Origin and fate of oval cells in dipin-induced hepatocarcinogenesis in the mouse

Abstract

We have studied the development and differentiation of oval cells in the Dipin model of hepatocarcinogenesis in the mouse and compared this process to generation of biliary epithelial cells by bile duct ligation using light and electron microscopy. The Dipin model of hepatocarcinogenesis consists of a single injection of an alkylating drug, Dipin (1,4-bis[N,N'-di(ethylene)-phosphamide]-piperazine), followed by partial hepatectomy. The Dipin treatment resulted in irreversible damage and gradual death of hepatocytes by necrosis and apoptosis. Earlier work provided evidence that regeneration of parenchyma occurred via oval cell proliferation and subsequent differentiation into hepatocytes that replaced the degenerating hepatocytes. Both autoradiographic and morphological data indicated that oval cells were derived from ductular cells of Hering canals. The first oval cells labeled with [3H]thymidine were similar in size and ultrastructure to ductular cells of Hering canals with whom intracellular connections existed. The proliferation of ductular cells of Hering canals gave rise to a new system of oval cell ducts that spread into the liver acinus. In the periportal areas, the transition of oval cells into hepatocytes was observed inside the ducts. Both growth patterns and ultrastructure of oval cells were different from the biliary epithelial cells in bile duct-ligated liver. Also, oval cells retained the property to interact with adjacent hepatocytes through desmosomes and intermediate junctions. Oval cell population was heterogeneous in terms of proliferating potential. A proportion of proliferating cells (38 to 45%) in the Hering canals and small oval cell ducts located in the periportal areas was similar throughout the period of oval cell development. The extent of proliferation of oval cells decreased from 62% at the stage of active migration into the acinus to 22% at maximum formation of oval cell ducts. These data suggest that in the mouse liver cells of the terminal biliary ductules harbor the hepatic stem cell compartment from which oval cells, capable of differentiating into hepatocytes, may be derived.