Dormant Pluripotent Cells Emerge during Neural Differentiation of Embryonic Stem Cells in a FoxO3-Dependent Manner
Dormant Pluripotent Cells Emerge during Neural Differentiation of Embryonic Stem Cells in a FoxO3-Dependent Manner
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DOI：
10.1128/mcb.00417-16
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发表时间：
2017-03-01
影响因子：
5.3
通讯作者：
Toyoshima, Fumiko
中科院分区：
文献类型：
--
作者：
Ikeda, Megumi;Toyoshima, Fumiko
胚胎干细胞（ESC）衍生细胞临床应用的一个主要问题是残余未分化细胞潜在致瘤性的增强。尽管使用了强化方法来消除残留的未分化细胞，但这些细胞的特性仍然难以捉摸。在这里，我们表明，在无血清神经分化条件下，残留的未分化细胞显着延迟其细胞周期的进展，而不损害其多能性。在无血清条件下重新培养细胞期间，这种休眠多能性得以维持，而在血清刺激下，细胞退出休眠状态并重新开始增殖和分化为所有三个胚层。微阵列分析显示，与增殖的ESCs中的调节水平相比，休眠ESCs中的一组基因显着上调。其中，我们发现转录因子 Forkhead box O3 (FoxO3) 是维持休眠 ESC 多能性的重要调节因子。我们的研究表明，向休眠状态的转变赋予残留的未分化细胞依赖 FoxO3 和白血病抑制因子/血清独立的多能性。
One major concern over the clinical application of embryonic stem cell (ESC)-derived cells is the potentiation of latent tumorigenicity by residual undifferentiated cells. Despite the use of intensive methodological approaches to eliminate residual undifferentiated cells, the properties of these cells remain elusive. Here, we show that under a serum-free neural differentiation condition, residual undifferentiated cells markedly delay progression of their cell cycle without compromising their pluripotency. This dormant pluripotency was maintained during reculture of the cells under a serum-free condition, whereas upon serum stimulation, the cells exited the dormant state and restarted proliferation and differentiation into all three germ layers. Microarray analysis revealed a set of genes that is significantly upregulated in the dormant ESCs compared with their levels of regulation in proliferating ESCs. Among them, we identified the transcription factor Forkhead box O3 (FoxO3) to be an essential regulator of the maintenance of pluripotency in dormant ESCs. Our study demonstrates that the transition into the dormant state endows residual undifferentiated cells with FoxO3-dependent and leukemia inhibitory factor/serum-independent pluripotency.