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Cell Lineages and Oval Cell Progenitors in Rat Liver Development¹

Department of Biology, Faculty of Science, Shizuoka University, Shizuoka, Japan [N. S.], and Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912 [J. M. L., N. F.]

We determined whether the formation of the hepatic primordium in the rat is associated with the expression of liver-specific markers. Further, we examined the origin of intra- and extrahepatic bile ducts and tried to establish whether there are cell types in the developing liver that might correspond to "stem-like" cells ("oval cells") that proliferate during carcinogenesis and toxic injury in adult livers. Using in situ hybridization and immunohistochemical methods, we show that -fetoprotein (AFP) mRNA is detected in cells of the ventral foregut at 10.5 days of development and that the protein is first detected 1 day later. Thus, AFP transcription occurs before liver morphogenesis, and translation of the protein is first detected when liver cords are being formed, indicating that AFP expression in endodermal cells signals their commitment toward the liver lineage. Although albumin is considered a trait of differentiated hepatocytes, its mRNA was first detected just 1 day later than the AFP message. An analysis of the expression of lineage-specific cytokeratins (cytokeratins 7, 9, 18, and 19), surface markers, and histochemical determination of -glutamyl transferase activity and glycogen revealed that (a) hepatoblasts undergo gradual maturation throughout liver development, (b) AFP- and albumin-containing hepatoblasts gave rise to intra-and extrahepatic bile ducts, and (c) hepatoblasts forming primitive intra-hepatic bile ducts during liver development have markers similar to those expressed by stem-like cells that proliferate during liver carcinogenesis.

¹ Supported by Grant CA35249 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 11/12/90. Accepted 3/ 4/91.

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