Oct4 is widely considered the most important among the four Yamanaka reprogramming factors. Here, we show that the combination of Sox2, Klf4, and cMyc (SKM) suffices for reprogramming mouse somatic cells to induced pluripotent stem cells (iPSCs). Simultaneous induction of Sox2 and cMyc in fibroblasts triggers immediate retroviral silencing, which explains the discrepancy with previous studies that attempted but failed to generate iPSCs without Oct4 using retroviral vectors. SKM induction could partially activate the pluripotency network, even in Oct4-knockout fibroblasts. Importantly, reprogramming in the absence of exogenous Oct4 results in greatly improved developmental potential of iPSCs, determined by their ability to give rise to all-iPSC mice in the tetraploid complementation assay. Our data suggest that overexpression of Oct4 during reprogramming leads to off-target gene activation during reprogramming and epigenetic aberrations in resulting iPSCs and thereby bear major implications for further development and application of iPSC technology.

中文翻译：

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从Yamanaka鸡尾酒中排除Oct4可以释放iPSC的发展潜力。

在四个Yamanaka重编程因素中，Oct4被广泛认为是最重要的。在这里，我们显示Sox2，Klf4和cMyc（SKM）的组合足以将小鼠体细胞重编程为诱导性多能干细胞（iPSCs）。在成纤维细胞中同时诱导Sox2和cMyc会立即引起逆转录病毒沉默，这解释了与先前尝试使用逆转录病毒载体尝试在没有Oct4的情况下产生iPSC的研究之间的差异。即使在Oct4基因敲除的成纤维细胞中，SKM诱导也可以部分激活多能网络。重要的是，在没有外源Oct4的情况下进行重编程可大大提高iPSC的发育潜力，这取决于它们在四倍体互补测定中产生全iPSC小鼠的能力。