Senescence impairs successful reprogramming to pluripotent stem cells
Senescence impairs successful reprogramming to pluripotent stem cells
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DOI：
10.1101/gad.1811609
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发表时间：
2009-09-15
影响因子：
10.5
通讯作者：
Gil, Jesus
中科院分区：
文献类型：
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作者：
Banito, Ana;Rashid, Sheikh T.;Gil, Jesus
通过过表达 Oct4、Sox2、Klf4 和 c-Myc 等因子的组合，可以将体细胞重编程为诱导多能干 (iPS) 细胞。重编程是缓慢且随机的，表明存在限制其效率的障碍。在这里，我们将衰老视为这样的障碍之一。四种重编程因子的表达通过上调 p53、p16(INK4a) 和 p21(CIP1) 触发衰老。 DNA 损伤反应的诱导和 INK4a/ARF 位点的染色质重塑是衰老诱导背后的两个机制。至关重要的是，不同衰老效应子的消融提高了重编程的效率，这提出了最大化 iPS 细胞生成的新策略。
Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by overexpressing combinations of factors such as Oct4, Sox2, Klf4, and c-Myc. Reprogramming is slow and stochastic, suggesting the existence of barriers limiting its efficiency. Here we identify senescence as one such barrier. Expression of the four reprogramming factors triggers senescence by up-regulating p53, p16(INK4a), and p21(CIP1). Induction of DNA damage response and chromatin remodeling of the INK4a/ARF locus are two of the mechanisms behind senescence induction. Crucially, ablation of different senescence effectors improves the efficiency of reprogramming, suggesting novel strategies for maximizing the generation of iPS cells.