人干细胞多潜能态基态研究新突破－Human embryonic stem cells with biological and

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摘要与摘要翻译（翻译水平不太好，大家感兴趣还是看看这篇文章）（文章附后）0 N# J( }* b/ w# c; t
Human and mouse embryonic stem cells (ESCs) are derived from
, X3 y" Y' m' h7 b& h" y$ Iblastocyst-stage embryos but have very different biological properties,8 Z/ t6 J) w& G' g5 J; \
and molecular analyses suggest that the pluripotent state of% x+ A  K/ @0 h5 D- L! Z
human ESCs isolated so far corresponds to that of mouse-derived
/ D1 Z: w% U% X2 C8 R+ M2 R) R' N9 Repiblast stem cells (EpiSCs). Here we rewire the identity of conventional; b, x4 j/ Y& k) m+ K
human ESCs into a more immature state that extensively
$ T7 }0 M7 q/ Q0 K/ }7 _7 Zshares defining features with pluripotent mouse ESCs. This was
- c, }: E  l1 d2 X. p3 Aachieved by ectopic induction of Oct4, Klf4, and Klf2 factors
: `6 _% Y2 ~: R; v$ `7 t3 gcombined with LIF and inhibitors of glycogen synthase kinase 3β; n9 D1 s3 K9 \% L$ d: I: C0 k" j
(GSK3β) and mitogen-activated protein kinase (ERK1/2) pathway.& u# A6 x8 F- e/ A9 |
Forskolin, a protein kinase A pathway agonist which can induce3 F1 [( l. X" p& u" ?; v
Klf4 and Klf2 expression, transiently substitutes for the requirement' X/ J' F4 Q3 ]" j# k6 [/ T+ h
for ectopic transgene expression. In contrast to conventional human
5 F7 H* P- o8 I/ o9 j& _) ]ESCs, these epigenetically convertedcellshave growth properties,an
7 V; ]* j/ p7 t0 R# }" o; dX-chromosome activation state (XaXa), a gene expression profile,
% Y# L6 i2 C# t2 Tand a signaling pathway dependence that are highly similar to those
) V" }0 x2 s" r9 Z* g# V: [of mouse ESCs. Finally, the same growth conditions allow the derivation7 @( z: E' O) P1 p8 q! _3 k  @
of human induced pluripotent stem (iPS) cells with similar
* c. F* Z9 F& W) nproperties as mouse iPS cells. The generation of validated “naïve”5 I. U+ e4 ~& h+ S0 |
human ESCs will allow the molecular dissection of a previously undefined
! X5 Q3 o; S3 N+ H; T  v: R1 c. Spluripotent state in humans and may open up new opportunities7 h0 {& n6 E( j4 `: E; v% M) [
for patient-specific, disease-relevant research.2 m# l- T( |, Y# b3 T: A% R$ h
人和鼠的胚胎干细胞ESC都是来自于胚胎胚泡期的细胞，但它们的生物学特性存在很大差异，而且分子水平研究表明分离的人胚胎干细胞ESC与小鼠的外胚层干细胞(EpiSCs)有相当的多潜能能态。我们的研究表明，人的ESC细胞可以转变到一种更不成熟状态，在这种状态下，人的ESC细胞广泛地呈现小鼠ESC细胞的特征。这一研究通过表达Oct4,Klf2和Klf4因子并联合使用LIF及GSK3β、ERK1/2抑制剂(PD/CH)而实现。Forskolin(血小板凝集抑制剂)，一种蛋白激酶A信号通路的激活剂，它能够诱导Klf2和Klf4因子表达,瞬间替代相应转基因的表达。与传统的人ESC细胞相比，这些表观遗传改变的ESC细胞与小鼠ESC细胞高度相似：生长特性、一条X染色体被激活（XaXi→XaXa）、基因转录集、信号通路。最后，在相同的培养条件下，证实人源iPS细胞与小鼠源iPS细胞具相似特性。人“基态“ESC细胞的产生将有助于从分子水平分析人ESC细胞先前未定义的多潜能状态，也为患者特异性和疾病相关性研究开辟新途径。

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