The role of progenitor cells in repair of liver injury and in liver transplantation.

There are three levels of cells in the hepatic lineage that respond to injury or carcinogenesis: the mature hepatocyte, the ductular "bipolar" progenitor cell, and a putative periductular stem cell. Hepatocytes are numerous, and respond rapidly to liver cell loss by one or two cell cycles but can only produce other hepatocytes. The ductular progenitor cells are less numerous, may proliferate for more cycles than hepatocytes, and are generally considered "bipolar," i.e., they can give rise to biliary cells or hepatocytes. Periductular stem cells are rare in the liver, have a very long proliferation potential, and may be multipotent. Extrahepatic (bone marrow) origin of the periductular stem cells is supported by recent data showing that hepatocytes may express genetic markers of donor hematopoietic cells after bone marrow transplantation. These different regenerative cells with variations in potential for proliferation and differentiation may provide different sources of cells for liver transplantation: hepatocytes for treatment of acute liver damage, liver progenitor cell lines for liver-directed gene therapy, and bone marrow-derived cells for chronic long-term liver replacement. A limiting factor in the success of liver cell transplantation is the condition of the hepatic microenvironment in which the cells must proliferate and set up housekeeping.