Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells.
Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells.
复制标题
用来自家族性高胆固醇血症诱导的多能干细胞的肝细胞产生人肝嵌合小鼠
DOI：
10.1016/j.stemcr.2017.01.027
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发表时间：
2017-03-14
影响因子：
5.9
通讯作者：
Tse HF
中科院分区：
文献类型：
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作者：
Yang J;Wang Y;Zhou T;Wong LY;Tian XY;Hong X;Lai WH;Au KW;Wei R;Liu Y;Cheng LH;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 CW;Huang Y;Esteban MA;Tse HF
家族性高胆固醇血症(FH)会导致血液中低密度脂蛋白胆固醇(LDL-C)的升高，并增加早发性心血管疾病的风险。探索FH新疗法的一个警告是缺乏足够的实验模型。我们已经建立了一个全面的FH干细胞模型，使用来自人诱导的多能干细胞(IPSCs)的分化肝细胞(IPSCs)，包括基因工程的IPSCs，用于测试FH的治疗方法。我们使用FH iHEPS来评估辛伐他汀和前蛋白转换酶枯草杆菌/可信9型(PCSK9)抗体在体外对低密度脂蛋白摄取和降低胆固醇的影响。此外，我们将FH iHeps植入Ldlr−/−/RAG2−/−/IL2RG−/−小鼠的肝脏，并评估了这些药物对体内低密度脂蛋白-C清除和内皮依赖性血管扩张的影响。我们的IHEP模型概括了PCSK9抗体与他汀类药物相比在逆转FH后果方面的更高效力的临床观察，展示了对FH患者进行新疗法临床前测试的有效性。家族性高胆固醇血症综合干细胞模型的建立移植人iPSC来源的iHeps FH iHeps嵌合小鼠体外和体内对降低密度脂蛋白药物的反应我们的模型可用于新型降低密度脂蛋白药物的临床前测试在本论文中，Tse、Esteban及其同事利用家族性高胆固醇血症(FH)诱导的多能干细胞来源的人肝细胞构建了嵌合小鼠。这些嵌合小鼠对临床级PCSK9抗体和他汀类药物的反应类似于FH患者。这些结果表明，该干细胞模型可用于FH患者降低低密度脂蛋白新疗法的临床前测试。
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. 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.