Generation of functional human hepatic endoderm from human induced pluripotent stem cells.
Generation of functional human hepatic endoderm from human induced pluripotent stem cells.
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DOI：
10.1002/hep.23335
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发表时间：
2010-01
期刊：
影响因子：
13.5
通讯作者：
Wilmut, Ian
中科院分区：
文献类型：
--
作者：
Sullivan, Gareth J.;Hay, David C.;Park, In-Hyun;Fletcher, Judy;Hannoun, Zara;Payne, Catherine M.;Dalgetty, Donna;Black, James R.;Ross, James A.;Samuel, Kay;Wang, Gang;Daley, George Q.;Lee, Je-Hyuk;Church, George M.;Forbes, Stuart J.;Iredale, John P.;Wilmut, Ian
随着诱导多能干细胞（iPSC）技术的出现，现在可以产生具有确定基因型或疾病状态的iPSC。当与明确谱系的直接分化相结合时，如肝内胚层（HE）。iPSC将彻底改变我们研究人类肝脏生物学的方式，并生成有效的人类肝脏疾病“现成”模型。在这里，我们展示了“概念证明”，即代表男性和女性性别以及两个种族起源的iPSC系可以使用模拟生理条件的方法以70- 90%的效率分化为HE。iPSC衍生的HE表现出肝脏形态，并表达肝脏标志物白蛋白和E-钙粘蛋白，如通过免疫组织化学评估的。它们还表达了甲胎蛋白（AFP）、HNF 4a和代谢标志物Cyp 7A 1，证明了确定的内胚层谱系分化。此外，iPSC衍生的肝细胞产生并分泌血浆蛋白、纤维蛋白原、纤连蛋白、甲状腺素运载蛋白（TTR）和AFP，这是功能性HE的基本特征。此外，iPSC衍生的HE支持CYP 1A 2和3A 4代谢，这对于药物和毒理学测试至关重要。这项工作首次证明了从人类iPSC有效产生肝内胚层谱系，其表现出肝细胞的关键属性，以及iPSC衍生的HE在研究人类肝脏生物学中的潜在应用。特别是，来自代表代谢基因和不同种族的高度多态性变体的个体的iPSC将为药物开发和毒理学研究提供一个独特的机会，以彻底改变预测性药物毒理学试验，并允许创建体外肝病模型。
With the advent of induced pluripotent stem cell (iPSC) technology, it is now feasible to generate iPSCs with a defined genotype or disease state. When coupled with direct differentiation of defined lineage, such as hepatic endoderm (HE). iPSC would revolutionise the way we study human liver biology and generate efficient “off the shelf” models of human liver disease. Here we show the `proof of concept' that iPSC lines representing both male and female sexes and two ethnic origins can be differentiated to HE at efficiencies of between 70–90%, using a method mimicking a physiological condition. iPSC-derived HE exhibited hepatic morphology, and expressed the hepatic markers, Albumin and E-Cadherin as assessed by immuno-histochemistry. They also expressed alpha fetal protein (AFP), HNF4a, and a metabolic marker, Cyp7A1, demonstrating a definitive endodermal lineage differentiation. Furthermore, iPSC-derived hepatocytes produced and secreted the plasma proteins, fibrinogen, fibronectin, transthyretin (TTR) and AFP, an essential feature for functional HE. Additionally iPSC-derived HE supported both CYP1A2 and 3A4 metabolism, which is essential for drug and toxicology testing. This work is first to demonstrate the efficient generation of hepatic endodermal lineage from human iPSC that exhibits key attributes of hepatocytes, and the potential application of iPSC-derived HE in studying human liver biology. In particular, iPSC from individuals representing highly polymorphic variants in metabolic genes and different ethnic groups will provide pharmaceutical development and toxicology studies a unique opportunity to revolutionise predictive drug toxicology assays and allow the creation of in vitro hepatic disease models.
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影响因子：
46.9
作者：
Ball, Madeleine P.;Li, Jin Billy;Gao, Yuan;Lee, Je-Hyuk;LeProust, Emily M.;Park, In-Hyun;Xie, Bin;Daley, George Q.;Church, George M.
通讯作者：
Church, George M.
影响因子：
64.5
作者：
Park IH;Arora N;Huo H;Maherali N;Ahfeldt T;Shimamura A;Lensch MW;Cowan C;Hochedlinger K;Daley GQ
通讯作者：
Daley GQ
影响因子：
64.8
作者：
Park, In-Hyun;Zhao, Rui;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
5.2
作者：
Gadue, Paul;Gouon-Evans, Valerie;Cheng, Xin;Wandzioch, Ewa;Zaret, Kenneth S.;Grompe, Markus;Streeter, Philip R.;Keller, Gordon M.
通讯作者：
Keller, Gordon M.
影响因子：
56.9
作者：
Yu, Junying;Vodyanik, Maxim A.;Thomson, James A.
通讯作者：
Thomson, James A.