The reconstituted ‘humanized liver’ in TK-NOG mice is mature and functional |
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| Authors: | Masami Hasegawa Kenji Kawai Tetsuya Mitsui Kenji Taniguchi Makoto Monnai Masatoshi Wakui Mamoru Ito Makoto Suematsu Gary Peltz Masato Nakamura Hiroshi Suemizu |
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| Institution: | aBiomedical Research Department, Central Institute for Experimental Animals, 1430 Nogawa, Miyamae, Kawasaki, Kanagawa 216-0001, Japan;bPathology Research Department, Central Institute for Experimental Animals, 1430 Nogawa, Miyamae, Kawasaki, Kanagawa 216-0001, Japan;cLaboratory Animal Research Department, Central Institute for Experimental Animals, 1430 Nogawa, Miyamae, Kawasaki, Kanagawa 216-0001, Japan;dDepartment of Biochemistry and JST ERATO Suematsu Gas Biology Project, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan;eDepartment of Laboratory Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan;fPre-Clinical Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan;gPharmaceutical Research Department II, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan;hChugai Research Institute for Medical Science, Inc., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan;iDepartment of Anesthesia, Stanford University, Stanford, CA 94305-5796, USA;jDepartment of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan |
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| Abstract: | To overcome the limitations of existing models, we developed a novel experimental in vivo platform for replacing mouse liver with functioning human liver tissue. To do this, a herpes simplex virus type 1 thymidine kinase (HSVtk) transgene was expressed within the liver of highly immunodeficient NOG mice (TK-NOG). Mouse liver cells expressing this transgene were ablated after a brief exposure to a non-toxic dose of ganciclovir (GCV), and transplanted human liver cells are stably maintained within the liver (humanized TK-NOG) without exogenous drug. The reconstituted liver was shown to be a mature and functioning “human organ” that had zonal position-specific enzyme expression and a global gene expression pattern representative of mature human liver; and could generate a human-specific profile of drug metabolism. The ‘humanized liver’ could be stably maintained in these mice with a high level of synthetic function for a prolonged period (8 months). This novel in vivo system provides an optimized platform for studying human liver physiology, including drug metabolism, toxicology, or liver regeneration. |
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