Egashira Mahiro, Hirota Yasushi, Shimizu-Hirota Ryoko, Saito-Fujita Tomoko, Haraguchi Hirofumi, Matsumoto Leona, Matsuo Mitsunori, Hiraoka Takehiro, Tanaka Tomoki, Akaeda Shun, Takehisa Chiaki, Saito-Kanatani Mayuko, Maeda Kei-Ichiro, Fujii Tomoyuki, Osuga Yutaka
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Department of Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Endocrinology. 2017 Jul 1;158(7):2344-2353. doi: 10.1210/en.2016-1886.
Cellular senescence, defined as an irreversible cell cycle arrest, exacerbates the tissue microenvironment. Our previous study demonstrated that mouse uterine senescent cells were physiologically increased according to gestational days and that their abnormal accumulation was linked to the onset of preterm delivery. We hypothesized that there is a mechanism for removal of senescent cells after parturition to maintain uterine function. In the current study, we noted abundant uterine senescent cells and their gradual disappearance in wild-type postpartum mice. F4/80+ macrophages were present specifically around the area rich in senescent cells. Depletion of macrophages in the postpartum mice using anti-F4/80 antibody enlarged the area of senescent cells in the uterus. We also found excessive uterine senescent cells and decreased second pregnancy success rate in a preterm birth model using uterine p53-deleted mice. Furthermore, a decrease in F4/80+ cells and an increase in CD11b+ cells with a senescence-associated inflammatory microenvironment were observed in the p53-deleted uterus, suggesting that uterine p53 deficiency affects distribution of the macrophage subpopulation, interferes with senescence clearance, and promotes senescence-induced inflammation. These findings indicate that the macrophage is a key player in the clearance of uterine senescent cells to maintain postpartum uterine function.
细胞衰老被定义为一种不可逆的细胞周期停滞，它会加剧组织微环境的恶化。我们之前的研究表明，小鼠子宫衰老细胞会随着妊娠天数的增加而在生理上增多，并且它们的异常积累与早产的发生有关。我们推测，分娩后存在一种清除衰老细胞以维持子宫功能的机制。在当前的研究中，我们注意到野生型产后小鼠子宫内存在大量衰老细胞，并且这些细胞会逐渐消失。F4/80+巨噬细胞特别存在于富含衰老细胞的区域周围。使用抗F4/80抗体耗尽产后小鼠体内的巨噬细胞，会扩大子宫内衰老细胞的区域。我们还发现，在使用子宫p53缺失小鼠的早产模型中，子宫衰老细胞过多且第二次妊娠成功率降低。此外，在p53缺失的子宫中观察到F4/80+细胞减少，CD11b+细胞增加，伴有衰老相关的炎症微环境，这表明子宫p53缺乏会影响巨噬细胞亚群的分布，干扰衰老清除，并促进衰老诱导的炎症。这些发现表明，巨噬细胞是清除子宫衰老细胞以维持产后子宫功能的关键因素。
