ORIGIN AND FATE OF OVAL CELLS IN DIPIN-INDUCED HEPATOCARCINOGENESIS IN THE MOUSE

We have studied the development and differentiation of oval cells in t he Dipin model of hepatocarcinogenesis in the mouse and compared this process to generation of biliary, epithelial cells by bile duct ligati on using light and electron microscopy. The Dipin model of hepatocarci nogenesis 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 p rovided evidence that regeneration of parenchyma occurred via oval cel l proliferation and subsequent differentiation into hepatocytes that r eplaced the degenerating hepatocytes. Both autoradiographic and morpho logical data indicated that oval cells were derived from ductular cell s of Hering canals. The first oval cells labeled with [H-3]thymidine w ere similar in size and ultrastructure to ductular cells of Hering can als 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 duc ts. Both growth patterns and ultrastructure of oval cells were differe nt 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 w as heterogeneous in terms of proliferating potential. A proportion of proliferating cells (38 to 45%) in the Hering canals and small oval ce ll ducts located in the periportal areas was similar throughout the pe riod of oval cell development. The extent of proliferation of oval cel ls decreased from 62% at the stage of active migration into the acinus to 22% at maximum formation of oval cell ducts. These data suggest th at in the mouse fiver cells of the terminal biliary ductules harbor th e hepatic stem cell compartment from which oval cells, capable of diff erentiating into hepatocytes, may be derived.