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The importance of transporters and cell polarization for the evaluation of human stem cell-derived hepatic cells.
PLOS ONE ( IF 2.9 ) Pub Date : 2020-01-23 , DOI: 10.1371/journal.pone.0227751 György Török 1 , Zsuzsa Erdei 1 , Julianna Lilienberg 1 , Ágota Apáti 1 , László Homolya 1
PLOS ONE ( IF 2.9 ) Pub Date : 2020-01-23 , DOI: 10.1371/journal.pone.0227751 György Török 1 , Zsuzsa Erdei 1 , Julianna Lilienberg 1 , Ágota Apáti 1 , László Homolya 1
Affiliation
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One of the most promising applications of human pluripotent stem cells is their utilization for human-based pharmacological models. Despite the fact that membrane transporters expressed in the liver play pivotal role in various hepatic functions, thus far only little attention was devoted to the membrane transporter composition of the stem cell-derived liver models. In the present work, we have differentiated HUES9, a human embryonic stem cell line, toward the hepatic lineage, and monitored the expression levels of numerous differentiation marker and liver transporter genes with special focus on ABC transporters. In addition, the effect of bile acid treatment and polarizing culturing conditions on hepatic maturation has been assessed. We found that most transporter genes crucial for hepatic functions are markedly induced during hepatic differentiation; however, as regards the transporter composition the end-stage cells still exhibited dual, hepatocyte and cholangiocyte character. Although the bile acid treatment and sandwich culturing only slightly influenced the gene expressions, the stimulated cell polarization resulted in formation of bile canaliculi and proper localization of transporters. Our results point to the importance of membrane transporters in human stem cell-derived hepatic models and demonstrate the relevance of cell polarization in generation of applicable cellular models with correctly localized transporters. On the basis of our observations we suggest that conventional criteria for the evaluation of the quality of stem cell-derived hepatocyte-like cells ought to be augmented with additional elements, such as polarized and functional expression of hepatic transporters.
中文翻译：
转运蛋白和细胞极化对于评估人类干细胞来源的肝细胞的重要性。
人多能干细胞最有希望的应用之一是将其用于基于人的药理模型。尽管在肝中表达的膜转运蛋白在各种肝功能中起着关键作用，但到目前为止，对干细胞衍生的肝模型的膜转运蛋白组成只有很少的关注。在目前的工作中，我们已经将人类胚胎干细胞系HUES9分化为肝谱系，并监测了许多分化标志物和肝转运蛋白基因的表达水平，并特别关注ABC转运蛋白。另外，已经评估了胆汁酸处理和极化培养条件对肝成熟的影响。我们发现大多数肝功能至关重要的转运蛋白基因在肝分化过程中被明显诱导。然而，就转运蛋白组成而言，终末期细胞仍表现出双重特征，即肝细胞和胆管细胞。尽管胆汁酸处理和三明治培养仅略微影响了基因表达，但是受激细胞极化导致胆管小管的形成和转运蛋白的适当定位。我们的结果指出了膜转运蛋白在人干细胞衍生的肝模型中的重要性，并证明了细胞极化在正确定位转运蛋白的适用细胞模型生成中的相关性。
更新日期：2020-01-24
中文翻译：
转运蛋白和细胞极化对于评估人类干细胞来源的肝细胞的重要性。
人多能干细胞最有希望的应用之一是将其用于基于人的药理模型。尽管在肝中表达的膜转运蛋白在各种肝功能中起着关键作用，但到目前为止，对干细胞衍生的肝模型的膜转运蛋白组成只有很少的关注。在目前的工作中，我们已经将人类胚胎干细胞系HUES9分化为肝谱系，并监测了许多分化标志物和肝转运蛋白基因的表达水平，并特别关注ABC转运蛋白。另外，已经评估了胆汁酸处理和极化培养条件对肝成熟的影响。我们发现大多数肝功能至关重要的转运蛋白基因在肝分化过程中被明显诱导。然而，就转运蛋白组成而言，终末期细胞仍表现出双重特征，即肝细胞和胆管细胞。尽管胆汁酸处理和三明治培养仅略微影响了基因表达，但是受激细胞极化导致胆管小管的形成和转运蛋白的适当定位。我们的结果指出了膜转运蛋白在人干细胞衍生的肝模型中的重要性，并证明了细胞极化在正确定位转运蛋白的适用细胞模型生成中的相关性。
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