从山中四因子OSKM中排除 Oct4 释放 iPSC 的发展潜力
Excluding Oct4 from Yamanaka Cocktail Unleashes the Developmental Potential of iPSCs - PubMed (nih.gov)
Cell Stem Cell：挑战常规！原本认为在构建iPS细胞中至关重要的Oct4实际上并不需要 - 干细胞&iPS专区 - 生物谷 (bioon.com)
摘要
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.
Oct4 被广泛认为是四个 Yamanaka 重编程因子中最重要的一个。在这里，我们展示了 Sox2、Klf4 和 cMyc (SKM) 的组合足以将小鼠体细胞重编程为诱导多能干细胞 (iPSC)。在成纤维细胞中同时诱导 Sox2 和 cMyc 会立即触发逆转录病毒沉默，这解释了与先前研究的差异，这些研究试图但未能使用逆转录病毒载体在没有 Oct4 的情况下生成 iPSC。 SKM 诱导可以部分激活多能网络，即使在 Oct4 敲除的成纤维细胞中也是如此。重要的是，在没有外源 Oct4 的情况下重新编程会大大提高 iPSC 的发育潜力，这取决于它们在四倍体互补试验中产生全 iPSC 小鼠的能力。我们的数据表明，重编程过程中 Oct4 的过表达导致重编程过程中的脱靶基因激活和所得 iPSC 的表观遗传畸变，从而对 iPSC 技术的进一步开发和应用具有重大意义。
