Bile ductular cells are simple cuboidal epithelial cells which line the short tubular biliary connections linking the bile canalicular network of the hepatocyte to the intrahepatic bile ducts located within the portal tracts of liver. Hyperplasia of these cells has been shown to be a common response in a variety of clinical and experimental forms of carcinogen and noncarcinogen-induced liver injury. Furthermore, the proliferative response exhibited in liver by """"""""oval"""""""" or bile ductular cells as a result of treatments with many hepatocarcinogens has been found to be much less orderly than the well differentiated pattern of bile ductular hyperplasia produced by noncarcinogenic treatments, such as bile duct ligation or chronic feeding of Alpha-naphthyl isothiocyanate (ANIT). Carcinogen-induced oval cell proliferation, but not well differentiated bile ductular hyperplasia, has also been demonstrated to be associated with the appearance of hepatic transitional cells possessing a morphology and functions that are intermediate between those of the hepatocyte and the bile ductular cell. The present proposal is designed to establish and then rigorously characterize novel primary and clonal cultures of well differentiated hyperplastic bile ductular cells isolated from the livers of bile duct ligated or ANIT-treated rats or hamsters, and to compare their cellular properties with those of oval and transitional cells obtained from rat liver following chronic administration of a choline-deficient diet containing 0.05% DL-ethionine. Specifically, important factors to be evaluated in the development of these cultures include substratum, basal medium conditions, regulatory substances known to influence epithelial cell differentiation or proliferation, and co-cultivation with normal adult liver hepatocytes or with fibroblasts derived from isolated cholangiofibrotic liver tissue. These cultured bile ductular and oval cells and their derivatives will then be characterized in terms of their morphology, growth kinetics, karyotype, selected enzymatic and metabolizing functions, such as gamma-glutamyl transpeptidase, leucine amino peptidase and alkaline phosphatase marker enzyme activites, and by their ability to become transformed in vitro either spontaneously or following exposures to select direct-acting or procarcinogens. Transplantation studies will also be performed in order to determine if bile ductular cells from bile duct ligated or ANIT-treated rodents can exhibit transitional hepatic cell functions when inoculated into the fat pads or spleen of host animals exhibiting severe hepatic injury.
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