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首页> 外文期刊>Archives of Toxicology >Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile
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Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile

机译：使用全局蛋白质组学分析的原发性人肝细胞培养的机械评价显示了一种选择性消化膜

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摘要

The application of primary human hepatocytes following isolation from human tissue is well accepted to be compromised by the process of dedifferentiation. This phenomenon reduces many unique hepatocyte functions, limiting their use in drug disposition and toxicity assessment. The aetiology of dedifferentiation has not been well defined, and further understanding of the process would allow the development of novel strategies for sustaining the hepatocyte phenotype in culture or for improving protocols for maturation of hepatocytes generated from stem cells. We have therefore carried out the first proteomic comparison of primary human hepatocyte differentiation. Cells were cultured for 0, 24, 72 and 168 h as a monolayer in order to permit unrestricted hepatocyte dedifferentiation, so as to reveal the causative signalling pathways and factors in this process, by pathway analysis. A total of 3430 proteins were identified with a false detection rate of < 1 %, of which 1117 were quantified at every time point. Increasing numbers of significantly differentially expressed proteins compared with the freshly isolated cells were observed at 24 h (40 proteins), 72 h (118 proteins) and 168 h (272 proteins) (p < 0.05). In particular, cytochromes P450 and mitochondrial proteins underwent major changes, confirmed by functional studies and investigated by pathway analysis. We report the key factors and pathways which underlie the loss of hepatic phenotype in vitro, particularly those driving the large-scale and selective remodelling of the mitochondrial and metabolic proteomes. In summary, these findings expand the current understanding of dedifferentiation should facilitate further development of simple and complex hepatic culture systems.
机译：在从人组织中分离后，初级人肝细胞的施用很好地被去分化的过程受到损害。这种现象可以减少许多独特的肝细胞功能，限制了它们在药物处理和毒性评估中的用途。去除湿症的病因没有明确定义，进一步了解该过程将允许开发用于维持培养物中肝细胞表型的新策略，或用于改善从干细胞产生的肝细胞成熟的方案。因此，我们已经进行了原发性人肝细胞分化的第一个蛋白质组学比较。将细胞培养为0,24,72和168小时作为单层，以允许不受限制的肝细胞消除剂，从而揭示该过程中的致病信号传导途径和因子，通过途径分析。通过假检测率鉴定了总共3430个蛋白质，其中每次点为1117定量1117。在24小时（40蛋白），72小时（118蛋白）和168小时（272蛋白）（P <0.05）中观察到与新分离的细胞相比，增加与新分离的细胞的显着差异表达蛋白质的数量。特别是，细胞学romes p450和线粒体蛋白质经历了主要变化，通过功能研究证实并通过途径分析研究。我们报告了在体外失去肝脏表型的关键因素和途径，特别是那些推动线粒体和代谢蛋白质组的大规模和选择性重塑的那些。总之，这些发现扩展了目前对消化剂的理解应促进简单和复杂的肝培养系统的进一步发展。

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  • 来源
    《Archives of Toxicology》 |2017年第1期|共14页
  • 作者

    Heslop James A.; Rowe Cliff; Walsh Joanne; Sison-Young Rowena; Jenkins Roz; Kamalian Laleh; Kia Richard; Hay David; Jones Robert P.; Malik Hassan Z.; Fenwick Stephen; Chadwick Amy E.; Mills John; Kitteringham Neil R.; Goldring Chris E. P.; Park B. Kevin;

  • 作者单位

    Univ Liverpool MRC Ctr Drug Safety Sci Div Mol &

    Clin Pharmacol Inst Translat Med Liverpool L69;

    Univ Oxford CN Bio Ctr Innovat &

    Enterprise Begbroke Sci Pk Begbroke OX5 1PF Oxon England;

    Univ Liverpool MRC Ctr Drug Safety Sci Div Mol &

    Clin Pharmacol Inst Translat Med Liverpool L69;

    Univ Liverpool MRC Ctr Drug Safety Sci Div Mol &

    Clin Pharmacol Inst Translat Med Liverpool L69;

    Univ Liverpool MRC Ctr Drug Safety Sci Div Mol &

    Clin Pharmacol Inst Translat Med Liverpool L69;

    Univ Liverpool MRC Ctr Drug Safety Sci Div Mol &

    Clin Pharmacol Inst Translat Med Liverpool L69;

    Univ Liverpool MRC Ctr Drug Safety Sci Div Mol &

    Clin Pharmacol Inst Translat Med Liverpool L69;

    Univ Liverpool MRC Ctr Drug Safety Sci Div Mol &

    Clin Pharmacol Inst Translat Med Liverpool L69;

    Aintree Univ Hosp NHS Fdn Trust Longmoor Lane Liverpool L9 7AL Merseyside England;

    Aintree Univ Hosp NHS Fdn Trust Longmoor Lane Liverpool L9 7AL Merseyside England;

    Aintree Univ Hosp NHS Fdn Trust Longmoor Lane Liverpool L9 7AL Merseyside England;

    Univ Liverpool MRC Ctr Drug Safety Sci Div Mol &

    Clin Pharmacol Inst Translat Med Liverpool L69;

    AstraZeneca Personalised Healthcare &

    Biomarkers Alderley Pk SK10 4TG Cheshire England;

    Univ Liverpool MRC Ctr Drug Safety Sci Div Mol &

    Clin Pharmacol Inst Translat Med Liverpool L69;

    Univ Liverpool MRC Ctr Drug Safety Sci Div Mol &

    Clin Pharmacol Inst Translat Med Liverpool L69;

    Univ Liverpool MRC Ctr Drug Safety Sci Div Mol &

    Clin Pharmacol Inst Translat Med Liverpool L69;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 毒物学（毒理学）;
  • 关键词

    Cytochrome P450s; Human hepatocytes; Mass spectrometry; Mitochondria; iTRAQ; Donor-variation;

    机译：细胞色素p450s;人肝细胞;质谱;线粒体;itraq;捐赠者 - 变异;

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