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 Models4 c9 s- Z5 v8 s8 q9 ]. s- a
for Long-QT Syndrome5 g8 B1 r, C: E' @. m
BACKGROUND% w% R7 B3 p# x. d
Long-QT syndromes are heritable diseases associated with prolongation of the QT. z5 `8 `& J) I$ j- V
interval on an electrocardiogram and a high risk of sudden cardiac death due to8 W+ u' M6 |" `( g+ r4 S$ ~
ventricular tachyarrhythmia. In long-QT syndrome type 1, mutations occur in the
2 W6 h/ @! ^, ]! MKCNQ1 gene, which encodes the repolarizing potassium channel mediating the delayed
+ u2 c, o& s) v0 I; x) nrectifier IKs current.' F9 y  x/ W$ V
METHODS
' S! `$ X) ?' z& K2 \3 YWe screened a family affected by long-QT syndrome type 1 and identified an autosomal
4 {  H4 f  \, G- R( o- C5 mdominant missense mutation (R190Q) in the KCNQ1 gene. We obtained' c  d4 t: K' g9 o0 d
dermal fibroblasts from two family members and two healthy controls and infected; L  L& t: T) i/ x2 P4 J# q' ~
them with retroviral vectors encoding the human transcription factors OCT3/4,( n6 i- R# S) P
SOX2, KLF4, and c-MYC to generate pluripotent stem cells. With the use of a specific) h& D2 Y& v" a& j  q% v
protocol, these cells were then directed to differentiate into cardiac myocytes.6 t4 s( C$ Q5 g6 ~2 Y2 I1 n
RESULTS
  Z6 M& M0 O' I' N& MInduced pluripotent stem cells maintained the disease genotype of long-QT syndrome* }  e9 p) h4 m; F
type 1 and generated functional myocytes. Individual cells showed a “ventricular,”# H. W" _# S: S) k! H
“atrial,” or “nodal” phenotype, as evidenced by the expression of celltype–
. Z& G& K1 q7 Ospecific markers and as seen in recordings of the action potentials in single6 D1 y& m; R7 C: R! F2 ]% O
cells. The duration of the action potential was markedly prolonged in “ventricular”
9 M: u6 t) h' D& k% P- tand “atrial” cells derived from patients with long-QT syndrome type 1, as compared; |9 @! _. X$ z( I
with cells from control subjects. Further characterization of the role of the R190Q–
, a! {5 v5 a8 V* GKCNQ1 mutation in the pathogenesis of long-QT syndrome type 1 revealed a dominant* [3 h" x( j* c( r+ i) D+ A
negative trafficking defect associated with a 70 to 80% reduction in IKs current
' z7 f- a& r5 j: E4 wand altered channel activation and deactivation properties. Moreover, we3 G) V/ C4 c1 Q
showed that myocytes derived from patients with long-QT syndrome type 1 had an) T6 E1 f, b1 r' y5 i) t9 U
increased susceptibility to catecholamine-induced tachyarrhythmia and that betablockade
2 `2 Z: m, `2 Z1 t* z4 Cattenuated this phenotype.
  n7 I# l1 j5 r8 i/ {# \CONCLUSIONS
0 N) B' `% {) e* e- bWe generated patient-specific pluripotent stem cells from members of a family affected
1 ^+ y5 g3 Q' ^& p* Gby long-QT syndrome type 1 and induced them to differentiate into functional/ U9 D# Q' f1 q, E! U) }& y
cardiac myocytes. The patient-derived cells recapitulated the electrophysiological* r- ?) S; Q3 K3 q, C5 r
features of the disorder. (Funded by the European Research Council and others.)
6 i1 t( N3 a" ~+ n/ Q1 Z8 hn engl j med 363;15 nejm.org october 7, 2010
! I9 h, `9 h, X0 _# b7 p$ v
7 p6 d" R' R7 `+ M5 q  ~- E
# D* C1 v; ]9 z5 R' j3 [1 ?, [http://www.nejm.org/doi/pdf/10.1056/NEJMoa0908679

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