Stage-specific regulation of reprogramming to induced pluripotent stem cells by Wnt signaling and T cell factor proteins.
Stage-specific regulation of reprogramming to induced pluripotent stem cells by Wnt signaling and T cell factor proteins.
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DOI：
10.1016/j.celrep.2013.05.015
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发表时间：
2013-06-27
期刊：
影响因子：
8.8
通讯作者：
Plath K
中科院分区：
文献类型：
--
作者：
Ho R;Papp B;Hoffman JA;Merrill BJ;Plath K
Wnt信号是小鼠胚胎干细胞自我更新的内在机制。因此，令人惊讶的是，Wnt信号传导并没有强烈增强体细胞重编程为诱导多能干细胞（iPSC）。在这里，我们证明了活跃的Wnt信号传导抑制了iPSCs重编程的早期阶段，而在晚期阶段，它是必需的，甚至是刺激的。从机制上讲，Wnt信号传导的这种双相效应伴随着其所有四种转录效应子的需求变化：Tcf1，Lef1，Tcf3和Tcf4。例如，Tcf3和Tcf4在重编程过程中早期是刺激性的，但晚期是抑制性的。因此，Tcf3在重编程早期的异位表达结合其功能丧失晚期使得在不存在异位Sox 2的情况下能够有效重编程。总之，我们的数据表明，重新编程为iPSC的逐步过程严重依赖于所有四种Tcfs和Wnt信号传导的阶段特异性控制和作用。
Wnt signaling is intrinsic to mouse embryonic stem cell self-renewal. Therefore it is surprising that reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is not strongly enhanced by Wnt signaling. Here, we demonstrate that active Wnt signaling inhibits the early stage of reprogramming to iPSCs, while it is required and even stimulating during the late stage. Mechanistically, this biphasic effect of Wnt signaling is accompanied by a change in the requirement of all four of its transcriptional effectors: Tcf1, Lef1, Tcf3, and Tcf4. For example, Tcf3 and Tcf4 are stimulatory early but inhibitory late in the reprogramming process. Accordingly, ectopic expression of Tcf3 early in reprogramming combined with its loss-of-function late enables efficient reprogramming in the absence of ectopic Sox2. Together, our data indicate that the step-wise process of reprogramming to iPSCs is critically dependent on the stage-specific control and action of all four Tcfs and Wnt signaling.
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影响因子：
10.5
作者：
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