Hepatology：诱导干细胞分化为肝细胞来筛查药物的肝脏毒性

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<div>近日，来自日本大阪大学的研究人员表示，他们将FOXA2及HNF1α转导到人多功能干细胞后，得到了具有代谢功能的肝细胞。相关研究成果于5月30日在线发表在<em>Journal of Hepatology上</em>。</div>
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由人胚胎干细胞(hESCs)以及诱导性多功能干细胞(hiPSCs)分化而来的肝细胞样细胞能够作为一种工具，在药物开发的早期，有效的用于筛查药物的肝脏毒性。之前的研究表明，连续转导SOX17、HEX及HNF4α（肝细胞核因子4α）到hESC或hiPSC衍生细胞后，促进了肝细胞的分化。但是，为了广泛应用于药物筛查，这些肝细胞样细胞还需要进一步的成熟。

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为了筛查肝细胞分化的促进因子，研究人员检测了与肝脏发育相关的7种候选基因。结果发现，两种转录因子FOXA2及HNF1α联合促进了hESCs及hiPSCs有效的分化为肝细胞。通过FOXA2及HNF1α的转导，这些干细胞获得了肝细胞相关基因的表达谱，比如细胞色素P450基因、结合酶基因、肝细胞转运体基因以及肝细胞核受体基因，进一步研究发现，这些功能特性与原代人类肝细胞无异。

研究发现，由FOXA2及HNF1α转导所产生了肝细胞样细胞能够表现出多方面的肝细胞功能，包括白蛋白及尿素分泌，摄取吲哚菁绿及低密度脂蛋白。此外，他们还发现，这些细胞能够代谢所测试的9种药物，并成功的用于评估了药物所引起的细胞毒性。

研究人员Hiroyuki Mizuguchi表示，利用导入FOXA2及HNF1α到hESCs/hiPSCs来产生具有代谢功能的肝细胞是一种有效的策略，对筛查由药物引起的细胞毒性将具有重大意义。 
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<a title="" href="http://dx.doi.org/10.1016/j.jhep.2012.04.038" target="_blank">doi: 10.1016/j.jhep.2012.04.038</a>
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<br/><strong>Generation of metabolically functioning hepatocytes from human pluripotent stem cells by FOXA2 and HNF1α transduction </strong><br/>


Kazuo Takayama, Mitsuru Inamura, Kenji Kawabata, Michiko Sugawara, Kiyomi Kikuchi, Maiko Higuchi, Yasuhito Nagamoto, Hitoshi Watanabe, Katsuhisa Tashiro, Fuminori Sakurai, Takao Hayakawa, Miho Kusuda Furue, Hiroyuki Mizuguchi.

Hepatocyte-like cells differentiated from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) can be utilized as a tool for screening for hepatotoxicity in the early phase of pharmaceutical development.We recently reported that hepatic differentiation is promoted by sequential transduction of SOX17, HEX, and HNF4α into hESC- or hiPSC-derived cells, but further maturation of hepatocyte-like cells is required for widespread use of drug screening.To screen for hepatic differentiation-promoting factors, we tested the seven candidate genes related to the liver development.The combination of two transcription factors, FOXA2 and HNF1α, promoted efficient hepatic differentiation from hESCs and hiPSCs. The expression profile of hepatocyte-related genes such as genes encoding cytochrome P450 enzymes, conjugating enzymes, hepatic transporters, and hepatic nuclear receptors achieved by FOXA2 and HNF1α transduction was comparable to that in primary human hepatocytes.The hepatocyte-like cells generated by FOXA2 and HNF1α transduction exerted various hepatocyte functions including the ability of albumin and urea secretion, and the uptake of indocyanine green and low density lipoprotein. Moreover, these cells had the capacity to metabolize all nine tested drugs and were successfully employed to evaluate drug-induced cytotoxicity.Our method employing the transduction of FOXA2 and HNF1α represents a useful tool for the efficient generation of metabolically functioning hepatocytes from hESCs and hiPSCs, and the screening of drug-induced cytotoxicity.
<div><br/>来源：生物谷</div>
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