatocytes, the most common type of liver cell, are transformed into intrahepatic cholangiocarcinoma cells or (ICCs), a process scientists previously thought all but impossible. The researchers were able to induce cholangiocarcinoma in mice by activating two well-known genes, Notch and AKT. Their discovery has therapeutic potential in that drugs targeting the aberrant activity of those genes could lead to the effective treatments currently lacking and to improved long-term survival.
Read full peer-reviewed article in JCI, Cholangiocarcinomas can originate from hepatocytes in mice
UCSF scientists have received two large grants from the California Institute for Regenerative Medicine to refine their human embryonic stem cell-based strategies for treating neurological diseases and liver failure. A team led by Mark Zern, MD, of the University of California, Davis, and including co-principal investigator Holger Willenbring, M.D., (pictured left) Assistant Professor of Surgery in the Division of Transplant Surgery at UCSF will use their $5 million grant to develop therapeutically effective liver cells, or hepatocytes, from human embryonic stem cells. According to Willenbring, results have been promising. "Now we have to put the strategy to the test and develop it further in animal models, with the ultimate goal of rescuing liver function in patients who would otherwise die of liver failure."
"International Stem Cell Corporation announced today that its human parthenogenetic stem cell lines will be used in studies aimed at creating liver cells to treat human liver disease. ......Holger Willenbring, MD, UCSF assistant professor of surgery, will direct the research. "The fact that Dr. Willenbring and the University of California at San Francisco are testing the ability of ISCO's human parthenogenetic stem cells to form liver cells is a strong validation of their potential value in creating therapeutic cells that have significant immune rejection advantages and significant ethical advantages," said Jeffrey Janus, ISCO's President."
Dr. Nancy Ascher and Dr. Holger Willenbring were interviewed by PBS NewsHour correspondent Spencer Michaels about the transformation of embryonic stem cells into new liver cells as a treatment for patients.