Developing High-Fidelity Hepatotoxicity Models From Pluripotent Stem Cells
Developing High-Fidelity Hepatotoxicity Models From Pluripotent Stem Cells
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DOI：
10.5966/sctm.2012-0138
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发表时间：
2013-07-01
影响因子：
6
通讯作者：
Hay, David C.
中科院分区：
文献类型：
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作者：
Medine, Claire N.;Lucendo-Villarin, Baltasar;Hay, David C.
从可再生资源中忠实地重述人类生理学，仍然是医学和制药行业的圣杯。已经描述了许多程序，在有限的范围内，在体外展示人类组织特有的功能。特别是，细胞分化不完全和/或细胞分化后表型丧失是造成这种空白的主要原因。我们已经开发了一种跨学科的方法来解决这个问题，使用细胞生物学、材料化学和药理学的技能集。多能干细胞在被复制到人造表面之前被分化为肝细胞。我们的方法产生了代谢活跃的肝细胞群体，在体外表现出稳定的功能超过2周。虽然代谢活性是细胞效用的一个重要指标，但准确预测特定药物对细胞的毒性是我们的目标。因此，我们进行了详细的肝细胞毒性分析，以响应定制和明确定义的化合物集，并与原代人类肝细胞进行比较。重要的是，干细胞来源的肝细胞显示出与原始人类材料的等价性。此外，我们证明了我们的方法能够模拟在人群中观察到的新陈代谢差异。总之，我们报告说，多能干细胞来源的肝细胞将以可预测的方式模拟毒性，并与目前的金标准检测方法相媲美，这是该领域的一大进步。
Faithfully recapitulating human physiology "in a dish" from a renewable source remains a holy grail for medicine and pharma. Many procedures have been described that, to a limited extent, exhibit human tissue-specific function in vitro. In particular, incomplete cellular differentiation and/or the loss of cell phenotype postdifferentiation play a major part in this void. We have developed an interdisciplinary approach to address this problem, using skill sets in cell biology, materials chemistry, and pharmacology. Pluripotent stem cells were differentiated to hepatocytes before being replated onto a synthetic surface. Our approach yielded metabolically active hepatocyte populations that displayed stable function for more than 2 weeks in vitro. Although metabolic activity was an important indication of cell utility, the accurate prediction of cellular toxicity in response to specific pharmacological compounds represented our goal. Therefore, detailed analysis of hepatocellular toxicity was performed in response to a custom-built and well-defined compound set and compared with primary human hepatocytes. Importantly, stem cell-derived hepatocytes displayed equivalence to primary human material. Moreover, we demonstrated that our approach was capable of modeling metabolic differences observed in the population. In conclusion, we report that pluripotent stem cell-derived hepatocytes will model toxicity predictably and in a manner comparable to current gold standard assays, representing a major advance in the field.