Ye Shoudong, Zhang Tao, Tong Chang, Zhou Xingliang, He Kan, Ban Qian, Liu Dahai, Ying Qi-Long
Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei 230601, People's Republic of China.
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Biol Open. 2017 Apr 15;6(4):511-517. doi: 10.1242/bio.022426.
Mouse and rat embryonic stem cell (ESC) self-renewal can be maintained by dual inhibition of glycogen synthase kinase 3 (GSK3) and mitogen-activated protein kinase kinase (MEK). Inhibition of GSK3 promotes ESC self-renewal by abrogating T-cell factor 3 (TCF3)-mediated repression of the pluripotency network. How inhibition of MEK mediates ESC self-renewal, however, remains largely unknown. Here, we show that inhibition of MEK can significantly suppress lymphoid enhancer factor 1 (LEF1) expression in mouse ESCs. Knockdown or knockout of partially mimics the self-renewal-promoting effect of MEK inhibitors. Moreover, depletion of both and enables maintenance of undifferentiated mouse ESCs without exogenous factors, cytokines or inhibitors. Transcriptome resequencing analysis reveals that LEF1 is closely associated with endoderm specification in ESCs. Thus, our study adds support to the notion that the key to maintaining the ESC ground state is to shield ESCs from differentiative cues.
小鼠和大鼠胚胎干细胞（ESC）的自我更新可通过糖原合酶激酶3（GSK3）和丝裂原活化蛋白激酶激酶（MEK）的双重抑制来维持。抑制GSK3可通过消除T细胞因子3（TCF3）介导的多能性网络抑制来促进ESC自我更新。然而，抑制MEK如何介导ESC自我更新在很大程度上仍不清楚。在这里，我们表明抑制MEK可显著抑制小鼠ESC中淋巴样增强因子1（LEF1）的表达。敲低或敲除部分模拟了MEK抑制剂的自我更新促进作用。此外，同时缺失和能够在无外源性因子、细胞因子或抑制剂的情况下维持未分化的小鼠ESC。转录组重测序分析表明，LEF1与ESC中的内胚层特化密切相关。因此，我们的研究支持了这样一种观点，即维持ESC基态的关键是使ESC免受分化信号的影响。
