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）; ]7 x- W! n3 Z  G/ N# i, u
Human and mouse embryonic stem cells (ESCs) are derived from
$ w/ N: T4 L/ ?  f5 _- M: L2 Rblastocyst-stage embryos but have very different biological properties,0 f2 V  f& X% D6 A$ H
and molecular analyses suggest that the pluripotent state of
7 p9 J- T0 E9 e0 m( l) c& `human ESCs isolated so far corresponds to that of mouse-derived0 c3 ^/ Y7 P$ Z. H4 |
epiblast stem cells (EpiSCs). Here we rewire the identity of conventional. Z. {4 [7 l  A2 {
human ESCs into a more immature state that extensively
& d" ]2 G* m8 W/ `- Y. W8 {7 eshares defining features with pluripotent mouse ESCs. This was  a) X$ ?* W! w$ I" U4 {4 m
achieved by ectopic induction of Oct4, Klf4, and Klf2 factors1 e& I1 ]' e& h- Q5 v
combined with LIF and inhibitors of glycogen synthase kinase 3β! V$ W9 ?6 ]: k! ^& W$ E
(GSK3β) and mitogen-activated protein kinase (ERK1/2) pathway.$ ]% r# W3 Y) S) {( l
Forskolin, a protein kinase A pathway agonist which can induce
5 i6 D, V' t' ~+ KKlf4 and Klf2 expression, transiently substitutes for the requirement
# Q; [! t+ [1 B5 Bfor ectopic transgene expression. In contrast to conventional human, y* c$ _3 B* K
ESCs, these epigenetically convertedcellshave growth properties,an' O  _' N1 o4 O& v
X-chromosome activation state (XaXa), a gene expression profile,
  M2 s. ~4 h) j9 Aand a signaling pathway dependence that are highly similar to those, A2 O% O0 [6 W, Q9 X
of mouse ESCs. Finally, the same growth conditions allow the derivation
% M9 I. B6 `; Bof human induced pluripotent stem (iPS) cells with similar
7 ]4 B9 d3 r' _4 C3 r% B' l  o$ W$ Uproperties as mouse iPS cells. The generation of validated “naïve”
# |' {# L8 W3 p# R; E, V- bhuman ESCs will allow the molecular dissection of a previously undefined4 E; m5 Q. r( n; R% z$ D$ S
pluripotent state in humans and may open up new opportunities
+ ]) ]$ v8 U+ h! {; u* Qfor patient-specific, disease-relevant research.2 K5 z& y7 [0 E6 q$ [: Y  z
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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