Efficient generation of hepatoblasts from human ES cells and iPS cells by transient overexpression of homeobox gene HEX.
Efficient generation of hepatoblasts from human ES cells and iPS cells by transient overexpression of homeobox gene HEX.
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通过同源盒基因 HEX 的瞬时过表达，从人 ES 细胞和 iPS 细胞中高效生成成肝细胞。
DOI：
10.1038/mt.2010.241
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发表时间：
2011-02
影响因子：
12.4
通讯作者：
Mizuguchi, Hiroyuki
中科院分区：
文献类型：
--
作者：
Inamura, Mitsuru;Kawabata, Kenji;Takayama, Kazuo;Tashiro, Katsuhisa;Sakurai, Fuminori;Katayama, Kazufumi;Toyoda, Masashi;Akutsu, Hidenori;Miyagawa, Yoshitaka;Okita, Hajime;Kiyokawa, Nobutaka;Umezawa, Akihiro;Hayakawa, Takao;Furue, Miho K.;Mizuguchi, Hiroyuki
人胚胎干细胞（ESCs）和诱导多能干细胞（iPSCs）在体外具有分化为包括肝细胞在内的所有细胞系的潜力。诱导肝细胞在生物医学研究、药物发现和肝脏疾病治疗方面具有广泛的潜在应用。然而，现有的PSCs肝分化方案不是很有效。在这项研究中，我们开发了一种有效的方法，通过在无血清/饲养细胞的化学条件下，使用表达HEX基因的腺病毒（Ad）载体，通过过表达HEX基因，从人ESCs和iPSCs中诱导肝细胞的祖细胞——肝细胞。HEX基因是一种同源基因，也是肝脏分化所必需的。ad - hex转导的细胞在第9天表达α-胎蛋白（AFP），在第12天表达白蛋白（ALB）。此外，来源于人多能干细胞的ad - hex转导细胞也产生了几种细胞色素P450 （CYP）同工酶，这些P450同工酶能够将底物转化为代谢物并对化学刺激做出反应。我们的分化方案使用Ad载体介导的瞬时HEX转导，在化学定义的条件下有效地从人类ESCs和iPSCs中生成肝母细胞。因此，我们的方法不仅可以用于药物筛选，还可以用于治疗应用。
Human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to differentiate into all cell lineages, including hepatocytes, in vitro. Induced hepatocytes have a wide range of potential application in biomedical research, drug discovery, and the treatment of liver disease. However, the existing protocols for hepatic differentiation of PSCs are not very efficient. In this study, we developed an efficient method to induce hepatoblasts, which are progenitors of hepatocytes, from human ESCs and iPSCs by overexpression of the HEX gene, which is a homeotic gene and also essential for hepatic differentiation, using a HEX-expressing adenovirus (Ad) vector under serum/feeder cell-free chemically defined conditions. Ad-HEX-transduced cells expressed α-fetoprotein (AFP) at day 9 and then expressed albumin (ALB) at day 12. Furthermore, the Ad-HEX-transduced cells derived from human iPSCs also produced several cytochrome P450 (CYP) isozymes, and these P450 isozymes were capable of converting the substrates to metabolites and responding to the chemical stimulation. Our differentiation protocol using Ad vector-mediated transient HEX transduction under chemically defined conditions efficiently generates hepatoblasts from human ESCs and iPSCs. Thus, our methods would be useful for not only drug screening but also therapeutic applications.
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