Wellcome Trust Centre for Stem Cell Research & Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK.
Cell Stem Cell. 2010 Sep 3;7(3):319-28. doi: 10.1016/j.stem.2010.06.022.
The cytokine leukemia inhibitory factor (Lif) sustains self-renewal of mouse embryonic and induced pluripotent stem cells by activating Jak kinase and the transcription factor Stat3. Here we investigate whether Jak/Stat3 may also contribute to induction of pluripotency. EpiSCs derived from postimplantation embryos express low levels of Lif receptor and Stat3. We introduced into EpiSCs a Jak/Stat3 activating receptor (GY118F) responsive to granulocyte colony stimulating factor (Gcsf). On transfer to ground state culture, in which MAPK signaling and glycogen synthase kinase are inhibited, Gcsf induced transcriptional resetting and functional reprogramming. Activation of a tamoxifen-regulatable fusion, Stat3ER(T2), also converted EpiSCs into chimera-competent iPSCs. We exploited GY118F to increase Jak/Stat3 activity during somatic cell reprogramming. Incompletely reprogrammed cells derived from neural stem cells or fibroblasts responded to Gcsf with elevated frequencies of progression to ground state pluripotency. These findings indicate that Jak/Stat3 participate directly in molecular reprogramming and that activation of this pathway is a limiting component.
细胞因子白血病抑制因子 (Lif) 通过激活 Jak 激酶和转录因子 Stat3 来维持小鼠胚胎和诱导多能干细胞的自我更新。在这里，我们研究了 Jak/Stat3 是否也有助于诱导多能性。来自植入后胚胎的 EpiSCs 表达低水平的 Lif 受体和 Stat3。我们将一种对粒细胞集落刺激因子 (Gcsf) 有反应的 Jak/Stat3 激活受体 (GY118F) 引入 EpiSCs。在转移到抑制 MAPK 信号和糖原合成酶激酶的基础状态培养物中时，Gcsf 诱导了转录重设和功能重编程。Tamoxifen 调节融合蛋白 Stat3ER(T2) 的激活也将 EpiSCs 转化为嵌合能力的 iPSCs。我们利用 GY118F 在体细胞重编程过程中增加 Jak/Stat3 活性。来自神经干细胞或成纤维细胞的不完全重编程细胞对 Gcsf 的反应是，向基础状态多能性的进展频率升高。这些发现表明 Jak/Stat3 直接参与分子重编程，并且该途径的激活是一个限制因素。
