Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
Hum Reprod Update. 2023 Jul 5;29(4):434-456. doi: 10.1093/humupd/dmad005.
Regulated cell death is a fundamental component of numerous physiological processes; spanning from organogenesis in utero, to normal cell turnover during adulthood, as well as the elimination of infected or damaged cells throughout life. Quality control through regulation of cell death pathways is particularly important in the germline, which is responsible for the generation of offspring. Women are born with their entire supply of germ cells, housed in functional units known as follicles. Follicles contain an oocyte, as well as specialized somatic granulosa cells essential for oocyte survival. Follicle loss-via regulated cell death-occurs throughout follicle development and life, and can be accelerated following exposure to various environmental and lifestyle factors. It is thought that the elimination of damaged follicles is necessary to ensure that only the best quality oocytes are available for reproduction.
Understanding the precise factors involved in triggering and executing follicle death is crucial to uncovering how follicle endowment is initially determined, as well as how follicle number is maintained throughout puberty, reproductive life, and ovarian ageing in women. Apoptosis is established as essential for ovarian homeostasis at all stages of development and life. However, involvement of other cell death pathways in the ovary is less established. This review aims to summarize the most recent literature on cell death regulators in the ovary, with a particular focus on non-apoptotic pathways and their functions throughout the discrete stages of ovarian development and reproductive life.
Comprehensive literature searches were carried out using PubMed and Google Scholar for human, animal, and cellular studies published until August 2022 using the following search terms: oogenesis, follicle formation, follicle atresia, oocyte loss, oocyte apoptosis, regulated cell death in the ovary, non-apoptotic cell death in the ovary, premature ovarian insufficiency, primordial follicles, oocyte quality control, granulosa cell death, autophagy in the ovary, autophagy in oocytes, necroptosis in the ovary, necroptosis in oocytes, pyroptosis in the ovary, pyroptosis in oocytes, parthanatos in the ovary, and parthanatos in oocytes.
Numerous regulated cell death pathways operate in mammalian cells, including apoptosis, autophagic cell death, necroptosis, and pyroptosis. However, our understanding of the distinct cell death mediators in each ovarian cell type and follicle class across the different stages of life remains the source of ongoing investigation. Here, we highlight recent evidence for the contribution of non-apoptotic pathways to ovarian development and function. In particular, we discuss the involvement of autophagy during follicle formation and the role of autophagic cell death, necroptosis, pyroptosis, and parthanatos during follicle atresia, particularly in response to physiological stressors (e.g. oxidative stress).
Improved knowledge of the roles of each regulated cell death pathway in the ovary is vital for understanding ovarian development, as well as maintenance of ovarian function throughout the lifespan. This information is pertinent not only to our understanding of endocrine health, reproductive health, and fertility in women but also to enable identification of novel fertility preservation targets.
细胞程序性死亡是众多生理过程的基本组成部分；从胚胎期的器官发生，到成年期的正常细胞更替，以及生命过程中感染或受损细胞的清除。通过调节细胞死亡途径进行质量控制在生殖系中尤为重要，生殖系负责产生后代。女性在出生时就拥有了全部的生殖细胞，这些生殖细胞储存在称为卵泡的功能性单位中。卵泡包含一个卵母细胞，以及对卵母细胞存活至关重要的专门的体颗粒细胞。卵泡通过细胞程序性死亡而丢失——这种丢失发生在卵泡发育和生命的整个过程中，并且在暴露于各种环境和生活方式因素后会加速。人们认为，消除受损的卵泡对于确保只有最好质量的卵母细胞可用于繁殖是必要的。
了解触发和执行卵泡死亡的确切因素对于揭示卵泡储备是如何最初确定的以及卵泡数量如何在女性青春期、生殖期和卵巢衰老过程中得到维持至关重要。细胞凋亡已被确立为在发育和生命的所有阶段维持卵巢内环境稳定的必要条件。然而，其他细胞死亡途径在卵巢中的参与程度尚不清楚。本综述旨在总结卵巢中细胞死亡调节剂的最新文献，特别关注非细胞凋亡途径及其在卵巢发育和生殖生命的不同阶段的功能。
使用 PubMed 和 Google Scholar 进行了全面的文献检索，使用以下搜索词搜索了截至 2022 年 8 月发表的人类、动物和细胞研究的文献：卵子发生、卵泡形成、卵泡闭锁、卵母细胞丢失、卵母细胞凋亡、卵巢中的细胞程序性死亡、卵巢中的非细胞凋亡性细胞死亡、卵巢早衰、原始卵泡、卵母细胞质量控制、颗粒细胞死亡、卵巢中的自噬、卵母细胞中的自噬、卵巢中的坏死性凋亡、卵母细胞中的坏死性凋亡、卵巢中的细胞焦亡、卵母细胞中的细胞焦亡、卵巢中的 parthanatos 和卵母细胞中的 parthanatos。
在哺乳动物细胞中存在许多细胞程序性死亡途径，包括凋亡、自噬性细胞死亡、坏死性凋亡和细胞焦亡。然而，我们对每个卵巢细胞类型和卵泡类在生命的不同阶段的特定细胞死亡介质的理解仍然是正在进行的研究的来源。在这里，我们强调了非细胞凋亡途径对卵巢发育和功能的贡献的最新证据。特别是，我们讨论了自噬在卵泡形成中的作用以及自噬性细胞死亡、坏死性凋亡、细胞焦亡和 parthanatos 在卵泡闭锁中的作用，特别是在对生理应激（例如氧化应激）的反应中。
更好地了解每个细胞程序性死亡途径在卵巢中的作用对于理解卵巢发育以及整个生命周期中卵巢功能的维持至关重要。这些信息不仅对于我们理解内分泌健康、生殖健康和女性生育能力很重要，而且对于确定新的生育力保存目标也很重要。
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