HEPATIC OVAL CELLS IN CULTURE AND IN VIVO

描述（改编自研究者摘要）：证据是 先前从严重肝损伤的新型体内大鼠模型中获得 和呋喃诱导的肝内胆管癌的发生， 提示典型增生胆管上皮细胞可 改变它们沿着胆管细胞谱系分化的承诺 以便作为化生小细胞兼性祖细胞 膀胱样腺体或独特的导管状肝细胞样细胞。 此外，胆汁细胞来源的“肠- 型”腺癌优先发展在肝脏的呋喃 治疗的老鼠为了更明确地确定是否为典型增生性 胆管上皮细胞能够作为一种兼性 多能干细胞样细胞在胆管癌发生过程中的作用， 严重肝损伤的类型，以下具体目标将是 追求：（1）实现培养群体的肿瘤转化 大鼠增生的胆管上皮细胞明显 与增殖的大鼠肝卵圆细胞群不同， 首次建立差异化潜力的目的 当这些更典型的胆管细胞转化为它们的 通过选择体外转化处理的致瘤表型;（2） 基于初步发现，确定（a）共转染 c-met原癌基因编码肝细胞受体， 生长因子/分散因子（HGF/SF）和HGF/SF生长因子基因 培养的大鼠增生性胆管上皮细胞 （B）如果这些相应的细胞的过表达 基因可能与转化的细胞的优先分化相关， 沿着小肠谱系的胆管细胞;和（3）使用间隙 连接基因作为分子生物标志物，以进一步建立 增生性胆管上皮细胞之间的谱系关系 型和导管肝细胞，形成在大鼠肝脏中的反应 呋喃引起的严重肝损伤。预计该 拟议研究产生的结果可能有助于 一个重要的方式来促进我们目前对肝脏的理解， 干细胞假说，以及大大增加我们目前的 肝胆管的细胞起源和组织发生的知识 癌的

DESCRIPTION (adapted from the investigator's abstract): Evidence was previously obtained from novel in vivo rat models of severe liver injury and intrahepatic cholangiocarcinogenesis induced by furan to strongly suggest that typical hyperplastic bile ductular epithelial cells can alter their commitment to differentiate along the biliary cell lineage so as to act as facultative cell progenitors of either metaplastic small intestinal-like glands or of unique ductular hepatocytic-like cells. Moreover, a very high incidence of biliary cell-derived "intestinal- type" adenocarcinomas preferentially developed in the livers of the furan treated rats. To more definitively establish if typical hyperplastic bile ductular epithelial cells are capable of acting as a facultative pluripotent stem-like cell during cholangiocarcinogenesis and in certain types of severe hepatic injury, the following specific aims will be pursued: (1) Achieve neoplastic transformation of cultured populations of rat hyperplastic bile ductular epithelial cells that are clearly distinct from proliferating rat liver oval cell populations for the purpose of establishing for the first time the differentiation potential of these more typical bile ductular cells when converted to their tumorigenic phenotype by selected in vitro transforming treatments; (2) Based on the preliminary findings, determine if (a) cotransfection of both the c-met protooncogene, which encodes the receptor for hepatocyte growth factor/scatter factor (HGF/SF), and the HGF/SF growth factor gene into cultured populations of rat hyperplastic bile ductular epithelial cells in tumorigenic, and (b) if the overexpression of these respective genes may correlate with a preferential differentiation of transformed biliary cells along the small intestinal lineage; and (3) Use gap junction genes as molecular biomarkers to further establish the temporal lineage relationship between hyperplastic bile ductular epithelial cell types and ductular hepatocytes that form in the rat liver in response to severe hepatic injury induced by furan. It is anticipated that the results generated by the proposed research are likely to contribute in a significant way to furthering our current understanding of the hepatic stem cell hypothesis, as well as to add considerably to our present knowledge of the cellular origins and histogenesis of hepatobiliary cancers.