Ethanol negatively regulates hepatic differentiation of hESC by inhibition of the MAPK/ERK signaling pathway in vitro.
Ethanol negatively regulates hepatic differentiation of hESC by inhibition of the MAPK/ERK signaling pathway in vitro.
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DOI：
10.1371/journal.pone.0112698
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Duan Y
中科院分区：
文献类型：
--
作者：
Gao W;Zhou P;Ma X;Tschudy-Seney B;Chen J;Magner NL;Revzin A;Nolta JA;Zern MA;Duan Y
酒精侮辱在肝脏中触发复杂的事件，促进纤维化/炎症信号，在更严重的情况下，异常基质沉积。众所周知，成人肝脏的再生能力在酒精损伤时会受到损害。肝脏祖细胞/干细胞已被证明在肝脏再生中发挥重要作用--在应对各种慢性损伤时；然而，酒精对肝脏干细胞分化的影响尚不清楚。我们使用来源于hESCs的肝祖细胞，通过在肝细胞分化过程中将这些祖细胞暴露在乙醇中来研究乙醇对肝细胞分化的影响。我们发现乙醇以剂量依赖的方式负性调节hESC来源的肝祖细胞的肝脏分化。乙醇处理的细胞在G1/S检查点也有中度的细胞周期停滞，这与这些细胞中细胞周期蛋白D1的水平降低有关。乙醇处理特异性地抑制ERK的激活，但不抑制JNK和p38MAP信号通路。同时，暴露于乙醇的细胞中的WNT信号通路也减少。在评价这两条信号通路的抑制剂的作用后，我们确定ERK抑制剂复制了乙醇对肝细胞分化的作用，并减弱了Wnt/β-catenin信号转导，而Wnt的抑制剂仅部分复制了乙醇对肝细胞分化的作用。我们的结果表明，乙醇通过抑制MAPK/ERK信号通路，进而减弱WNT信号通路，对hESC来源的肝祖细胞的肝脏分化具有负性调节作用。因此，我们的发现为酒精调节hESC来源的肝祖细胞的细胞命运选择的机制提供了新的见解，所识别的途径可能为促进酒精损伤时的肝脏修复和再生提供治疗靶点。
Alcohol insult triggers complex events in the liver, promoting fibrogenic/inflammatory signals and in more advanced cases, aberrant matrix deposition. It is well accepted that the regenerative capacity of the adult liver is impaired during alcohol injury. The liver progenitor/stem cells have been shown to play an important role in liver regeneration -in response to various chronic injuries; however, the effects of alcohol on stem cell differentiation in the liver are not well understood. We employed hepatic progenitor cells derived from hESCs to study the impact of ethanol on hepatocyte differentiation by exposure of these progenitor cells to ethanol during hepatocyte differentiation. We found that ethanol negatively regulated hepatic differentiation of hESC-derived hepatic progenitor cells in a dose-dependent manner. There was also a moderate cell cycle arrest at G1/S checkpoint in the ethanol treated cells, which is associated with a reduced level of cyclin D1 in these cells. Ethanol treatment specifically inhibited the activation of the ERK but not JNK nor the p38 MAP signaling pathway. At the same time, the WNT signaling pathway was also reduced in the cells exposed to ethanol. Upon evaluating the effects of the inhibitors of these two signaling pathways, we determined that the Erk inhibitor replicated the effects of ethanol on the hepatocyte differentiation and attenuated the WNT/β-catenin signaling, however, inhibitors of WNT only partially replicated the effects of ethanol on the hepatocyte differentiation. Our results demonstrated that ethanol negatively regulated hepatic differentiation of hESC-derived hepatic progenitors through inhibiting the MAPK/ERK signaling pathway, and subsequently attenuating the WNT signaling pathway. Thus, our finding provides a novel insight into the mechanism by which alcohol regulates cell fate selection of hESC-derived hepatic progenitor cells, and the identified pathways may provide therapeutic targets aimed at promoting liver repair and regeneration during alcoholic injury.
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