Overview of recent experimental studies on liver stem cells.

Since our review of the experimental evidence for liver epithelial stem cells in 1997, a large body of new data has been added. The new studies have focused on the analysis of differentiation of candidate liver stem cells when they are transplanted into the liver in vivo and when cultured in vitro under defined conditions. The new studies that we review substantiate the existence of stem cells that can generate new lineages of hepatocytes and cholangiocytes, especially in severely damaged livers. However, the recent studies have introduced new areas of controversy about the essential nature of liver stem cells and about appropriate methods to analyze their properties and functions. Whether the major stem cell for hepatocytes and cholangiocytes is an endodermal epithelial cell that resides in the liver or a mesodermal cell from bone marrow is a current area of controversy. Another controversial topic concerns the appropriateness of cell culture to analyze liver epithelial cells. Both of these situations are addressed, if not yet conclusively solved, by the new data. From our review of recent data, we conclude that the major liver stem cell is an epithelial cell that is a liver resident, and that cell culture is a valuable, even necessary, adjunct for analyzing the properties of liver stem cells and for eventually identifying the molecular mechanisms that regulate their activation, proliferation, and differentiation.