Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11842-7. doi: 10.1073/pnas.1101791108. Epub 2011 Jul 11.
"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.
“人源化”小鼠为研究人类生理学的某些方面提供了窗口，而这些方面是无法直接研究的。目前用于肝脏人源化的最佳方法依赖于将细胞移植到具有肝损伤的免疫缺陷小鼠中，但由于肝细胞再殖的持续时间和可变性，这些方法并未得到广泛应用。鉴于临床细胞移植在组织工程方面取得的重大进展，我们试图开发一种基于简便的异位植入组织工程化人肝的人源化小鼠模型。这些人异位人工肝脏（HEAL）通过聚合物支架中的旁分泌和自分泌信号稳定冷冻保存的原代人肝细胞的功能。与当前的方法相比，HEAL 可以在具有正常肝功能的免疫功能正常的小鼠中有效地建立。移植 HEAL 的小鼠表现出持续数周的人源化肝脏功能，包括合成人蛋白、人药物代谢、药物相互作用和药物性肝损伤。在这里，使用具有 HEAL 的小鼠通过多种给药途径和监测来预测“主要”人代谢物的不成比例代谢和毒性。这些进展可能使制造用于各种药物开发和研究应用的可重复的体内模型成为可能。
