Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells.
Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells.
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DOI：
10.1007/s00204-017-1983-0
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发表时间：
2017-11
影响因子：
6.1
通讯作者：
Hay DC
中科院分区：
文献类型：
--
作者：
Lucendo-Villarin B;Filis P;Swortwood MJ;Huestis MA;Meseguer-Ripolles J;Cameron K;Iredale JP;O'Shaughnessy PJ;Fowler PA;Hay DC
肝脏是一个动态器官，具有多功能和高度再生能力。肝脏的主要作用是处理内源性物质和外源性物质。香烟是一种合法且广泛使用的药物的一个例子，如果母亲在怀孕期间吸烟，它可能会给成年人带来严重的健康问题，并对胎儿构成特别的风险。香烟烟雾含有数千种不同异生物质的复杂混合物，包括尼古丁和多环芳烃。这些以性别特异性方式影响胎儿发育，在不同器官中诱导性别依赖性分子反应。迄今为止，已经利用细胞系、原代组织和动物模型在体外研究了母亲吸烟对胎儿肝脏的影响。虽然这些模型已被证明是有用的，但不良的细胞表型、组织稀缺、批次间的变异和物种差异导致了对人类发育的数据外推的困难。因此，在这项研究中，我们采用源自多能干细胞的成肝细胞来模拟香烟烟雾中的异生物质对人类肝细胞发育的影响。高纯度的肝细胞群（>90%）是在体外产生的，并暴露于香烟烟雾中的因子。对 ATP 水平的分析表明，无论性别如何，大多数单独测试的吸烟衍生物不会将 ATP 水平消耗到 50% 以下。然而，在接触吸烟衍生物的混合物后，ATP 的产生量以性别依赖性方式下降到 50% 以下。与此同时，雌性和雄性肝细胞的代谢活性和分泌能力均丧失。有趣的是，女性肝细胞中的细胞消耗不太明显，而半胱天冬酶的激活大约是其两倍，表明暴露于测试的吸烟衍生物后细胞死亡的性别差异。本文的在线版本 (doi:10.1007/s00204-017-1983-0) 包含补充材料，可供授权用户使用。
The liver is a dynamic organ which is both multifunctional and highly regenerative. A major role of the liver is to process both endo and xenobiotics. Cigarettes are an example of a legal and widely used drug which can cause major health problems for adults and constitute a particular risk to the foetus, if the mother smokes during pregnancy. Cigarette smoke contains a complex mixture of thousands of different xenobiotics, including nicotine and polycyclic aromatic hydrocarbons. These affect foetal development in a sex-specific manner, inducing sex-dependant molecular responses in different organs. To date, the effect of maternal smoking on the foetal liver has been studied in vitro using cell lines, primary tissue and animal models. While these models have proven to be useful, poor cell phenotype, tissue scarcity, batch-to-batch variation and species differences have led to difficulties in data extrapolation toward human development. Therefore, in this study we have employed hepatoblasts, derived from pluripotent stem cells, to model the effects of xenobiotics from cigarette smoke on human hepatocyte development. Highly pure hepatocyte populations (>90%) were produced in vitro and exposed to factors present in cigarette smoke. Analysis of ATP levels revealed that, independent of the sex, the majority of smoking derivatives tested individually did not deplete ATP levels below 50%. However, following exposure to a cocktail of smoking derivatives, ATP production fell below 50% in a sex-dependent manner. This was paralleled by a loss metabolic activity and secretory ability in both female and male hepatocytes. Interestingly, cell depletion was less pronounced in female hepatocytes, whereas caspase activation was ~twofold greater, indicating sex differences in cell death upon exposure to the smoking derivatives tested. The online version of this article (doi:10.1007/s00204-017-1983-0) contains supplementary material, which is available to authorized users.
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