CELLULAR AND MOLECULAR BIOLOGY OF THE HEPATIC STEM CELL COMPARTMENT

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The existence of a stem cell compartment in rat liver is now well established, and considerable body of data indicates that the human liver also contains a stem cell compartment. The research is currently focused on defining the cellular and molecular biology of this stem cell compartment in normal and neoplastic liver (see also Project No. ZOICPO5262). Rat liver epithelial (RLE) cells share many cellular markers with the "oval" cell population found in adult rat liver after a certain type of hepatic injury. We have hypothesized that these cell types are derived from a common stem cell compartment present in the adult liver. Investigation of patterns of cytokeratin expression in adult and fetal livers and during early stages of "oval" cell proliferation revealed that cytokeratin 14 was transiently expressed in early fetal hepatocytes and oval cells. The expression of cytokeratin 14 in adult rat liver was found in small epithelial cells in the periductal space. These results indicate that cytokeratin 14 may be a marker for early progeny derived from the hepatic stem cell compartment. Transplantation of spontaneous transformed RLE cells in vitro resulted in formation of highly differentiated hepatocellular carcinomas. We have examined the stages of this in vitro transformation of RLE cells and discovered that coincident with the transformation process is an activation of a hepatocytic differentiation program that includes expression of albumin, alpha-fetoprotein, switching from connexin 43 to connexin 32 expression, and the expression of cytokeratin 8 and 18. These results formally demonstrate that progeny from the hepatic stem cell compartment such as the RLE cells and "oval" cells in vivo can be a target cell population in hepatocarcinogenesis and a precursor for hepatocellular carcinomas. We have recently obtained evidence that epithelial cell lines obtained from adult pancreas have, similar to the RLE cells, an extended capacity for proliferation in vitro, and share close lineage relationship to the RLE cells. These data indicate a common cell of origin for primitive cells isolated from rat liver and pancreas.