Max-Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, D-48149 Münster, Germany.
Aging Cell. 2011 Feb;10(1):80-95. doi: 10.1111/j.1474-9726.2010.00644.x. Epub 2010 Dec 7.
The mammalian oocyte has the unique feature of supporting fertilization and normal development, while capable of reprogramming nuclei of somatic cells toward pluripotency, and occasionally even totipotency. While oocyte quality is known to decay with somatic aging, it is not a given that different biological functions decay concurrently. In this study, we tested whether oocyte's reprogramming ability decreases with aging. We show that oocytes isolated from mice aged beyond the usual reproductive age (climacteric) yield ooplasts that retain reprogramming capacity after somatic nuclear transfer (SCNT), giving rise to higher blastocysts rates compared to young donors ooplasts. Despite the differences in transcriptome between climacteric and young ooplasts, gene expression profiles of SCNT blastocysts were very similar. Importantly, embryonic stem cell lines with capacity to differentiate into tissues from all germ layers were derived from SCNT blastocysts obtained from climacteric ooplasts. Although apoptosis-related genes were down-regulated in climacteric ooplasts, and reprogramming by transcription factors (direct-induced pluripotency) benefits from the inhibition of p53-mediated apoptosis, reprogramming capacity of young ooplasts was not improved by blocking p53. However, more outgrowths were derived from SCNT blastocysts developed in the presence of a p53 inhibitor, indicating a beneficial effect on trophectoderm function. Results strongly suggest that oocyte-induced reprogramming outcome is determined by the availability and balance of intrinsic pro- and anti-reprogramming factors tightly regulated and even improved throughout aging, leading to the proposal that oocytes can still be a resource for somatic reprogramming when they cease to be considered safe for sexual reproduction.
哺乳动物卵母细胞具有支持受精和正常发育的独特功能，同时能够将体细胞的核重编程为多能性，甚至偶尔为全能性。虽然卵母细胞的质量随着体细胞衰老而下降，但并非所有生物学功能都会同时衰退。在这项研究中，我们测试了卵母细胞的重编程能力是否随年龄增长而下降。我们发现，从超过通常生殖年龄（更年期）的小鼠中分离出的卵母细胞产生的卵胞质，在体细胞核移植（SCNT）后仍保留重编程能力，与年轻供体的卵胞质相比，产生更高的囊胚率。尽管更年期和年轻卵胞质之间的转录组存在差异，但 SCNT 囊胚的基因表达谱非常相似。重要的是，从更年期卵胞质获得的 SCNT 囊胚可以衍生出具有分化为所有胚层组织能力的胚胎干细胞系。尽管更年期卵胞质中的凋亡相关基因下调，并且转录因子介导的重编程（直接诱导多能性）受益于 p53 介导的凋亡抑制，但通过阻断 p53 并不能提高年轻卵母细胞的重编程能力。然而，在存在 p53 抑制剂的情况下，SCNT 囊胚发育出更多的滋养外胚层，表明对滋养外胚层功能有有益影响。研究结果强烈表明，卵母细胞诱导的重编程结果取决于内在的促重编程和抗重编程因子的可用性和平衡，这些因子受到严格调控，甚至在衰老过程中得到改善，这表明当卵母细胞不再被认为适合进行有性生殖时，它们仍然可以成为体细胞重编程的资源。
