Autoradiography of "oval cells" appearing rapidly in the livers of rats fed N-2-fluorenylacetamide in a choline devoid diet.

Autoradiographic analysis of liver sections from rats fed the hepatocarcinogen N-2-fluorenylacetamide (FAA) in a choline devoid (CD) diet suggests that proliferating small "oval" cells arise from a few small portally-situated cells, and spread rapidly across the entire liver lobule. Small cells with detectable grains are first located where liver plates meet the portal areas. This cell type gradually increases in number over a 10-12 day period, then proliferates rapidly. After 28 days, microscopic nodules consisting of heavily labeled large eosinophilic cells appear, whereas residual hepatocytes are not labeled. Combined immunofluorescent and autoradiographic labeling studies reveal that many of the small cells contain AFP; approximately half of the alpha-fetoprotein-containing cells are labeled with [3H]thymidine (dT). Feeding CD-FAA diets to rats with hepatocytes prelabeled with [3H]dT after 70% hepatectomy 7 weeks earlier provides data which suggest that small "oval" cells do not arise from prelabeled hepatocytes but, instead, infiltrate the prelabeled hepatocytes during the diet induced proliferative phase. We conclude that "oval" cells arise from a small number of portal cells, not from hepatocytes. Exact identification of the oval cell precursor is not possible, but it could be a "stem" cell. Although hepatocyte-like properties are found in small cells (e.g., albumin staining), there is no evidence that they differentiate into normally functioning hepatocytes.