Humanized mice with ectopic artificial liver tissues
Humanized mice with ectopic artificial liver tissues
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DOI：
10.1073/pnas.1101791108
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发表时间：
2011-07-19
影响因子：
11.1
通讯作者：
Bhatia, Sangeeta N.
中科院分区：
文献类型：
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作者：
Chen, Alice A.;Thomas, David K.;Bhatia, Sangeeta N.
“人源化”小鼠为了解人类生理学的各个方面提供了一个窗口，而这些方面是其他方法无法了解的。肝脏人源化的最佳可用方法依赖于将细胞移植到肝损伤的免疫缺陷小鼠中，但由于肝细胞重建的持续时间和可变性，这些方法尚未得到广泛使用。鉴于通过组织工程在临床细胞移植方面取得的重大进展，我们试图开发一种基于组织工程人类肝脏的简便异位植入的人源化小鼠模型。这些人类异位人工肝 (HEAL) 通过聚合物支架中的近分泌和旁分泌信号稳定冷冻保存的原代人肝细胞的功能。与目前的方法相比，HEAL 可以在具有正常肝功能的免疫活性小鼠中有效建立。移植 HEAL 的小鼠表现出持续数周的人源化肝功能，包括人类蛋白质的合成、人类药物代谢、药物相互作用和药物引起的肝损伤。在这里，具有 HEAL 的小鼠被用来通过多种给药和监测途径来预测“主要”人类代谢物的不成比例的代谢和毒性。这些进步可能使得能够为多种药物开发和研究应用制造可重复的体内模型。
"Humanized" mice offer a window into aspects of human physiology that are otherwise inaccessible. The best available methods for liver humanization rely on cell transplantation into immunodeficient mice with liver injury but these methods have not gained widespread use due to the duration and variability of hepatocyte repopulation. In light of the significant progress that has been achieved in clinical cell transplantation through tissue engineering, we sought to develop a humanized mouse model based on the facile and ectopic implantation of a tissue-engineered human liver. These human ectopic artificial livers (HEALs) stabilize the function of cryopreserved primary human hepatocytes through juxtacrine and paracrine signals in polymeric scaffolds. In contrast to current methods, HEALs can be efficiently established in immunocompetent mice with normal liver function. Mice transplanted with HEALs exhibit humanized liver functions persistent for weeks, including synthesis of human proteins, human drug metabolism, drug-drug interaction, and drug-induced liver injury. Here, mice with HEALs are used to predict the disproportionate metabolism and toxicity of "major" human metabolites using multiple routes of administration and monitoring. These advances may enable manufacturing of reproducible in vivo models for diverse drug development and research applications.