Multi-omic rejuvenation of human cells by maturation phase transient reprogramming.
Multi-omic rejuvenation of human cells by maturation phase transient reprogramming.
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DOI：
10.7554/elife.71624
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发表时间：
2022-04-08
期刊：
影响因子：
7.7
通讯作者：
Reik, Wolf
中科院分区：
文献类型：
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作者：
Gill, Diljeet;Parry, Aled;Santos, Fatima;Okkenhaug, Hanneke;Todd, Christopher D.;Hernando-Herraez, Irene;Stubbs, Thomas M.;Milagre, Ines;Reik, Wolf
衰老是随着时间的推移发生的生物体适应性的逐渐下降，导致组织功能障碍和疾病。在细胞水平上，衰老与功能下降、基因表达改变和表观基因组紊乱有关。最近的工作表明，表观基因组已经通过体细胞重编程的成熟阶段恢复活力，这表明完全重编程不需要逆转体细胞的老化。在这里，我们开发了第一个“成熟期瞬时重编程”（MPTR）方法，其中重编程因子选择性地表达，直到这个复兴点，然后撤回。将MPTR应用于来自中年供体的真皮成纤维细胞，我们发现细胞暂时失去然后重新获得其成纤维细胞身份，这可能是由于增强子的表观遗传记忆和/或一些成纤维细胞基因的持续表达。令人兴奋的是，我们的方法基本上恢复了多个细胞属性，包括转录组，根据新的转录组时钟测量，转录组恢复了约30年。表观基因组恢复到类似的程度，包括H3 K9 me 3水平和DNA甲基化老化时钟。由MPTR激发的恢复活力的幅度似乎大大大于在先前的瞬时重编程方案中实现的恢复活力的幅度。此外，MPTR成纤维细胞产生年轻水平的胶原蛋白，并显示其迁移速度的部分功能性恢复。最后，我们的工作表明，最佳的时间窗口存在振兴的转录组和表观基因组。总的来说，我们证明了将年轻化与完整的多能性重编程分开是可能的，这将有助于发现新的抗衰老基因和疗法。
Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of somatic cell reprogramming, which suggests full reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first “maturation phase transient reprogramming” (MPTR) method, where reprogramming factors are selectively expressed until this rejuvenation point then withdrawn. Applying MPTR to dermal fibroblasts from middle-aged donors, we found that cells temporarily lose and then reacquire their fibroblast identity, possibly as a result of epigenetic memory at enhancers and/or persistent expression of some fibroblast genes. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome was rejuvenated to a similar extent, including H3K9me3 levels and the DNA methylation ageing clock. The magnitude of rejuvenation instigated by MPTR appears substantially greater than that achieved in previous transient reprogramming protocols. In addition, MPTR fibroblasts produced youthful levels of collagen proteins, and showed partial functional rejuvenation of their migration speed. Finally, our work suggests that optimal time windows exist for rejuvenating the transcriptome and the epigenome. Overall, we demonstrate that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.