Department of Obstetrics and Gynecology, University of Colorado-Anschutz Medical Center, Aurora, Colorado, United States.
Department of Statistics and Data Science, Yale University, New Haven, Connecticut, United States.
PeerJ. 2022 Aug 22;10:e13941. doi: 10.7717/peerj.13941. eCollection 2022.
Mechanism(s) that control whether individual human primordial ovarian follicles (PFs) remain dormant, or begin to grow, are all but unknown. One of our groups has recently shown that activation of the Integrated Stress Response (ISR) pathway can slow follicular granulosa cell proliferation by activating cell cycle checkpoints. Those data suggest that the ISR is active and fluctuates according to local conditions in dormant PFs. Because cell cycle entry of (pre)granulosa cells is required for PF growth activation (PFGA), we propose that rare ISR checkpoint resolution allows individual PFs to begin to grow. Fluctuating ISR activity within individual PFs can be described by a random process. In this article, we model ISR activity of individual PFs by one-dimensional random walks (RWs) and monitor the rate at which simulated checkpoint resolution and thus PFGA threshold crossing occurs. We show that the simultaneous recapitulation of (i) the loss of PFs over time within simulated subjects, and (ii) the timing of PF depletion in populations of simulated subjects equivalent to the distribution of the human age of natural menopause can be produced using this approach. In the RW model, the probability that individual PFs grow is influenced by regionally fluctuating conditions, that over time manifests in the known pattern of PFGA. Considered at the level of the ovary, randomness appears to be a key, purposeful feature of human ovarian aging.
控制个体人类原始卵泡（PFs）是继续休眠还是开始生长的机制尚不清楚。我们的一个研究小组最近表明，整合应激反应（ISR）通路的激活可以通过激活细胞周期检查点来减缓卵泡颗粒细胞的增殖。这些数据表明 ISR 是活跃的，并根据休眠 PFs 中的局部条件波动。由于（前）颗粒细胞的细胞周期进入是 PF 生长激活（PFGA）所必需的，我们假设罕见的 ISR 检查点分辨率允许个别 PF 开始生长。个别 PF 内 ISR 活性的波动可以用随机过程来描述。在本文中，我们通过一维随机游走（RW）来模拟单个 PF 的 ISR 活性，并监测模拟检查点分辨率和因此 PFGA 阈值穿越的速率。我们表明，使用这种方法可以同时再现（i）模拟个体中随时间丢失的 PF，以及（ii）模拟个体中 PF 耗尽的时间，相当于人类自然绝经年龄分布。在 RW 模型中，个体 PF 生长的概率受到局部波动条件的影响，这些条件随着时间的推移表现为已知的 PFGA 模式。从卵巢水平来看，随机性似乎是人类卵巢衰老的一个关键的、有目的的特征。
