Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells
Autor: | Andrew P. Hutchins, David P. Ibañez, Liu Yuqing, Wing-Hon Lai, Rui Wei, Shuhan Chen, Wenxia Fan, Miguel A. Esteban, Chung-Wah Siu, Liangxue Lai, Xichen Bao, Ka-Wing Au, Zhiwei Luo, Guichan Liang, Xueyu Hong, Lai-Hung Cheng, Lai-Yung Wong, Yu Huang, Ting Zhou, Zhijian Huang, Dongye Wang, Hung-Fat Tse, Xiwei Wang, Jiayin Yang, Xiaofen Zhong, Yu Wang, Ping Zhao, Baoming Qin, Li Li, Yingying Li, Xiao Yu Tian |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Familial hypercholesterolemia Biochemistry human liver chimeric mice Mice Induced pluripotent stem cell lcsh:QH301-705.5 Mice Knockout lcsh:R5-920 familial hypercholesterolemia Cell Differentiation Pedigree Kexin lipids (amino acids peptides and proteins) hepatocytes Stem cell Proprotein Convertase 9 lcsh:Medicine (General) PCSK9 antibodies medicine.drug medicine.medical_specialty Heterozygote induced pluripotent stem cells Mice Transgenic Biology Article statins Hyperlipoproteinemia Type II 03 medical and health sciences Internal medicine Genetics medicine Animals Humans genetic engineering Chimera PCSK9 LDL receptor Cell Biology Cholesterol LDL Proprotein convertase medicine.disease endothelium-dependent vasodilation 030104 developmental biology Endocrinology Receptors LDL lcsh:Biology (General) Simvastatin Mutation Cancer research Hydroxymethylglutaryl-CoA Reductase Inhibitors Developmental Biology |
Zdroj: | Stem Cell Reports, Vol 8, Iss 3, Pp 605-618 (2017) Stem Cell Reports |
ISSN: | 2213-6711 |
DOI: | 10.1016/j.stemcr.2017.01.027 |
Popis: | Summary Familial hypercholesterolemia (FH) causes elevation of low-density lipoprotein cholesterol (LDL-C) in blood and carries an increased risk of early-onset cardiovascular disease. A caveat for exploration of new therapies for FH is the lack of adequate experimental models. We have created a comprehensive FH stem cell model with differentiated hepatocytes (iHeps) from human induced pluripotent stem cells (iPSCs), including genetically engineered iPSCs, for testing therapies for FH. We used FH iHeps to assess the effect of simvastatin and proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies on LDL-C uptake and cholesterol lowering in vitro. In addition, we engrafted FH iHeps into the liver of Ldlr−/−/Rag2−/−/Il2rg−/− mice, and assessed the effect of these same medications on LDL-C clearance and endothelium-dependent vasodilation in vivo. Our iHep models recapitulate clinical observations of higher potency of PCSK9 antibodies compared with statins for reversing the consequences of FH, demonstrating the utility for preclinical testing of new therapies for FH patients. Graphical Abstract Highlights • Generation of a comprehensive stem cell model for familial hypercholesterolemia • Generation of chimeric mice with engrafted human iPSC-derived iHeps • FH iHeps respond to LDL-C-lowering medications in vitro and in vivo • Our model can be used for preclinical testing of novel LDL-C-lowering medications In this paper, Tse, Esteban and colleagues have generated chimeric mice with human hepatocytes derived from familial hypercholesterolemia (FH) induced pluripotent stem cells. These chimeric mice resemble FH patients in the response to clinical-grade PCSK9 antibodies and statins. These results indicate the utility of this stem cell model for preclinical testing of new LDL-C-lowering therapies for FH patients. |
Databáze: | OpenAIRE |
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