Macrophage-derived extracellular vesicles regulate follicular activation and improve ovarian function in old mice by modulating local environment.
Macrophage-derived extracellular vesicles regulate follicular activation and improve ovarian function in old mice by modulating local environment.
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巨噬细胞衍生的细胞外囊泡通过调节局部环境调节老年小鼠卵泡活化并改善卵巢功能
DOI：
10.1002/ctm2.1071
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发表时间：
2022-10
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
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在哺乳动物中，卵巢功能依赖于原始卵泡库，原始卵泡的激活速率决定了雌性的生殖寿命。卵巢衰老的特征是慢性低度炎症，伴有原始卵泡加速耗竭和卵母细胞质量下降。巨噬细胞（Mφs）在卵巢功能的多个方面发挥着关键作用；然而，目前尚不清楚巨噬细胞是否调节原始卵泡库，以及它们在卵巢衰老中扮演何种角色。在此，通过使用超排卵或自然排卵小鼠模型，我们首次证明，排卵诱导的局部炎症是每个发情周期中周围原始卵泡选择性激活的驱动因素。这一发现与排卵卵泡中浸润的巨噬细胞以及该过程中两种极化的巨噬细胞（M1和M2巨噬细胞）的动态变化有关。对与不同亚型巨噬细胞共培养的新生卵巢的进一步研究表明，M1巨噬细胞对原始卵泡有刺激作用，而M2巨噬细胞使卵泡维持在静止状态。其潜在机制与通过分泌的细胞外囊泡（EVs）以及其中所含的特定微小RNA（miR - 107（M1巨噬细胞）和miR - 99a - 5p（M2巨噬细胞））对磷脂酰肌醇3 - 激酶/雷帕霉素靶蛋白（PI3K/mTOR）信号通路的差异调节有关。在老年小鼠中，静脉注射M2 - EVs可改善卵巢功能并改善卵巢内的炎症微环境。因此，基于M2巨噬细胞在老年小鼠中的抗衰老作用，M2 - EVs可能代表了一种改善女性炎症相关不孕症的新方法。
排卵诱导的局部炎症环境选择性激活原始卵泡。
M1巨噬细胞对原始卵泡有刺激作用，而M2巨噬细胞使原始卵泡维持在静止状态。
体内给予M2 - EVs可改善老年小鼠卵巢内的炎症微环境并提高卵巢功能。
In mammals, ovarian function is dependent on the primordial follicle pool and the rate of primordial follicle activation determines a female's reproductive lifespan. Ovarian ageing is characterised by chronic low‐grade inflammation with accelerated depletion of primordial follicles and deterioration of oocyte quality. Macrophages (Mφs) play critical roles in multiple aspects of ovarian functions; however, it remains unclear whether Mφs modulate the primordial follicle pool and what is their role in ovarian ageing. Here, by using super‐ or naturally ovulated mouse models, we demonstrated for the first time that ovulation‐induced local inflammation acted as the driver for selective activation of surrounding primordial follicles in each estrous cycle. This finding was related to infiltrating Mφs in ovulatory follicles and the dynamic changes of the two polarised Mφs, M1 and M2 Mφs, during the process. Further studies on newborn ovaries cocultured with different subtypes of Mφs demonstrated the stimulatory effect of M1 Mφs on primordial follicles, whereas M2 Mφs maintained follicles in a dormant state. The underlying mechanism was associated with the differential regulation of the Phosphatidylinositol 3‐kinase/Mechanistic target of rapamycin (PI3K/mTOR) signaling pathway through secreted extracellular vesicles (EVs) and the containing specific miRNAs miR‐107 (M1 Mφs) and miR‐99a‐5p (M2 Mφs). In aged mice, the intravenous injection of M2‐EVs improved ovarian function and ameliorated the inflammatory microenvironment within the ovary. Thus, based on the anti‐ageing effects of M2 Mφs in old mice, M2‐EVs may represent a new approach to improve inflammation‐related infertility in women. Ovulation induced local inflammation environment selectively activates primordial follicles. M1 Mφs have a stimulatory effect on primordial follicles while M2 Mφs maintain them in a dormant state. M2‐EVs in vivo treatment ameliorate the inflammatory microenvironment within the ovary and improve ovarian function in aged mice.
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影响因子：
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作者：
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通讯作者：
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