CELLULAR AND MOLECULAR BIOLOGY OF THE HEPATIC STEM CELL COMPARTMENT

大鼠肝脏中干细胞室的存在现在是很好的 大量的数据表明，人类的肝脏 还包括一个干细胞室。这项研究目前主要集中在 关于定义干细胞的细胞和分子生物学的问题 正常肝脏和肿瘤肝脏的隔室(另见项目编号。 ZOICPO5262)。大鼠肝上皮(RLE)细胞共享许多 在成年大鼠肝脏中发现的“卵圆形”细胞群的标志物 某种类型的肝脏损伤。我们假设这些细胞 类型是从常见的干细胞隔间派生出来的 成人肝脏。细胞角蛋白表达模式的研究 成人和胎儿肝脏以及“卵圆形”细胞的早期阶段 增殖实验显示细胞角蛋白14在细胞中瞬时表达 早期胎肝细胞和卵圆细胞。细胞角蛋白14的表达 成年大鼠肝脏可见导管周围的小上皮细胞 太空。这些结果表明，细胞角蛋白14可能是一种 早期的后代来源于肝脏干细胞室。 自发转化的RLE细胞体外移植的结果 高分化肝细胞癌的形成。我们有 检测了RLE细胞体外转化的各个阶段和 发现与转变过程一致的是一个 激活肝细胞分化程序，包括 白蛋白、甲胎蛋白的表达，从连接蛋白43切换到 连接蛋白32的表达，以及细胞角蛋白8和18的表达。 这些结果正式证明了来自肝干细胞的后代 体内的RLE细胞和“卵圆形”细胞等细胞室可以是 肝癌发生中的靶细胞群及其前驱作用 肝细胞癌。我们最近获得的证据表明 从成人胰腺获得的上皮细胞系具有类似于 RLE细胞，一种扩展的体外增殖能力，并分享 与RLE细胞的血缘关系密切。这些数据表明 大鼠肝脏和肝脏分离的原始细胞的共同来源 胰腺。

The existence of a stem cell compartment in rat liver is now well established, and considerable body of data indicates that the human liver also contains a stem cell compartment. The research is currently focused on defining the cellular and molecular biology of this stem cell compartment in normal and neoplastic liver (see also Project No. ZOICPO5262). Rat liver epithelial (RLE) cells share many cellular markers with the "oval" cell population found in adult rat liver after a certain type of hepatic injury. We have hypothesized that these cell types are derived from a common stem cell compartment present in the adult liver. Investigation of patterns of cytokeratin expression in adult and fetal livers and during early stages of "oval" cell proliferation revealed that cytokeratin 14 was transiently expressed in early fetal hepatocytes and oval cells. The expression of cytokeratin 14 in adult rat liver was found in small epithelial cells in the periductal space. These results indicate that cytokeratin 14 may be a marker for early progeny derived from the hepatic stem cell compartment. Transplantation of spontaneous transformed RLE cells in vitro resulted in formation of highly differentiated hepatocellular carcinomas. We have examined the stages of this in vitro transformation of RLE cells and discovered that coincident with the transformation process is an activation of a hepatocytic differentiation program that includes expression of albumin, alpha-fetoprotein, switching from connexin 43 to connexin 32 expression, and the expression of cytokeratin 8 and 18. These results formally demonstrate that progeny from the hepatic stem cell compartment such as the RLE cells and "oval" cells in vivo can be a target cell population in hepatocarcinogenesis and a precursor for hepatocellular carcinomas. We have recently obtained evidence that epithelial cell lines obtained from adult pancreas have, similar to the RLE cells, an extended capacity for proliferation in vitro, and share close lineage relationship to the RLE cells. These data indicate a common cell of origin for primitive cells isolated from rat liver and pancreas.