The development of humanized liver with rag1 knockout rats

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Abstract

Background The animal model with humanized liver is useful for testing drug metabolism and toxicity in preclinical studies. A mouse model has been reported in which the liver was repopulated more than 90% with human hepatocytes; however, in the rat, the target is far from being reached. In this study, we attempt to develop a humanized liver model with an immunodeficient rat. Methods Rag1 knockout rats were treated with neonatal thymectomy. At 3 and 4 weeks of age, they were injected with hepatotoxin retrorsine; 2 weeks after, the animals were subjected to 70% partial hepatectomy and transplanted with immature human hepatocytes via portal vein. The recipients were also treated with anti-asialo GM1 antibody weekly from the day before transplantation and were injected with FK506 every 3 days after transplantation. Results In Rag1 knockout rats, B lymphocytes were deleted almost completely in peripheral blood. However, T and natural killer (NK) lymphocytes were kept present. When they were treated additionally with neonatal thymectomy for T-lymphocyte deletion and suppressed neutralized NK lymphocytes with anti-asialo GM1, B, T, and NK cells in lymphocytes were reduced to very low levels of 0.75%, 1.58%, and 0.26%, respectively. After transplanting human donor hepatocytes into retrorsine-treated recipient livers, at week 3 the human cell-derived hepatic colonies were expanded in the recipient liver and the liver repopulation rate with human hepatocytes reached approximately 17%. The human hepatocyte-specific genes, albumin, CYP3A4, CYP2C18, and CYP2C9, also could be detected in the recipient rat. Conclusion It is possible to generate a chimera animal with humanized liver in a novel severely immunodeficient rat model. © 2014 by Elsevier Inc. All rights reserved.

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Tsuchida, T., Zheng, Y. W., Zhang, R. R., Takebe, T., Ueno, Y., Sekine, K., & Taniguchi, H. (2014). The development of humanized liver with rag1 knockout rats. In Transplantation Proceedings (Vol. 46, pp. 1191–1193). Elsevier USA. https://doi.org/10.1016/j.transproceed.2013.12.026

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