Dabeva M D, Alpini G, Hurston E, Shafritz D A
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461.
Proc Soc Exp Biol Med. 1993 Dec;204(3):242-52. doi: 10.3181/00379727-204-43660.
Activation of liver progenitor cells was studied in rat liver induced to regenerate after carbon tetrachloride (CCl4) or D-galactosamine (GalN) injury. A change in the concentration of histone-3 mRNA was used as a marker for cell proliferation and the fetal form of alpha-fetoprotein (AFP) mRNA as a marker for fetal hepatoblasts. gamma-Glutamyltranspeptidase (GGT) and glutathione-S-transferase P were used as markers for activation of putative liver progenitor cells. After CCl4 administration, the proliferative response was high but confined primarily to parenchymal cells. No changes in the relative expression of albumin, glutathione-S-transferase P or insulin-like growth factor-II were observed. On the other hand, the level of AFP mRNA was increased modestly and predominantly in the nonparenchymal cell (NPC) fraction. After GalN administration, proliferation of NPC began within 24 hr, primarily in the portal area around the bile ducts. Activated cells were bile "duct-like" in appearance, had scant cytoplasm, and a pale, oval-shaped nucleus. On Day 2, they formed rows and clusters, expanding from the portal zone and invading the parenchyma, as well as proliferating in regions of focal necrosis. On Days 3 and 5, NPC expressing histone-3 mRNA expanded further, forming pseudoducts and islet-like structures (NPC structures) throughout the hepatic lobule. Proliferating NPC were positive for GGT. Some GGT-positive cells on Days 3 and 5 were also positive for fetal AFP mRNA. Expression of fetal AFP mRNA lagged behind that of GGT by 24 hr, was highest on Day 5, and then declined. Expression of albumin mRNA and glucose 6-phosphatase decreased during the first 48 hr after GalN administration and then resumed. These findings indicate that after GalN injury, the liver responds with activation of putative progenitor cells that proliferate and then differentiate through the hepatocyte lineage, whereas the regenerative response after CCl4 administration is primarily through proliferation of preexisting hepatocytes.
在四氯化碳（CCl4）或D-半乳糖胺（GalN）损伤后诱导再生的大鼠肝脏中，对肝祖细胞的激活进行了研究。组蛋白-3 mRNA浓度的变化被用作细胞增殖的标志物，而甲胎蛋白（AFP）mRNA的胎儿形式被用作胎儿肝母细胞的标志物。γ-谷氨酰转肽酶（GGT）和谷胱甘肽-S-转移酶P被用作假定肝祖细胞激活的标志物。给予CCl4后，增殖反应强烈，但主要局限于实质细胞。白蛋白、谷胱甘肽-S-转移酶P或胰岛素样生长因子-II的相对表达未见变化。另一方面，AFP mRNA水平适度升高，且主要在非实质细胞（NPC）部分升高。给予GalN后，NPC在24小时内开始增殖，主要在胆管周围的门管区。活化的细胞外观呈胆管样，细胞质稀少，细胞核苍白、呈椭圆形。在第2天，它们形成行和簇，从门管区扩展并侵入实质，同时在局灶性坏死区域增殖。在第3天和第5天，表达组蛋白-3 mRNA的NPC进一步扩展，在整个肝小叶形成假导管和胰岛样结构（NPC结构）。增殖的NPC对GGT呈阳性。第3天和第5天的一些GGT阳性细胞对胎儿AFP mRNA也呈阳性。胎儿AFP mRNA的表达比GGT滞后24小时，在第5天最高，然后下降。给予GalN后48小时内，白蛋白mRNA和葡萄糖6-磷酸酶的表达下降，然后恢复。这些发现表明，GalN损伤后，肝脏通过假定祖细胞的激活做出反应，这些祖细胞增殖然后通过肝细胞谱系分化，而给予CCl4后的再生反应主要是通过现存肝细胞的增殖。
