JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia.
JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia.
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DOI：
10.1002/hep.25871
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发表时间：
2012-12
期刊：
影响因子：
13.5
通讯作者：
Duncan, Stephen A.
中科院分区：
文献类型：
--
作者：
Cayo, Max A.;Cai, Jun;DeLaForest, Ann;Noto, Fallon K.;Nagaoka, Masato;Clark, Brian S.;Collery, Ross F.;Si-Tayeb, Karim;Duncan, Stephen A.
血浆中低密度脂蛋白胆固醇（LDL-C）水平升高是心血管疾病（CVD）的主要原因，心血管疾病是全球死亡的主要原因。全基因组关联研究（GWAS）已经确定了95个与脂质/胆固醇代谢控制相关的基因座。尽管GWAS结果具有高度挑衅性，但由于难以获得受影响患者的适当细胞，因此直接分析特定等位基因变异在调节LDL-C中的作用具有挑战性。负责控制胆固醇和脂质流动的主要细胞类型是肝细胞。最近，我们已经表明，具有肝细胞特征的细胞可以从人诱导多能干细胞（iPSC）中产生。这一发现提出了使用患者特异性iPSC衍生的肝细胞来研究GWAS基因座在调节脂质代谢中的功能贡献的可能性。为了测试这种方法的有效性，我们从具有导致家族性高胆固醇血症（FH）的低密度脂蛋白受体（LDLR）基因突变的患者中产生iPSC。结论：我们证明了1）肝细胞可以从FH iPSC有效地产生，2）与对照细胞相比，FH iPSC衍生的肝细胞缺乏LDL-C摄取，3）对照而非FH iPS细胞衍生的肝细胞响应于洛伐他汀而增加LDL摄取，和4）FH iPSC衍生的肝细胞显示脂化ApoB-100分泌的显著升高。累积地，这些发现表明FH iPSC衍生的肝细胞概括了培养物中FH的复杂病理生理学。这些结果还证实，患者特异性iPSC衍生的肝细胞可用于明确确定等位基因变异在调节脂质和胆固醇代谢中的功能贡献，并可能为鉴定CVD的新型治疗提供平台。
Elevated levels of low density lipoprotein cholesterol (LDL-C) in plasma are a major contributor to cardiovascular disease (CVD), which is the leading cause of death worldwide. Genome–wide association studies (GWAS) have identified 95 loci that associate with control of lipid/cholesterol metabolism. Although GWAS results are highly provocative, direct analyses of the contribution of specific allelic variations in regulating LDL-C has been challenging due to the difficulty in accessing appropriate cells from affected patients. The primary cell type responsible for controlling cholesterol and lipid flux is the hepatocyte. Recently we have shown that cells with hepatocyte characteristics can be generated from human induced pluripotent stem cells (iPSC). This finding raises the possibility of using patient–specific iPSC–derived hepatocytes to study the functional contribution of GWAS loci in regulating lipid metabolism. To test the validity of this approach we produced iPSCs from a patient with mutations in the Low density lipoprotein receptor(LDLR) gene that result in familial hypercholesterolemia (FH). Conclusion: We demonstrate that 1) hepatocytes can be efficiently generated from FH iPSCs, 2) in contrast to control cells FH iPSC–derived hepatocytes are deficient in LDL–C uptake, 3) control but not FH iPS cell–derived hepatocytes increase LDL uptake in response to lovastatin, and 4) FH iPSC–derived hepatocytes display a marked elevation in secretion of lipidated ApoB-100. Cumulatively, these findings demonstrate that FH iPSC–derived hepatocytes recapitulate the complex pathophysiology of FH in culture. These results also establish that patient specific iPSC–derived hepatocytes could be used to definitively determine the functional contribution of allelic variation in regulating lipid and cholesterol metabolism and could potentially provide a platform for the identification of novel treatments of CVD.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1161/circgenetics.108.795013
发表时间：
2008-12
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Voora D;Shah SH;Reed CR;Zhai J;Crosslin DR;Messer C;Salisbury BA;Ginsburg GS
通讯作者：
Ginsburg GS
影响因子：
64.5
作者：
Park IH;Arora N;Huo H;Maherali N;Ahfeldt T;Shimamura A;Lensch MW;Cowan C;Hochedlinger K;Daley GQ
通讯作者：
Daley GQ
影响因子：
6.5
作者：
Tremblay, AJ;Lamarche, B;Couture, P
通讯作者：
Couture, P
影响因子：
64.5
作者：
Soldner F;Hockemeyer D;Beard C;Gao Q;Bell GW;Cook EG;Hargus G;Blak A;Cooper O;Mitalipova M;Isacson O;Jaenisch R
通讯作者：
Jaenisch R