Contributions of Hepatocytes and Bile Ductular Cells in Ductular Reactions and Remodeling of the Biliary System after Chronic Liver Injury
Contributions of Hepatocytes and Bile Ductular Cells in Ductular Reactions and Remodeling of the Biliary System after Chronic Liver Injury
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DOI：
10.1016/j.ajpath.2014.07.005
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发表时间：
2014-11-01
影响因子：
6
通讯作者：
Nishikawa, Yuji
中科院分区：
文献类型：
--
作者：
Nagahama, Yasuharu;Sone, Masayuki;Nishikawa, Yuji
成熟的肝细胞被认为具有胆管转分化的能力，但肝细胞是否以及如何参与慢性肝病的胆管反应尚未阐明。我们采用三维胶原凝胶培养方法和体内肝脏再分化模型，将Alb-CRE x ROSA26R小鼠的β-半乳糖苷酶阳性肝细胞移植到野生型小鼠的肝脏中，研究了小鼠肝细胞能否在体外转分化为胆管细胞。在Mx1-Cre x ROSA26R小鼠的肝细胞谱系追踪模型中，我们进一步研究了固有肝细胞在胆管反应中的相对贡献。在胶原凝胶中，肝细胞表现出与胆管样表型相关的分支形态发生。在肝脏再繁殖模型中，发现了许多β-半乳糖苷酶阳性的肝细胞来源的胆管结构；这些结构在肝损伤后显著增加。在Mx1-Cre x ROSA26R小鼠中，肝细胞来源的胆管在门静脉周围和小叶中心的胆管反应中都有相对较少但显著的贡献。随着小叶中心小管反应的进展，门静脉导管或小管向损伤区移动，并与肝细胞来源的小管连接，使门管失去胆道结构。我们的结论是，肝细胞和咬合管或小管是胆管反应的重要来源，肝内胆管系统在慢性肝损伤时经历了显着的重构。
Mature hepatocytes are suggested to possess a capacity for bile ductular transdifferentiation, but whether and how hepatocytes contribute to ductular reaction in chronic liver diseases has not been elucidated. We examined whether mouse hepatocytes can transdifferentiate into bile ductular cells in vitro, using a three-dimensional collagen gel culture method, and in vivo, using a liver repopulation model in which beta-galactosidase-positive hepatocytes from Alb-Cre x ROSA26R mice were transplanted into the liver of wild-type mice. We further examined the relative contribution of intrinsic hepatocytes in ductular reaction in a hepatocyte lineage-tracing model using Mx1-Cre x ROSA26R mice treated with polyinosinic-polycytidylic acid. Within collagen gels, hepatocytes exhibited branching morphogenesis associated with the emergence of bile duct-like phenotype. In the Liver repopulation model, many beta-galactosidase- positive, hepatocyte-derived bile ductular structures were identified; these markedly increased after liver injury. In Mx1-Cre x ROSA26R mice, relatively minor but significant contributions of hepatocyte-derived bile ductules were observed in both periportal and centrilobular ductular reaction. As the centrilobular ductular reaction progressed, the portal ducts or ductules migrated toward the injured area and joined with hepatocyte-derived ductules, Leaving the portal tract without biliary structures. We conclude that hepatocytes and bite ducts or ductules are important sources of ductular reaction and that the intrahepatic biliary system undergoes remarkable remodeling in response to chronic liver injury.