A mouse with humanized liver as an animal model for predicting drug effects and for studying hepatic viral infection: where to next?

Abstract

Introduction: The mouse is a common model used in evaluating drug metabolism and hepatitis infectivity. However, these models have limited value due to species difference in hepatic functions, leading to the creation of the chimeric mouse 12 years ago. These models were unique in that their hepatocytes had been replaced with human (hu) hepatocytes (dubbed the ‘first-generation chimeric mouse'). Since then, the chimeric mouse has become a practical tool for this area of studies. However, some shortcomings have also been recognized. One major shortcoming is that the mouse cannot mimic hu-liver diseases due to immunodeficiency and also it is unable to provide sufficient amounts of blood for analysis compared to the rat. There are also issues around donor-to-donor variability of hu-hepatocytes such as variable engraftment efficiency.

Areas covered: This review provides the current status of the first-generation chimeric mouse. Furthermore, the authors review studies intended to create a ‘second-generation of the chimeric mouse' in which inflammation/immune-response cells as well as hepatocytes are humanized. A brief comment is also made on studies aiming at producing chimeric rats. Finally, the authors consider induced pluripotent stem cells (iPS cells) as new sources of hu-hepatocytes.

Expert opinion: The authors believe that the current rapid progress in the field of biotechnology should enable us to create a mouse model with a humanized liver that is made by iPS-derived hu-hepatocytes and hu-immune cells. This development will provide researchers with a model that will be able to effectively mimic human liver disease under experimental conditions.

Keywords::

• chimeric mouse
• drug testing
• hepatitis infection model
• mouse with humanized liver

Acknowledgments

The authors acknowledge the studies that were undertaken which have investigated drug metabolism in chimeric mouse livers and hepatitis virus infections led by Professors Y Yokoi of Kanazawa University and K Chayama of Hiroshima University, respectively. Furthermore, the authors express their appreciation to S Sugai for providing them practical information about the success rate of candidate compounds that survive for a sufficient periods of time as drugs for public use. The authors acknowledge permission of reproduction of the Figures from the Nature Publishing Group.

Notes

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