NEJM--LQTS患者皮肤成纤维细胞体外诱导分化细胞模型--引发新思考

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5 _8 M  U, d: C7 H: t; T7 EPatient-Specific Induced Pluripotent Stem Cell Models for Long-QT Syndrome( C9 t. L0 U- Y/ l: a

" {" }' W8 J4 I; V& q/ YABSTRACT
( w* x) E; O. ^& U+ _% w& uBACKGROUND5 y4 R" [" I8 F, ~/ S
Long-QT syndromes are heritable diseases associated with prolongation of the QT interval on an electrocardiogram and a high risk of sudden cardiac death due to ventricular tachyarrhythmia. In long-QT syndrome type 1, mutations occur in the KCNQ1 gene, which encodes the repolarizing potassium channel mediating the delayed rectifier IKs current.
1 I# b; t, n! E" DMETHODS
2 y1 s* }! u1 J+ k. W" oWe screened a family affected by long-QT syndrome type 1 and identified an autosomal dominant missense mutation (R190Q) in the  KCNQ1 gene. We obtained dermal fibroblasts from two family members and two healthy controls and infected them with retroviral vectors encoding the human transcription factors OCT3/4,SOX2, KLF4, and c-MYC to generate pluripotent stem cells. With the use of a specific protocol, these cells were then directed to differentiate into cardiac myocytes.
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Induced pluripotent stem cells maintained the disease genotype of long-QT syndrome type 1 and generated functional myocytes. Individual cells showed a “ventricular,” “atrial,” or “nodal” phenotype, as evidenced by the expression of cell type–specific markers and as seen in recordings of the action potentials in single cells. The duration of the action potential was markedly prolonged in “ventricular”and “atrial” cells derived from patients with long-QT syndrome type 1, as compared with cells from control subjects. Further characterization of the role of the R190Q-KCNQ1 mutation in the pathogenesis of long-QT syndrome type 1 revealed a dominant negative trafficking defect associated with a 70 to 80% reduction in IKs current and altered channel activation and deactivation properties. Moreover, we showed that myocytes derived from patients with long-QT syndrome type 1 had an increased susceptibility to catecholamine-induced tachyarrhythmia and that beta-blockade attenuated this phenotype
3 g+ C( @4 D8 `' Y  u; r6 HCONCLUSIONS
$ u% X! i- D* D* W" G$ D. uWe generated patient-specific pluripotent stem cells from members of a family affected by long-QT syndrome type 1 and induced them to differentiate into functional cardiac myocytes. The patient-derived cells recapitulated the electrophysiological 2 W7 `* q2 f5 _' }5 l6 B
features of the disorder. (Funded by the European Research Council and others.)! w% h: k3 V' Q# S9 g: }: O
利用特殊患病个体，提取其细胞诱导分化为特殊疾病模型，从而针对其展开一系列的临床基础研究，以及个体化治疗是本文提供的一条干细胞发展的新思路；有可鉴之处。

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