Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes.
Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes.
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DOI：
10.1016/j.jhep.2014.10.016
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发表时间：
2015-03
影响因子：
25.7
通讯作者：
Hanley, Neil A.
中科院分区：
文献类型：
--
作者：
Baxter, Melissa;Withey, Sarah;Harrison, Sean;Segeritz, Charis-Patricia;Zhang, Fang;Atkinson-Dell, Rebecca;Rowe, Cliff;Gerrard, Dave T.;Sison-Young, Rowena;Jenkins, Roz;Henry, Joanne;Berry, Andrew A.;Mohamet, Lisa;Best, Marie;Fenwick, Stephen W.;Malik, Hassan;Kitteringham, Neil R.;Goldring, Chris E.;Hanley, Karen Piper;Vallier, Ludovic;Hanley, Neil A.
肝细胞样细胞（HLC）通过使用可溶性因子从多能干细胞分化而来，可以模拟人类肝功能和毒性。然而，目前 HLC 成熟度以及任何缺陷是否代表真正的胎儿状态或异常分化尚不清楚，并且与潜在恶化的成年肝细胞相比，情况更加复杂。因此，我们使用两种不同的方案从多个谱系生成 HLC，以便与新鲜胎儿和成人肝细胞直接比较。开发协议是为了实现稳健的差异化。多项转录本、蛋白质和功能分析将 HLC 与新鲜的人类胎儿和成人肝细胞进行比较。 HLC 在多个参数上与其他实验室的 HLC 相当。分化过程中的转录变化模仿了人类胚胎发生，并且与中央肝细胞比与门静脉周围肝细胞更相似。无偏见的蛋白质组学表明，与其他 30 个人体器官或组织相比，它更接近肝脏。然而，通过与新鲜材料相比，HLC成熟度经转录物、蛋白质和功能证明是胎儿样的并且缺乏成人表型。 HLC 中 81% 的 1 相酶表达显着上调，其中一半与胎儿肝细胞在统计学上没有差异。 HLC 与胎儿肝细胞一样，分泌白蛋白、代谢睾酮 (CYP3A) 和右啡烷 (CYP2D6)。在七项定制测试中，通过主成分分析设计来区分胎儿肝细胞和成人肝细胞，来自两个不同来源实验室的 HLC 一致地证明了胎儿特征。来自不同来源的 HLC 与肝脏谱系的忠实分化的无偏见蛋白质组学证据具有广泛的可比性。目前的表型模仿人类胎儿肝细胞而不是成人肝细胞。
Hepatocyte-like cells (HLCs), differentiated from pluripotent stem cells by the use of soluble factors, can model human liver function and toxicity. However, at present HLC maturity and whether any deficit represents a true fetal state or aberrant differentiation is unclear and compounded by comparison to potentially deteriorated adult hepatocytes. Therefore, we generated HLCs from multiple lineages, using two different protocols, for direct comparison with fresh fetal and adult hepatocytes. Protocols were developed for robust differentiation. Multiple transcript, protein and functional analyses compared HLCs to fresh human fetal and adult hepatocytes. HLCs were comparable to those of other laboratories by multiple parameters. Transcriptional changes during differentiation mimicked human embryogenesis and showed more similarity to pericentral than periportal hepatocytes. Unbiased proteomics demonstrated greater proximity to liver than 30 other human organs or tissues. However, by comparison to fresh material, HLC maturity was proven by transcript, protein and function to be fetal-like and short of the adult phenotype. The expression of 81% phase 1 enzymes in HLCs was significantly upregulated and half were statistically not different from fetal hepatocytes. HLCs secreted albumin and metabolized testosterone (CYP3A) and dextrorphan (CYP2D6) like fetal hepatocytes. In seven bespoke tests, devised by principal components analysis to distinguish fetal from adult hepatocytes, HLCs from two different source laboratories consistently demonstrated fetal characteristics. HLCs from different sources are broadly comparable with unbiased proteomic evidence for faithful differentiation down the liver lineage. This current phenotype mimics human fetal rather than adult hepatocytes.
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影响因子：
13.5
作者：
Rowe, Cliff;Gerrard, Dave T.;Jenkins, Roz;Berry, Andrew;Durkin, Kesta;Sundstrom, Lars;Goldring, Chris E.;Park, B. Kevin;Kitteringham, Neil R.;Hanley, Karen Piper;Hanley, Neil A.
通讯作者：
Hanley, Neil A.
影响因子：
4.1
作者：
Brolen, Gabriella;Sivertsson, Louise;Heins, Nico
通讯作者：
Heins, Nico
影响因子：
5.2
作者：
Hay, David C.;Zhao, Debiao;Cui, Wei
通讯作者：
Cui, Wei
影响因子：
7.7
作者：
Harries, Lorna W.;Locke, Jonathan M.;Hattersley, Andrew T.
通讯作者：
Hattersley, Andrew T.
影响因子：
6.4
作者：
Matsukuma, Susumu;Takeo, Hiroaki;Sato, Kimiya
通讯作者：
Sato, Kimiya