Generation of human hepatocytes by stem cell technology: definition of the hepatocyte.
Generation of human hepatocytes by stem cell technology: definition of the hepatocyte.
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DOI：
10.1517/17425255.1.1.61
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发表时间：
2005-06-01
影响因子：
4.3
通讯作者：
von Mach, Marc-Alexander
中科院分区：
文献类型：
--
作者：
Hengstler, Jan G;Brulport, Marc;von Mach, Marc-Alexander
自1999年以来，许多文章报道了从不同类型的肝外干细胞或前体细胞产生肝细胞。这为药理学和毒理学以及细胞治疗开辟了令人兴奋的新可能性。将不同类型的人干细胞移植到实验动物的肝脏中或在体外与细胞因子孵育后，观察到肝细胞标志物的表达，包括白蛋白、细胞角蛋白18、c-met、甲胎蛋白和细胞色素P450 3A 4和-2B6。这些有趣的观察促使科学家将干细胞衍生的细胞群分类为肝细胞。然而，这个结论可能还为时过早。已经表明，肝脏微环境的因素可以诱导非肝细胞类型中有限数量的肝细胞标志物基因的表达。根据有限数量的标志物得出结论，这些细胞是真正的肝细胞，这并不意味着。在这种情况下，应该仔细评估关键的肝细胞定义酶的特性。本条：i）回顾了描述实验室动物肝脏中肝外人类干细胞和前体细胞命运的研究，包括细胞融合的可能性; ii）批判性地讨论了应用各种分化方案以产生人类肝细胞后干细胞的表型。此外，定义一个真正的肝细胞所需的必要标准的建议。确定干细胞衍生肝细胞的必要属性是及时和合理的，从而避免了进一步的误导性语义混淆。最后，必须理解，真正肝细胞的定义不应仅限于定性测定，如逆转录酶聚合酶链反应和免疫组织化学，而是必须包括酶活性的定量分析，这允许与原代肝细胞直接比较。虽然干细胞衍生的肝细胞还不存在，但这一目标在未来很有可能实现。
Since 1999, numerous articles have reported the generation of hepatocytes from different types of extrahepatic stem or precursor cells. This opens exciting new possibilities for pharmacology and toxicology, as well as for cell therapy. Hepatocyte marker expression, including albumin, cytokeratin 18, c-met, alpha-fetoprotein and cytochrome P450 3A4 and -2B6, has been observed after transplantation of different types of human stem cells into the liver of laboratory animals or in vitro after incubation with cytokines. These intriguing observations have prompted scientists to classify stem cell-derived cell populations as hepatocytes. However, this conclusion may be premature. It has been shown that factors of the liver microenvironment can induce expression of a limited number of hepatocyte marker genes in nonhepatic cell types. To conclude on the grounds of a limited number of markers that these cells are true hepatocytes is not indicated. In this case one should carefully evaluate crucial hepatocyte-defining enzymatic properties. The present article: i) reviews studies describing the fate of extrahepatic human stem and precursor cells in livers of laboratory animals, including the possibility of cell fusion; and ii) critically discusses the phenotype of stem cells after application of various differentiation protocols aimed at generating human hepatocytes. In addition, the necessary criteria needed for defining a true hepatocyte are suggested. Establishing the necessary properties for stem cell-derived hepatocytes is timely and reasonable, and thus avoids further misleading semantic confusion. Finally, it is essential to understand that the definition of a bona fide hepatocyte should not be limited to qualitative assays, such as reverse transcriptase polymerase chain reaction and immunohistochemistry, but has to include a quantitative analysis of enzymatic activities, which allows direct comparison with primary hepatocytes. Although the stem cell-derived-hepatocyte does not yet exist there is a good chance that this aim may be achieved in the future.