Proper action of the female sex steroids 17β-estradiol (E2) and progesterone (P4) on the endometrium is essential for fertility. Beyond its role in regulating the cell cycle, cyclin A2 (CCNA2) also mediates E2 and P4 signaling in vitro, but a potential role in modulating steroid action for proper endometrial tissue development and function is unknown. To fill this gap in our knowledge, we examined human endometrial tissue from fertile and infertile cisgender women for CCNA2 expression and correlated this with pregnancy outcome. Functional assessment of CCNA2 was validated in vivo using a conditional Ccna2 uterine-deficient mouse model, while in vitro function was assessed using human cell culture models. We found that CCNA2 expression was significantly reduced in endometrial tissue, specifically the stromal cells, from women undergoing in vitro fertilization who failed to achieve pregnancy. Conditional deletion of Ccna2 from mouse uterine tissue resulted in an inability to achieve pregnancy, which appeared to be due to alterations in the process of decidualization, which was confirmed using in vitro models. From these studies, we conclude that CCNA2 expression during the proliferative/regenerative stage of the menstrual cycle allows for proper steroid responsiveness, decidualization, and pregnancy. When CCNA2 expression levels are insufficient, there is impaired endometrial responsiveness, aberrant decidualization, and loss of pregnancy.

中文翻译：

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子宫周期蛋白 A2 缺陷小鼠作为女性早期妊娠丢失的模型


女性性类固醇 17β-雌二醇 （E2） 和黄体酮 （P4） 对子宫内膜的适当作用对于生育至关重要。除了在调节细胞周期中的作用外，细胞周期蛋白 A2 （CCNA2） 还在体外介导 E2 和 P4 信号传导，但在调节类固醇作用以促进子宫内膜组织正常发育和功能方面的潜在作用尚不清楚。为了填补我们知识中的这一空白，我们检查了可育和不育顺性别女性的人类子宫内膜组织的 CCNA2 表达，并将其与妊娠结局相关联。使用条件性 Ccna2 子宫缺陷小鼠模型在体内验证 CCNA2 的功能评估，而使用人类细胞培养模型评估体外功能。我们发现 CCNA2 表达在接受体外受精但未能怀孕的妇女的子宫内膜组织中，特别是基质细胞中显着降低。小鼠子宫组织中 Ccna2 的条件缺失导致无法怀孕，这似乎是由于蜕膜化过程的改变，这已使用体外模型得到证实。从这些研究中，我们得出结论，CCNA2 在月经周期的增殖/再生阶段的表达允许适当的类固醇反应、蜕膜化和怀孕。当 CCNA2 表达水平不足时，子宫内膜反应性受损、蜕膜化异常和流产。