Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
J Cell Physiol. 2019 Dec;234(12):22554-22564. doi: 10.1002/jcp.28819. Epub 2019 May 20.
As a fundamental aging mechanism, cellular senescence causes chronic inflammation via the senescence-associated secretory phenotype (SASP). Theca-interstitial cells are an essential but little-studied component of follicle development in the ovarian microenvironment. In the present study, we observed significant cellular senescence in theca-interstitial cells and secretion of chemokine (C-C motif) ligand 5 (CCL5) by these cells during aging. Furthermore, we aimed to investigate whether and how senescence-associated secretory phenotype (SASP)-associated CCL5 may be involved in follicle development. Increased levels of CCL5 in the microenvironment of follicles attenuated preantral follicle growth, survival, and estradiol secretion. Oocyte maturation and the expression of zona pellucida 3 and differentiation factor 9 (GDF9) were also inhibited by CCL5. Granulosa cell apoptosis in follicles was promoted by CCL5, accompanied by the phosphorylation of nuclear factor-κB by CCL5 and inhibition of the PI3K/AKT pathway. These results suggest that SASP-associated CCL5 produced by senescent theca-interstitial cells may impair follicle development and maturation during ovarian aging by promoting granulosa cell apoptosis.
作为一种基本的衰老机制，细胞衰老通过衰老相关分泌表型 (SASP) 引起慢性炎症。卵泡发育的卵巢微环境中，间质细胞是一个重要但研究较少的成分。在本研究中，我们观察到间质细胞发生明显的衰老，以及这些细胞分泌趋化因子 (C-C 基序) 配体 5 (CCL5)。此外，我们旨在研究 SASP 相关的 CCL5 是否以及如何参与卵泡发育。卵泡微环境中 CCL5 水平的升高，减弱了原始卵泡的生长、存活和雌二醇分泌。CCL5 还抑制了卵母细胞成熟和透明带 3 和分化因子 9 (GDF9) 的表达。CCL5 促进卵泡中的颗粒细胞凋亡，同时 CCL5 使核因子-κB 磷酸化，并抑制 PI3K/AKT 通路。这些结果表明，衰老的间质细胞产生的 SASP 相关的 CCL5 通过促进颗粒细胞凋亡，可能损害卵巢衰老过程中的卵泡发育和成熟。
