Alcohol Increases Liver Progenitor Populations and Induces Disease Phenotypes in Human IPSC-Derived Mature Stage Hepatic Cells.
Alcohol Increases Liver Progenitor Populations and Induces Disease Phenotypes in Human IPSC-Derived Mature Stage Hepatic Cells.
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DOI：
10.7150/ijbs.15811
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发表时间：
2016
影响因子：
9.2
通讯作者：
Jang YY
中科院分区：
文献类型：
--
作者：
Tian L;Deshmukh A;Prasad N;Jang YY
长期以来，饮酒一直是一个影响人类健康的全球性问题，人们发现酒精会影响胎儿和成人的肝功能。然而，酒精是如何影响人类肝脏发育和肝祖细胞的，在很大程度上仍然未知。在这里，我们使用人类诱导多能干细胞（iPSCs）作为模型来研究酒精对多阶段肝细胞的影响，包括肝祖细胞、早期和成熟的肝细胞样细胞，这些细胞来源于人类iPSCs。虽然酒精对多能干细胞的内胚层发育几乎没有影响，但它会减少早期肝脏分化过程中肝祖细胞的形成。酒精暴露后，早期和成熟肝细胞样细胞的增殖活性显著降低。重要的是，在肝细胞样细胞成熟阶段，酒精治疗增加了两个肝祖细胞亚群，导致线粒体氧化损伤，并以剂量依赖的方式导致肝脏疾病表型（即脂肪变性和肝细胞癌相关标志物）。抗氧化处理显著改善了部分表型。本报告提示胎儿酒精暴露可能在肝脏发育早期损害肝祖细胞的生成，并减少胎儿肝细胞的增殖；同时，酒精损伤在出生后或成熟阶段的人肝脏可能有助于疾病的表型。这种酒精性肝损伤的人类iPSC模型对于研究胎儿酒精性损伤以及了解其发病机制并最终开发成人酒精性肝病的有效治疗方法具有很高的价值。
Alcohol consumption has long been a global problem affecting human health, and has been found to influence both fetal and adult liver functions. However, how alcohol affects human liver development and liver progenitor cells remains largely unknown. Here, we used human induced pluripotent stem cells (iPSCs) as a model to examine the effects of alcohol, on multi-stage hepatic cells including hepatic progenitors, early and mature hepatocyte-like cells derived from human iPSCs. While alcohol has little effect on endoderm development from iPSCs, it reduces formation of hepatic progenitor cells during early hepatic specification. The proliferative activities of early and mature hepatocyte-like cells are significantly decreased after alcohol exposure. Importantly, at a mature stage of hepatocyte-like cells, alcohol treatment increases two liver progenitor subsets, causes oxidative mitochondrial injury and results in liver disease phenotypes (i.e., steatosis and hepatocellular carcinoma associated markers) in a dose dependent manner. Some of the phenotypes were significantly improved by antioxidant treatment. This report suggests that fetal alcohol exposure may impair generation of hepatic progenitors at early stage of hepatic specification and decrease proliferation of fetal hepatocytes; meanwhile alcohol injury in post-natal or mature stage human liver may contribute to disease phenotypes. This human iPSC model of alcohol-induced liver injury can be highly valuable for investigating alcoholic injury in the fetus as well as understanding the pathogenesis and ultimately developing effective treatment for alcoholic liver disease in adults.