The ground state of embryonic stem cell self-renewal
The ground state of embryonic stem cell self-renewal
复制标题
DOI：
10.1038/nature06968
复制
发表时间：
2008-05-22
期刊：
影响因子：
64.8
通讯作者：
Smith, Austin
中科院分区：
文献类型：
--
作者：
Ying, Qi-Long;Wray, Jason;Smith, Austin
自从首次描述多能小鼠胚胎干（ES）细胞以来的三十年中（1，2），它们已经通过使用饲养细胞、条件培养基、细胞因子、生长因子、激素、胎牛血清和血清提取物的各种经验组合来衍生和维持（1 - 7）。因此，ES细胞自我更新通常被认为依赖于专用转录回路的多因子刺激，其中最突出的是细胞因子对STAT 3的激活（参考文献8）。然而，在这里，我们表明，外部刺激是胚胎干细胞的衍生，繁殖和多能性。自我更新是通过消除丝裂原活化蛋白激酶的分化诱导信号而实现的。糖原合成酶激酶3的额外抑制巩固生物合成能力并抑制残余分化。通过分离遗传上缺乏STAT3的ES细胞来证实细胞因子信号传导的完全旁路。这些发现表明，胚胎干细胞有一个天生的自我复制程序，不需要外部指令。这种特性可能是它们潜在的致瘤性的原因。自我更新的最低要求的划定，现在提供了一个明确的平台，精确的描述和解剖的多能状态。
In the three decades since pluripotent mouse embryonic stem (ES) cells were first described(1,2) they have been derived and maintained by using various empirical combinations of feeder cells, conditioned media, cytokines, growth factors, hormones, fetal calf serum, and serum extracts(1-7). Consequently ES-cell self-renewal is generally considered to be dependent on multifactorial stimulation of dedicated transcriptional circuitries, pre-eminent among which is the activation of STAT3 by cytokines (ref. 8). Here we show, however, that extrinsic stimuli are dispensable for the derivation, propagation and pluripotency of ES cells. Self-renewal is enabled by the elimination of differentiation-inducing signalling from mitogen-activated protein kinase. Additional inhibition of glycogen synthase kinase 3 consolidates biosynthetic capacity and suppresses residual differentiation. Complete bypass of cytokine signalling is confirmed by isolating ES cells genetically devoid of STAT3. These findings reveal that ES cells have an innate programme for self-replication that does not require extrinsic instruction. This property may account for their latent tumorigenicity. The delineation of minimal requirements for self-renewal now provides a defined platform for the precise description and dissection of the pluripotent state.