Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor
Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor
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DOI：
10.1002/hep.21536
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发表时间：
2007-04-01
期刊：
影响因子：
13.5
通讯作者：
Corlu, Anne
中科院分区：
文献类型：
--
作者：
Cerec, Virginie;Glaise, Denise;Corlu, Anne
肝肿瘤，表现为成熟的肝细胞和未分化的细胞合并胆管细胞和肝细胞表型，经常被描述。它们发生的机制尚不清楚。我们报告了从一个连续发展到慢性HCV感染的分化肿瘤中分离的人HepaRG细胞的分化和转分化行为。我们证明，在体外，增殖的HepaRG细胞分化向肝细胞样和胆汁样细胞汇合。如果肝细胞样细胞被选择性地分离并以高细胞密度培养，它们会增殖并保持其分化状态。然而，当以低密度接种时，它们通过双能祖细胞转分化成肝细胞和胆管谱系。因此，在uPA/SCID小鼠损伤的肝脏中移植未分化或分化的HepaRG细胞主要引起功能性人肝细胞浸润小鼠实质。对分化/转分化过程的分析表明：（1）HepaRG细胞的可逆分化命运与分化细胞中p21（CIP 1）和p53积累的缺乏有关;（2）HepaRG双能祖细胞表达体内肝祖细胞的主要标志物，并且细胞分化过程与其表达的丧失有关;（3）HepaRG细胞肝胆定向分化过程中，P-连环蛋白定位和HNF 3 β表达的早期和短暂变化与Notch 3表达上调有关。结论：我们的研究结果表明，巨大的可塑性转化的肝祖细胞，并建议转分化过程中可以提供池的肝祖细胞。此外，他们强调了单能肝细胞的转分化和增殖可能在混合和分化肿瘤的发展中合作的可能机制。
Hepatic tumors, exhibiting mature hepatocytes and undifferentiated cells merging with cholangiocyte and hepatocyte phenotypes, are frequently described. The mechanisms by which they occur remain unclear. We report differentiation and transdifferentiation behaviors of human HepaRG cells isolated from a differentiated tumor developed consecutively to chronic HCV infection. We demonstrate that, in vitro, proliferating HepaRG cells differentiate toward hepatocyte-like and biliary-like cells at confluence. If hepatocyte-like cells are selectively isolated and cultured at high cell density, they proliferate and preserve their differentiation status. However, when plated at low density, they transdifferentiate into hepatocytic and biliary lineages through a bipotent progenitor. In accordance, transplantation of either undifferentiated or differentiated HepaRG cells in uPA/SCID mouse damaged liver gives rise mainly to functional human hepatocytes infiltrating mouse parenchyma. Analysis of the differentiation/transdifferentiation process reveals that: (1) the reversible differentiation fate of HepaRG cells is related to the absence of p21(CIP1) and p53 accumulation in differentiated cells; (2) HepaRG bipotent progenitors express the main markers of in vivo hepatic progenitors, and that cell differentiation process is linked to loss of their expression; (3) early and transient changes of P-catenin localization and HNF3 beta expression are correlated to Notch3 upregulation during hepatobiliary commitment of HepaRG cells. Conclusion: Our results demonstrate the great plasticity of transformed hepatic progenitor cells and suggest that the transdifferentiation process could supply the pool of hepatic progenitor cells. Moreover, they highlight possible mechanisms by which transdifferentiation and proliferation of unipotent hepatocytes might cooperate in the development of mixed and differentiated tumors.