A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog.
A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog.
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DOI：
10.1016/j.stem.2009.09.012
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发表时间：
2009-11-06
期刊：
影响因子：
23.9
通讯作者：
Eggan K
中科院分区：
文献类型：
--
作者：
Ichida JK;Blanchard J;Lam K;Son EY;Chung JE;Egli D;Loh KM;Carter AC;Di Giorgio FP;Koszka K;Huangfu D;Akutsu H;Liu DR;Rubin LL;Eggan K
三种转录因子的组合活性可以将成体细胞重编程为诱导多能干细胞（iPS）。然而，用于递送重编程因子的转基因方法引起了对所得干细胞未来效用的关注。这些不确定性可以克服，如果每个转基因因子被替换为一个小分子，直接激活其表达的体细胞基因组或以某种方式补偿其活动。为此，我们使用高含量的化学筛选来鉴定可以在重编程中取代Sox 2的小分子。我们发现这些分子中的一种通过抑制在该过程中形成的稳定和被捕获的中间细胞类型中的TGF-β信号传导而在重编程中起作用。我们发现，这种抑制通过诱导转录因子Nanog来促进重编程的完成。
The combined activity of three transcription factors can reprogram adult cells into induced pluripotent stem (iPS) cells. However, the transgenic methods used to deliver reprogramming factors have raised concerns regarding the future utility of the resulting stem cells. These uncertainties could be overcome if each transgenic factor were replaced with a small molecule that either directly activated its expression from the somatic genome or in some way compensated for its activity. To this end, we have used high-content chemical screening to identify small molecules that can replace Sox2 in reprogramming. We show that one of these molecules functions in reprogramming by inhibiting Tgf-β signaling in a stable and trapped intermediate cell type that forms during the process. We find that this inhibition promotes the completion of reprogramming through induction of the transcription factor Nanog.
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