Braun Kristin M, Thompson Anne W, Sandgren Eric P
School of Veterinary Medicine, University of Wisconsin-Madison, 53706, USA.
Am J Pathol. 2003 Jan;162(1):195-202. doi: 10.1016/S0002-9440(10)63810-2.
Mice carrying an albumin-urokinase type plasminogen activator transgene (AL-uPA) develop liver disease secondary to uPA expression in hepatocytes. Transgene-expressing parenchyma is replaced gradually by clones of cells that have deleted transgene DNA and therefore are not subject to uPA-mediated damage. Diseased liver displays several abnormalities, including hepatocyte vacuolation and changes in nonparenchymal tissue. The latter includes increases in laminin protein within parenchyma and the appearance of cytokeratin 19-positive bile ductule-like cells (oval cells) both in portal regions and extending into the hepatic parenchyma. In this study, we subjected AL-uPA mice to two-thirds partial hepatectomy to identify the response of these livers to additional growth stimulation. We observed several changes in hepatic morphology. First, the oval cells increased in number and often formed ductules in the parenchyma. Second, this cellular change was accompanied by a further increase in laminin associated with single or clusters of oval cells. Third, desmin-positive Ito cells increased in number and maintained close association with oval cells. Fourth, these changes were localized precisely to uPA-expressing areas of liver. Regenerating clones of uPA-deficient cells appeared to be unaffected both by stromal and cellular alterations. Thus, additional growth stimulation of diseased uPA-expressing liver induces an oval cell-like response, as observed in other models of severe hepatic injury, but the localization of this response seems to be highly regulated by the hepatic microenvironment.
携带白蛋白-尿激酶型纤溶酶原激活剂转基因（AL-uPA）的小鼠会因肝细胞中uPA的表达而引发肝病。表达转基因的实质组织会逐渐被缺失转基因DNA的细胞克隆所取代，因此这些细胞不会受到uPA介导的损伤。患病肝脏呈现出多种异常，包括肝细胞空泡化和非实质组织的变化。后者包括实质组织中层粘连蛋白的增加以及门静脉区域和延伸至肝实质中的细胞角蛋白19阳性胆小管样细胞（卵圆细胞）的出现。在本研究中，我们对AL-uPA小鼠进行了三分之二部分肝切除术，以确定这些肝脏对额外生长刺激的反应。我们观察到肝脏形态发生了几种变化。首先，卵圆细胞数量增加，并且经常在实质组织中形成胆小管。其次，这种细胞变化伴随着与单个或成簇的卵圆细胞相关的层粘连蛋白的进一步增加。第三，结蛋白阳性的肝星状细胞数量增加，并与卵圆细胞保持密切联系。第四，这些变化精确地定位于肝脏中表达uPA的区域。uPA缺陷细胞的再生克隆似乎不受基质和细胞改变的影响。因此，对表达uPA的患病肝脏进行额外的生长刺激会诱导出类似卵圆细胞的反应，正如在其他严重肝损伤模型中所观察到的那样，但这种反应的定位似乎受到肝脏微环境的高度调控。
