Animal Models for Assessing the Contribution of Stem Cells to Liver Development

Abstract

A lineage progression from small undifferentiated cells to bipotent cells expressing both biliary and hepatocytic products to unipotent mature hepatocyte or bile duct cells has been identified by a number of laboratories during liver development or in response to injury or carcinogenesis. This leads to a multitiered system of cell renewal designed to provide alternative pathways to liver regeneration that will ensure retention of the reestablishment of liver functionality even when mature hepatocytes and ductal cells have been severely compromised. Recent experiments indicate that the small undifferentiated liver progenitor cell (LPC) may actually be bone marrow derived. Selective activation of LPCs may be accomplished in rodents by combining agents or events that activate proliferation with those that inhibit hepatocyte proliferation. Different injury or carcinogenesis regimens applied to rodents appear to activate the liver lineage cells at different levels including small intraportal undifferentiated cells, bipotent ductal cells, and small hepatocytes. Early lineage (oval) cells also are seen in the livers of humans with chronic liver injury or carcinogen exposure and are a consistent feature of viral hepatocarcinogensis in both animals and humans. Experimental models of chemical hepatocarcinogenesis also implicate LPCs as the cells of origin of hepatocellular carcinoma. Identification of the potential of a cell using transplantation into the liver has been complicated by several confounding factors, but it has been shown that adult hepatocytes have the capacity to replace extensively damaged liver tissue by undergoing a number of cell divisions. This clearly shows that the mature hepatocyte is capable of sustained symmetric divisions, but the proliferation capacity of putative LPCs has not been determined in this fashion. Future directions in using proliferation of endogenous or transplanted stem cells for replacement or gene therapy seem boundless, but much more needs to be known about the liver stem cell lineage and how to control its potential in vivo.