Phenotypic fidelity (or not?) of epithelial cells in the liver.
Phenotypic fidelity (or not?) of epithelial cells in the liver.
复制标题
DOI：
10.1002/hep.25703
复制
发表时间：
2012-06
期刊：
影响因子：
13.5
通讯作者：
Michalopoulos, George K
中科院分区：
文献类型：
--
作者：
Michalopoulos, George K
最近的证据与流行的观点相矛盾，即成人肝脏的稳态和再生是由谱系限制性肝细胞和胆管上皮细胞的自我复制介导的。这些新数据表明，肝祖细胞不仅仅充当慢性肝损伤的后备系统；相反，它们在急性损伤后也会产生肝细胞，并且实际上是正常肝细胞周转期间新肝细胞的主要来源。此外，其他证据表明，肝细胞能够进行谱系转换，在胆道损伤期间充当胆道上皮细胞的前体。为了测试这些概念，我们基于带有腺相关病毒载体的成年 Rosa26 报告小鼠的所有肝细胞中的定时和特异性 Cre 重组酶表达和标记基因激活，生成了肝细胞命运追踪模型。我们发现新形成的肝细胞源自正常肝脏中先前存在的肝细胞，并且肝祖细胞对急性肝细胞再生的贡献微乎其微。此外，我们没有发现任何证据表明胆道损伤诱导肝细胞转化为胆道上皮细胞。因此，这些结果恢复了先前盛行的肝脏稳态和再生范例。此外，我们的新载体系统将成为肝细胞中固定序列的定时、高效和特定循环的有价值的工具。
Recent evidence has contradicted the prevailing view that homeostasis and regeneration of the adult liver are mediated by self duplication of lineage-restricted hepatocytes and biliary epithelial cells. These new data suggest that liver progenitor cells do not function solely as a backup system in chronic liver injury; rather, they also produce hepatocytes after acute injury and are in fact the main source of new hepatocytes during normal hepatocyte turnover. In addition, other evidence suggests that hepatocytes are capable of lineage conversion, acting as precursors of biliary epithelial cells during biliary injury. To test these concepts, we generated a hepatocyte fate-tracing model based on timed and specific Cre recombinase expression and marker gene activation in all hepatocytes of adult Rosa26 reporter mice with an adenoassociated viral vector. We found that newly formed hepatocytes derived from preexisting hepatocytes in the normal liver and that liver progenitor cells contributed minimally to acute hepatocyte regeneration. Further, we found no evidence that biliary injury induced conversion of hepatocytes into biliary epithelial cells. These results therefore restore the previously prevailing paradigms of liver homeostasis and regeneration. In addition, our new vector system will be a valuable tool for timed, efficient, and specific loop out of floxed sequences in hepatocytes.