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首页> 外文期刊>Archives of Toxicology >The role of epigenetic modifiers in extended cultures of functional hepatocyte-like cells derived from human neonatal mesenchymal stem cells
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The role of epigenetic modifiers in extended cultures of functional hepatocyte-like cells derived from human neonatal mesenchymal stem cells

机译：表观遗传调节剂在衍生自人新生间充质干细胞的功能性肝细胞样细胞延长培养中的作用

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The development of predictive in vitro stem cell-derived hepatic models for toxicological drug screening is an increasingly important topic. Herein, umbilical cord tissue-derived mesenchymal stem cells (hnMSCs) underwent hepatic differentiation using an optimized three-step core protocol of 24 days that mimicked liver embryogenesis with further exposure to epigenetic markers, namely the histone deacetylase inhibitor trichostatin A (TSA), the cytidine analogue 5-azacytidine (5-AZA) and dimethyl sulfoxide (DMSO). FGF-2 and FGF-4 were also tested to improve endoderm commitment and foregut induction during Step 1 of the differentiation protocol, being HHEX expression increased with FGF-2 (4 ng/mL). DMSO (1%, v/v) when added at day 10 enhanced cell morphology, glycogen storage ability, enzymatic activity and induction capacity. Moreover, the stability of the hepatic phenotype under the optimized differentiation conditions was examined up to day 34. Our findings showed that hepatocyte-like cells (HLCs) acquired the ability to metabolize glucose, produce albumin and detoxify ammonia. Global transcriptional analysis of the HLCs showed a partial hepatic differentiation degree. Global analysis of gene expression in the different cells revealed shared expression of gene groups between HLCs and human primary hepatocytes (hpHeps) that were not observed between HepG2 and hpHeps. In addition, bioinformatics analysis of gene expression data placed HLCs between the HepG2 cell line and hpHeps and distant from hnMSCs. The enhanced hepatic differentiation observed was supported by the presence of the hepatic drug transporters OATP-C and MRP-2 and gene expression of the hepatic markers CK18, TAT, AFP, ALB, HNF4A and CEBPA; and by their ability to display stable UGT-, EROD-, ECOD-, CYP1A1-, CYP2C9- and CYP3A4-dependent activities at levels either comparable with or even higher than those observed in primary hepatocytes and HepG2 cells. Overall, an improvement of the hepatocyte-like phenotype was achieved for an extended culture time suggesting a role of the epigenetic modifiers in hepatic differentiation and maturation and presenting hnMSC-HLCs as an advantageous alternative for drug discovery and in vitro toxicology testing.
机译：用于毒理药物筛查的预测性体外干细胞衍生肝脏模型的发展是越来越重要的话题。在此，使用24天的优化的三步核心方案进行肝脏分化的脐带组织衍生的间充质干细胞（HNMSCs），其模仿肝胚胎发生，即进一步暴露于表观遗传标记，即组蛋白脱乙酰化酶抑制剂richostatina（TSA），即胞苷类似物5-氮杂辛胺（5-α）和二甲基亚砜（DMSO）。还测试FGF-2和FGF-4以改善分化方案的步骤1期间的内胚层的承诺和预防诱导，是HHEX表达随FGF-2（4ng / mL）而增加。 DMSO（1％，v / v）在第10天添加时增强细胞形态，糖原储存能力，酶活性和诱导能力。此外，在优化的分化条件下肝脏表型的稳定性预计34。我们的研究结果表明，肝细胞样细胞（HLCS）获得了代谢葡萄糖的能力，产生白蛋白和排毒氨。 HLC的全局转录分析显示出局部肝脏分化程度。在不同细胞中的基因表达的全局分析揭示了在HepG2和HPheps之间未观察到的HLC和人原发性肝细胞（HPHEP）之间的基因组的共同表达。此外，基因表达数据的生物信息学分析在HEPG2细胞系和HPHEP之间放置了HLC，以及来自HNMSC的遥远。观察到观察到的增强的肝脏分化通过肝脏药物转运蛋白和MRP-2和肝脏标记物CK18，TAT，AFP，ALB，HNF4A和CEBPA的基因表达支持;通过它们在与原发性肝细胞和HepG2细胞中观察到的级别显示稳定的UGT，EROD-，CYP1A1-，CYP2C9和CYP3A4依赖性活动的能力。总的来说，对肝细胞样表型的改善是为了延长培养时间，表明表观遗传调节剂在肝脏分化和成熟中的作用以及呈现HNMSC-HLC作为药物发现和体外毒理学测试的有利替代方案。

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