Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells

Jiayin Yang; Yu Wang; Ting Zhou; Lai-Yung Wong; Xiao-Yu Tian; Xueyu Hong; Wing-Hon Lai; Ka-Wing Au; Rui Wei; Yuqing Liu; Lai-Hung Cheng; Guichan Liang; Zhijian Huang; Wenxia Fan; Ping Zhao; Xiwei Wang; David P. Ibañez; Zhiwei Luo; Yingying Li; Xiaofen Zhong; Shuhan Chen; Dongye Wang; Li Li; Liangxue Lai; Baoming Qin; Xichen Bao; Andrew P. Hutchins; Chung-Wah Siu; Yu Huang; Miguel A. Esteban; Hung-Fat Tse

doi:10.1016/j.stemcr.2017.01.027

Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells

Jiayin Yang, Yu Wang, Ting Zhou, Lai-Yung Wong, Xiao-Yu Tian, Xueyu Hong, Wing-Hon Lai, Ka-Wing Au, Rui Wei, Yuqing Liu, Lai-Hung Cheng, Guichan Liang, Zhijian Huang, Wenxia Fan, Ping Zhao, Xiwei Wang, David P. Ibañez, Zhiwei Luo, Yingying Li, Xiaofen ZhongShuhan Chen, Dongye Wang, Li Li, Liangxue Lai, Baoming Qin, Xichen Bao, Andrew P. Hutchins, Chung-Wah Siu, Yu Huang, Miguel A. Esteban^*, Hung-Fat Tse

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

28 Citations (Scopus)

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Abstract

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.

Original language	English
Pages (from-to)	605-618
Journal	Stem Cell Reports
Volume	8
Issue number	3
DOIs	https://doi.org/10.1016/j.stemcr.2017.01.027
Publication status	Published - 14 Mar 2017
Externally published	Yes

Bibliographical note

Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

Research Keywords

endothelium-dependent vasodilation
familial hypercholesterolemia
genetic engineering
hepatocytes
human liver chimeric mice
induced pluripotent stem cells
LDL receptor
PCSK9 antibodies
statins

Publisher's Copyright Statement

This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.stemcr.2017.01.027

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Yang, J., Wang, Y., Zhou, T., Wong, L.-Y., Tian, X.-Y., Hong, X., Lai, W.-H., Au, K.-W., Wei, R., Liu, Y., Cheng, L.-H., Liang, G., Huang, Z., Fan, W., Zhao, P., Wang, X., Ibañez, D. P., Luo, Z., Li, Y., ... Tse, H.-F. (2017). Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells. Stem Cell Reports, 8(3), 605-618. https://doi.org/10.1016/j.stemcr.2017.01.027

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title = "Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells",

abstract = "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.",

keywords = "endothelium-dependent vasodilation, familial hypercholesterolemia, genetic engineering, hepatocytes, human liver chimeric mice, induced pluripotent stem cells, LDL receptor, PCSK9 antibodies, statins",

author = "Jiayin Yang and Yu Wang and Ting Zhou and Lai-Yung Wong and Xiao-Yu Tian and Xueyu Hong and Wing-Hon Lai and Ka-Wing Au and Rui Wei and Yuqing Liu and Lai-Hung Cheng and Guichan Liang and Zhijian Huang and Wenxia Fan and Ping Zhao and Xiwei Wang and Iba{\~n}ez, {David P.} and Zhiwei Luo and Yingying Li and Xiaofen Zhong and Shuhan Chen and Dongye Wang and Li Li and Liangxue Lai and Baoming Qin and Xichen Bao and Hutchins, {Andrew P.} and Chung-Wah Siu and Yu Huang and Esteban, {Miguel A.} and Hung-Fat Tse",

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Yang, J, Wang, Y, Zhou, T, Wong, L-Y, Tian, X-Y, Hong, X, Lai, W-H, Au, K-W, Wei, R, Liu, Y, Cheng, L-H, Liang, G, Huang, Z, Fan, W, Zhao, P, Wang, X, Ibañez, DP, Luo, Z, Li, Y, Zhong, X, Chen, S, Wang, D, Li, L, Lai, L, Qin, B, Bao, X, Hutchins, AP, Siu, C-W, Huang, Y, Esteban, MA & Tse, H-F 2017, 'Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells', Stem Cell Reports, vol. 8, no. 3, pp. 605-618. https://doi.org/10.1016/j.stemcr.2017.01.027

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AU - Yang, Jiayin

AU - Wang, Yu

AU - Zhou, Ting

AU - Wong, Lai-Yung

AU - Tian, Xiao-Yu

AU - Hong, Xueyu

AU - Lai, Wing-Hon

AU - Au, Ka-Wing

AU - Wei, Rui

AU - Liu, Yuqing

AU - Cheng, Lai-Hung

AU - Liang, Guichan

AU - Huang, Zhijian

AU - Fan, Wenxia

AU - Zhao, Ping

AU - Wang, Xiwei

AU - Ibañez, David P.

AU - Luo, Zhiwei

AU - Li, Yingying

AU - Zhong, Xiaofen

AU - Chen, Shuhan

AU - Wang, Dongye

AU - Li, Li

AU - Lai, Liangxue

AU - Qin, Baoming

AU - Bao, Xichen

AU - Hutchins, Andrew P.

AU - Siu, Chung-Wah

AU - Huang, Yu

AU - Esteban, Miguel A.

AU - Tse, Hung-Fat

N1 - Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

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N2 - 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.

AB - 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.

KW - endothelium-dependent vasodilation

KW - familial hypercholesterolemia

KW - genetic engineering

KW - hepatocytes

KW - human liver chimeric mice

KW - induced pluripotent stem cells

KW - LDL receptor

KW - PCSK9 antibodies

KW - statins

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M3 - RGC 21 - Publication in refereed journal

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JF - Stem Cell Reports

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ER -

Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells

Abstract

Bibliographical note

Research Keywords

Publisher's Copyright Statement

UN SDGs

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