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,Liu Yuqing,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 +30 more
Reads0
Chats0
TLDR
The 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.Abstract:
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.read more
Citations
More filters
Journal ArticleDOI
Induced pluripotent stem cells in disease modelling and drug discovery.
R. Grant Rowe,George Q. Daley +1 more
TL;DR: This Review summarizes the progress in iPSC-based disease modelling over the past decade, with a focus on 3D organoid systems and chimeric models being exploited for new therapeutic approaches.
Journal ArticleDOI
Highly efficient and expedited hepatic differentiation from human pluripotent stem cells by pure small-molecule cocktails
TL;DR: Highly efficient and expedited hepatic differentiation from human pluripotent stem cells could be achieved by the present novel, pure, small-molecule cocktails strategy, which provides a cost-effective platform for in vitro studies of the molecular mechanisms of human liver development and holds significant potential for future clinical applications.
Journal ArticleDOI
Distinct Gene Expression and Epigenetic Signatures in Hepatocyte-like Cells Produced by Different Strategies from the Same Donor
Yimeng Gao,Xiaoran Zhang,L. Zhang,Jin Cen,Xuan Ni,Xiaoying Liao,Chenxi Yang,Ying Li,Xiaotao Chen,Zhao Zhang,Yajing Shu,Xin Cheng,David C. Hay,Dongmei Lai,Guoyu Pan,Gang Wei,Lijian Hui,Lijian Hui +17 more
TL;DR: In conclusion, functional HLCs can be obtained from the same donor using two strategies and displayed partial but markedly improved hepatic function following transplantation in vivo, demonstrating plasticity and the potential for cell-based modeling in the dish and cell- based therapy in the future.
Journal ArticleDOI
Pluripotent stem cell-derived bile canaliculi-forming hepatocytes to study genetic liver diseases involving hepatocyte polarity.
Arend W. Overeem,Karin Klappe,Silvia Parisi,Petra Klöters-Planchy,Lavinija Matakovic,Marines du Teil Espina,Christian Drouin,Karl Heinz Weiss,Sven C.D. van IJzendoorn +8 more
TL;DR: Functional cell polarity can be achieved in patient pluripotent stem cell-derived hiHeps, enabling, for the first time, the study of the endogenous mutant proteins, patient-specific pathogenesis and drug responses for diseases where hepatocyte polarity is a key factor.
Journal ArticleDOI
Low-density lipoprotein receptor-deficient hepatocytes differentiated from induced pluripotent stem cells allow familial hypercholesterolemia modeling, CRISPR/Cas-mediated genetic correction, and productive hepatitis C virus infection
Jérôme Caron,Véronique Pène,Laia Tolosa,Maxime Villaret,E. Luce,Angélique Fourrier,Jean-Marie Heslan,Samir Saheb,Eric Bruckert,María José Gómez-Lechón,Tuan Huy Nguyen,Arielle R. Rosenberg,Anne Weber,Anne Dubart-Kupperschmitt +13 more
TL;DR: This work provides the first LDLR-null FH cell model and its corrected counterpart to study the regulation of cholesterol metabolism and host determinants of HCV life cycle, and a platform to screen drugs for treating dyslipidemia and HCV infection.
References
More filters
Journal ArticleDOI
Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors
Kazutoshi Takahashi,Koji Tanabe,Mari Ohnuki,Megumi Narita,Tomoko Ichisaka,Kiichiro Tomoda,Shinya Yamanaka +6 more
TL;DR: It is demonstrated that iPS cells can be generated from adult human fibroblasts with the same four factors: Oct3/4, Sox2, Klf4, and c-Myc.
Journal ArticleDOI
A receptor-mediated pathway for cholesterol homeostasis.
TL;DR: The approach was to apply the techniques of cell culture to unravel the postulated regulatory defect in FH, which led to the discovery of a cell surface receptor for a plasma cholesterol transport protein called low density lipoprotein (LDL) and to the elucidation of the mechanism by which this receptor mediates feedback control of cholesterol synthesis.
Journal ArticleDOI
Induction of Pluripotent Stem Cells From Adult Human Fibroblasts by Defined Factors
Kazutoshi Takahashi,Koji Tanabe,Mari Ohnuki,Megumi Narita,Tomoko Ichisaka,Kiichiro Tomoda,Shinya Yamanaka +6 more
TL;DR: This work generated induced pluripotent stem cells capable of germline transmission from murine somatic cells by transd, and demonstrated the ability of these cells to reprogram into patient-specific and disease-specific stem cells.
Journal ArticleDOI
Ezetimibe added to statin therapy after acute coronary syndromes
TL;DR: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes and lowering LDL cholesterol to levels below previous targets provided additional benefit.
Journal ArticleDOI
Human Induced Pluripotent Stem Cells Free of Vector and Transgene Sequences
Junying Yu,Junying Yu,Kejin Hu,Kim Smuga-Otto,Kim Smuga-Otto,Shulan Tian,Shulan Tian,Ron Stewart,Ron Stewart,Igor I. Slukvin,James A. Thomson +10 more
TL;DR: Results demonstrate that reprograming human somatic cells does not require genomic integration or the continued presence of exogenous reprogramming factors and removes one obstacle to the clinical application of human iPS cells.