Wellcome Trust Centre for Stem Cell Research, University of Cambridge, UK.
Cell Stem Cell. 2009 Dec 4;5(6):597-609. doi: 10.1016/j.stem.2009.11.003.
Embryonic stem cell (ESC) pluripotency is dependent on an intrinsic gene regulatory network centered on Oct4. Propagation of the pluripotent state is stimulated by the cytokine leukemia inhibitory factor (LIF) acting through the transcriptional regulator Stat3. Here, we show that this extrinsic stimulus converges with the intrinsic circuitry in Krüppel-factor activation. Oct4 primarily induces Klf2 while LIF/Stat3 selectively enhances Klf4 expression. Overexpression of either factor reduces LIF dependence, but with quantitative and qualitative differences. Unlike Klf4, Klf2 increases ESC clonogenicity, maintains undifferentiated ESCs in the genetic absence of Stat3, and confers resistance to BMP-induced differentiation. ESCs expanded with Klf2 remain capable of contributing to adult chimeras. Postimplantation-embryo-derived EpiSCs lack both Klf2 and Klf4 and expression of either can reinstate naive pluripotency. These findings indicate that Oct4 and Stat3 intersect in directing expression of Klf transcriptional regulators with overlapping properties that additively reinforce ground-state ESC pluripotency, identity, and self-renewal.
胚胎干细胞（ESC）的多能性依赖于以 Oct4 为中心的内在基因调控网络。细胞因子白血病抑制因子（LIF）通过转录调节因子 Stat3 发挥作用，刺激多能状态的增殖。在这里，我们表明这种外在刺激与 Krüppel 因子激活的内在电路相吻合。Oct4 主要诱导 Klf2，而 LIF/Stat3 则选择性增强 Klf4 的表达。过表达这两种因子都能降低对 LIF 的依赖性，但存在数量和质量上的差异。与 Klf4 不同，Klf2 增加 ESC 的集落形成能力，在没有 Stat3 的遗传条件下维持未分化的 ESCs，并赋予对 BMP 诱导分化的抗性。用 Klf2 扩增的 ESC 仍然能够为成年嵌合体做出贡献。植入后胚胎衍生的 EpiSCs 既缺乏 Klf2 也缺乏 Klf4，表达其中任何一种都可以恢复原始的多能性。这些发现表明，Oct4 和 Stat3 在指导 Klf 转录调节因子的表达上相交，这些调节因子具有重叠的特性，可累加增强 ESC 多潜能性、身份和自我更新。
