New strategy for in vitro activation of primordial follicles with mTOR and PI3K stimulators.
New strategy for in vitro activation of primordial follicles with mTOR and PI3K stimulators.
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mTOR 和 PI3K 刺激剂体外激活原始卵泡的新策略
DOI：
10.1080/15384101.2014.995496
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Sun X;Su Y;He Y;Zhang J;Liu W;Zhang H;Hou Z;Liu J;Li J
哺乳动物卵巢中的原始卵泡以一定数量聚集在一起，代表着整个生殖生命中的卵巢储备，这一点几十年来一直是已知的。卵母细胞内的PI3K/mTOR通路在原始卵泡的激活中起着核心作用。原始卵母细胞中PI3K/mTOR信号慢性激活的转基因小鼠模型显示，所有原始卵泡过早激活，最终耗尽。另一方面，这可能表明，与PI3K/mTOR的慢性激活不同，PI3K/mTOR在不孕症中的急性激活将激活原始卵泡，从而在治疗期间允许生育。此前，PI3K刺激物被报道为促进原始卵泡激活和卵泡发育的临时措施，并被用于治疗卵巢早衰(POF)患者的不孕症。为了说明mTOR刺激物是否可以在这一过程中发挥类似的作用，我们用mTOR刺激物-磷脂酸(PA)和心得安对新生和老年小鼠卵巢进行了短暂处理。我们的结果表明，刺激物增加了原始卵泡的激活和后代的产生。体外培养的人卵巢皮质细胞也用mTOR或/和PI3K刺激剂处理。单独使用时，两者对原始卵泡的促进作用相似。令人惊讶的是，在两种刺激剂联合作用后，观察到了对卵泡发育的协同效应。基于人类卵泡激活效率的提高，我们建议使用mTOR和PI3K刺激剂进行体外瞬时治疗，作为一种优化方案，以适用于不同临床条件下有限的卵泡储备。
It had been known for decades that primordial follicles in mammalian ovaries are assembled with definite numbers and represent the ovarian reserve throughout the reproductive life. Intra-oocyte PI3K/mTOR pathways have been indicated to play a central role on the activation of primordial follicles. Genetic modified mouse models with chronic activation of PI3K/mTOR signals in primordial oocytes showed premature activation of all primordial follicles and eventually their exhaustion. On the other hand, this may suggest that, unlike chronic activation of PI3K/mTOR, its acute activation in infertility would activate primordial follicles, permitting fertility during the treatment. Previously, PI3K stimulators were reported as a temporary measure to accelerate primordial follicle activation and follicular development in both mouse and human, and were applied in the treatment of infertility in premature ovarian failure (POF) patients. To address whether mTOR stimulators could play similar role in the process, we transiently treated neonatal and aged mouse ovaries with mTOR stimulators-phosphatidic acid (PA) and propranolol. Our results demonstrated the stimulators increased activation of primordial follicles and the production of progeny. Human ovarian cortex cubes were also treated with mTOR or/and PI3K stimulators in vitro. When they were used separately, both of them showed similar promotive effects on primordial follicles. Surprisingly, after joint-treatment with the 2 kinds of stimulators together, synergistic effects on follicular development were observed. Based on increased efficiency of follicular activation in humans, here we propose in vitro transient treatment with mTOR and PI3K stimulators as an optimized protocol for the application in different clinical conditions with limited follicle reserve.