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

doi:10.1002/advs.202101188

	Survival-Assured Liver Injury Preconditioning (SALIC) Enables Robust Expansion of Human Hepatocytes in Fah(-/-)Rag2(-/-)IL2rg(-/-) Rats
	Zhang, Ludi 1; Ge, Jian-Yun 2,3; Zheng, Yun-Wen 2,3,4,5; Sun, Zhen 10; Wang, Chenhua 1; Peng, Zhaoliang 6; Wu, Baihua 1; Fang, Mei 4; Furuya, Kinji 2; Ma, Xiaolong 1
刊名	ADVANCED SCIENCE
	2021-08-11
页码	14
关键词	bioreactor humanized liver liver xeno-repopulation pharmacological study
DOI	10.1002/advs.202101188
通讯作者	Zheng, Yun-Wen(ywzheng@md.tsukuba.ac.jp) ; Li, Dali(dlli@bio.ecnu.edu.cn) ; Hui, Lijian(ljhui@sibcb.ac.cn)
英文摘要	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.
资助项目	National Key Research and Development Project[2020YFA0112503] ; National Key Research and Development Project[2019YFA0110802] ; Strategic Priority Research Program of the Chinese Academy of Sciences (CAS)[XDA16020201] ; National Natural Science Foundation of China (NSFC)[82070638] ; National Natural Science Foundation of China (NSFC)[32070797] ; National Natural Science Foundation of China (NSFC)[81770621] ; National Natural Science Foundation of China (NSFC)[31930030] ; National Natural Science Foundation of China (NSFC)[32025023] ; Japan Society for the Promotion of Science (JSPS) KAKENHI[JP18H02866] ; MEXT (Ministry of Education, Culture, Sports, Science & Technology in Japan) scholarship ; Youth Innovation Promotion Association CAS ; SA-SIBS Scholarship Program
WOS关键词	LARGE-ANIMAL-MODEL ; IN-VIVO ; CHIMERIC MICE ; MURINE MODEL ; HEPATITIS-B ; MOUSE-LIVER ; LONG-TERM ; FUMARYLACETOACETATE ; REPOPULATION ; REPLACEMENT
WOS研究方向	Chemistry ; Science & Technology - Other Topics ; Materials Science
语种	英语
出版者	WILEY
WOS记录号	WOS:000684040300001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298082]
专题	中国科学院上海药物研究所
通讯作者	Zheng, Yun-Wen; Li, Dali; Hui, Lijian
作者单位	1.Chinese Acad Sci, Univ Chinese Acad Sci, State Key Lab Cell Biol, Shanghai Inst Biochem & Cell Biol,Ctr Excellence, Shanghai 200031, Peoples R China 2.Univ Tsukuba, Dept Gastrointestinal & Hepatobiliary Pancreat Su, Fac Med, Tsukuba, Ibaraki 3058575, Japan 3.Wuyi Univ, Sch Biotechnol & Heath Sci, Guangdong Prov Key Lab Large Anim Models Biomed, Jiangmen 529020, Guangdong, Peoples R China 4.Jiangsu Univ, Affiliated Hosp, Inst Regenerat Med, Zhenjiang 212001, Jiangsu, Peoples R China 5.Yokohama City Univ, Sch Med, Yokohama, Kanagawa 2340006, Japan 6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 7.East China Normal Univ, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai 200241, Peoples R China 8.East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China 9.Univ Yamanashi, Dept Mol Pathol, Fac Med, Interdisciplinary Grad Sch Med, Shimokato, Yamanashi 4093898, Japan 10.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Ludi,Ge, Jian-Yun,Zheng, Yun-Wen,et al. Survival-Assured Liver Injury Preconditioning (SALIC) Enables Robust Expansion of Human Hepatocytes in Fah(-/-)Rag2(-/-)IL2rg(-/-) Rats[J]. ADVANCED SCIENCE,2021:14.
APA	Zhang, Ludi.,Ge, Jian-Yun.,Zheng, Yun-Wen.,Sun, Zhen.,Wang, Chenhua.,...&Hui, Lijian.(2021).Survival-Assured Liver Injury Preconditioning (SALIC) Enables Robust Expansion of Human Hepatocytes in Fah(-/-)Rag2(-/-)IL2rg(-/-) Rats.ADVANCED SCIENCE,14.
MLA	Zhang, Ludi,et al."Survival-Assured Liver Injury Preconditioning (SALIC) Enables Robust Expansion of Human Hepatocytes in Fah(-/-)Rag2(-/-)IL2rg(-/-) Rats".ADVANCED SCIENCE (2021):14.