新英格兰医学杂志最最新干细胞文献---无私奉献

07292462

Patient-Specific Induced Pluripotent Stem-Cell Models
1 z! X5 u* }! i* s% bfor Long-QT Syndrome3 l6 s8 A$ C) H- _. E
BACKGROUND
3 B  G7 F3 @/ B: v; MLong-QT syndromes are heritable diseases associated with prolongation of the QT3 \$ s: W" m% C" I- x
interval on an electrocardiogram and a high risk of sudden cardiac death due to
5 c( C3 u1 h8 ?: Wventricular tachyarrhythmia. In long-QT syndrome type 1, mutations occur in the
/ h3 \; g5 a8 a: a- Z: i' h5 t- ~KCNQ1 gene, which encodes the repolarizing potassium channel mediating the delayed
* |& l1 O, Z0 V1 Nrectifier IKs current.4 ~+ f" b# Y) o9 e6 U, L* h
METHODS7 F# ?9 x2 C" z" h, ]% y2 k4 h
We screened a family affected by long-QT syndrome type 1 and identified an autosomal
; E5 @4 T( h3 [; t, \dominant missense mutation (R190Q) in the KCNQ1 gene. We obtained7 }  Y' {1 v& o  q  O' n; K
dermal fibroblasts from two family members and two healthy controls and infected
5 d4 r2 _8 ~, T. F7 gthem with retroviral vectors encoding the human transcription factors OCT3/4,# ?! J" N7 c4 C; d0 w1 P0 a0 E
SOX2, KLF4, and c-MYC to generate pluripotent stem cells. With the use of a specific
) s7 _9 k1 Y. D/ ]/ L2 h; j/ n! V( pprotocol, these cells were then directed to differentiate into cardiac myocytes.1 m* o; e2 P; \9 Z+ i! x
RESULTS, s+ H8 a2 I2 Q! n
Induced pluripotent stem cells maintained the disease genotype of long-QT syndrome0 D9 r  ]' c% z' }
type 1 and generated functional myocytes. Individual cells showed a “ventricular,”
& h' ?- w3 Z$ U" J" g“atrial,” or “nodal” phenotype, as evidenced by the expression of celltype–. }5 V" S. z7 R3 A! e
specific markers and as seen in recordings of the action potentials in single
" p& \+ z4 d/ x' X* Q6 ^cells. The duration of the action potential was markedly prolonged in “ventricular”7 c/ V2 y( ]3 z8 i% M& e0 g* w# Z
and “atrial” cells derived from patients with long-QT syndrome type 1, as compared
4 Y4 F7 F7 ~: W, r7 \, Ewith cells from control subjects. Further characterization of the role of the R190Q–
5 f* }! Z" |* f" b) TKCNQ1 mutation in the pathogenesis of long-QT syndrome type 1 revealed a dominant, `+ ?9 \' c# A& s9 G2 W
negative trafficking defect associated with a 70 to 80% reduction in IKs current! M6 P% [& P7 p4 w0 G% g3 i: Z
and altered channel activation and deactivation properties. Moreover, we
* u- D; m5 U5 s- Y$ W4 f3 o/ tshowed that myocytes derived from patients with long-QT syndrome type 1 had an
8 `* X" \& u% Z( c& L! Pincreased susceptibility to catecholamine-induced tachyarrhythmia and that betablockade
/ L; R' h) h; }4 c: Rattenuated this phenotype.
+ U: T  _! a' @  P) m* m' A: ^+ rCONCLUSIONS
; T& [! @6 G' b2 ]  r4 p& I+ rWe generated patient-specific pluripotent stem cells from members of a family affected
4 C* W2 i0 z! C5 {by long-QT syndrome type 1 and induced them to differentiate into functional
# o" d, U3 W3 a- p$ wcardiac myocytes. The patient-derived cells recapitulated the electrophysiological+ \$ U/ X. y! F# ~# l3 P. k5 I/ G
features of the disorder. (Funded by the European Research Council and others.)
' T0 m$ N+ B( {% W, Yn engl j med 363;15 nejm.org october 7, 20101 j+ q# `" z* U- m  [
4 Y3 A: ~+ D. C' _! C8 C( J6 S. D

0 w7 O1 p4 Y8 Y+ u4 D) ihttp://www.nejm.org/doi/pdf/10.1056/NEJMoa0908679

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