NF-κB activation impairs somatic cell reprogramming in ageing (Publication with Expression of Concern. See vol. 21, pg. 410, 2019) (Retracted Article)
NF-κB activation impairs somatic cell reprogramming in ageing (Publication with Expression of Concern. See vol. 21, pg. 410, 2019) (Retracted Article)
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DOI：
10.1038/ncb3207
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发表时间：
2015-08-01
影响因子：
21.3
通讯作者：
Lopez-Otin, Carlos
中科院分区：
文献类型：
--
作者：
Soria-Valles, Clara;Osorio, Fernando G.;Lopez-Otin, Carlos
衰老是体细胞重编程的关键障碍。我们已经探索了构成年龄相关障碍的调控机制，通过诱导多能干细胞（iPSC）从过早或生理老化的个体中衍生出来。我们证明了NF-κ B激活阻断了衰老过程中iPSC的生成。我们还表明，NF-κ B B阻遏发生在细胞重编程向多能状态。相反，衰老相关的NF-κ B超活化通过引发重编程阻遏物DOT 1 L而损害iPSC的产生，DOT 1 L增强衰老信号并下调多能性基因。遗传和药理学NF-κ B抑制策略显著增加Nestor-Guillermo早衰综合征和Hutchinson-Gilford早衰综合征患者以及正常老年供体的成纤维细胞的重编程效率。最后，我们证明，DOT 1 L抑制体内延长寿命，改善早衰小鼠的加速老化表型，支持研究年龄相关的分子损伤，以确定年轻化策略的目标的兴趣。
Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-kappa B activation blocks the generation of iPSCs in ageing. We also show that NF-kappa B repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-kappa B hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-kappa B inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Nestor-Guillermo progeria syndrome and Hutchinson-Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies.