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
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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