DataVXAdvanced SciencePaper
journal article·2021-10Open access

Survival‐Assured Liver Injury Preconditioning (SALIC) Enables Robust Expansion of Human Hepatocytes in Fah–/–Rag2–/–IL2rg–/– Rats

Ludi Zhang, Jian‐Yun Ge, Yun‐Wen Zheng, Zhen Sun, Chenhua Wang, Zhaoliang Peng, Baihua Wu, Mei Fang, Kinji Furuya, Xiaolong Ma, Yanjiao Shao, Nobuhiro Ohkohchi, Tatsuya Oda, Jianglin Fan, Guoyu Pan, Dali Li, Lijian Hui

Advanced Science· Volume 8· Issue 19
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Source abstract

Abstract

Abstract Although liver‐humanized animals are desirable tools for drug development and expansion of human hepatocytes in large quantities, their development is restricted to mice. In animals larger than mice, a precondition for efficient liver humanization remains preliminary because of different xeno‐repopulation kinetics in livers of larger sizes. Since rats are ten times larger than mice and widely used in pharmacological studies, liver‐humanized rats are more preferable. Here, Fah–/–Rag2–/–IL2rg–/– (FRG) rats are generated by CRISPR/Cas9, showing accelerated liver failure and lagged liver xeno‐repopulation compared to FRG mice. A survival‐assured liver injury preconditioning (SALIC) protocol, which consists of retrorsine pretreatment and cycling 2‐(2‐nitro‐4‐trifluoromethylbenzoyl)‐1,3‐cyclohexanedione (NTBC) administration by defined concentrations and time intervals, is developed to reduce the mortality of FRG rats and induce a regenerative microenvironment for xeno‐repopulation. Human hepatocyte repopulation is boosted to 31 ± 4% in rat livers at 7 months after transplantation, equivalent to approximately a 1200‐fold expansion. Human liver features of transcriptome and zonation are reproduced in humanized rats. Remarkably, they provide sufficient samples for the pharmacokinetic profiling of human‐specific metabolites. This model is thus preferred for pharmacological studies and human hepatocyte production. SALIC may also be informative to hepatocyte transplantation in other large‐sized species.
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Research context

OpenAlex topics: Organ Transplantation Techniques and Outcomes · Liver physiology and pathology · Anesthesia and Neurotoxicity Research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences University of Chinese Academy of Science Shanghai 200031 China

Department of Gastrointestinal and Hepato‐Biliary‐Pancreatic Surgery, Faculty of Medicine University of Tsukuba Tsukuba Ibaraki 305‐8575 Japan

Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine School of Biotechnology and Heath Sciences Wuyi University Jiangmen Guangdong 529020 China

Institute of Regenerative Medicine Affiliated Hospital of Jiangsu University Jiangsu University Zhenjiang Jiangsu 212001 China

Yokohama City University School of Medicine Yokohama Kanagawa 234‐0006 Japan

School of Life Science and Technology ShanghaiTech University Shanghai 201210 China

Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 China

Department of Molecular Pathology, Faculty of Medicine Interdisciplinary Graduate School of Medicine University of Yamanashi Shimokato Yamanashi 409‐3898 Japan

School of Life Science, Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences Hangzhou 310024 China

Institute for Stem Cell and Regeneration Chinese Academy of Sciences Beijing 100101 China

Bio‐Research Innovation Center Shanghai Institute of Biochemistry and Cell Biology Suzhou Jiangsu 215121 China

Funding

Chinese Academy of Sciences · National Natural Science Foundation of China · Japan Society for the Promotion of Science · Youth Innovation Promotion Association of the Chinese Academy of Sciences

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