Zhang Mengxue, Xing Jie, Zhao Shijie, Lu Minjun, Liu Yueqin, Lin Li, Gao Wujiang, Chen Lu, Li Wenxin, Shang Junyu, Zhou Jiamin, Yin Xinming, Zhu Xiaolan
Reproductive Center, The Fourth Affiliated Hospital of Jiangsu University, 20 Zhengdong Road, Zhenjiang, Jiangsu, 212001, People's Republic of China.
Center for Reproductive Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China.
Cell Biol Toxicol. 2024 May 3;40(1):29. doi: 10.1007/s10565-024-09871-8.
Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. Mesenchymal stem cells-derived small extracellular vesicles (MSCs-sEVs) are attractive candidates for ovarian function restoration and folliculogenesis for POF due to their safety and efficacy, however, the key mediator in MSCs-sEVs that modulates this response and underlying mechanisms remains elusive. Herein, we reported that YB-1 protein was markedly downregulated in vitro and in vivo models of POF induced with HO and CTX respectively, accompanied by granulosa cells (GCs) senescence phenotype. Notably, BMSCs-sEVs transplantation upregulated YB-1, attenuated oxidative damage-induced cellular senescence in GCs, and significantly improved the ovarian function of POF rats, but that was reversed by YB-1 depletion. Moreover, YB-1 showed an obvious decline in serum and GCs in POF patients. Mechanistically, YB-1 as an RNA-binding protein (RBP) physically interacted with a long non-coding RNA, MALAT1, and increased its stability, further, MALAT1 acted as a competing endogenous RNA (ceRNA) to elevate FOXO levels by sequestering miR-211-5p to prevent its degradation, leading to repair of ovarian function. In summary, we demonstrated that BMSCs-sEVs improve ovarian function by releasing YB-1, which mediates MALAT1/miR-211-5p/FOXO axis regulation, providing a possible therapeutic target for patients with POF.
卵巢早衰（POF）影响许多40岁以下的成年女性，并导致不孕。间充质干细胞衍生的小细胞外囊泡（MSCs-sEVs）因其安全性和有效性，成为恢复POF卵巢功能和促进卵泡生成的有吸引力的候选者，然而，MSCs-sEVs中调节这种反应的关键介质及其潜在机制仍不清楚。在此，我们报道，在分别用HO和CTX诱导的POF体外和体内模型中，YB-1蛋白明显下调，同时伴有颗粒细胞（GCs）衰老表型。值得注意的是，BMSCs-sEVs移植上调了YB-1，减轻了氧化损伤诱导的GCs细胞衰老，并显著改善了POF大鼠的卵巢功能，但YB-1的缺失逆转了这一作用。此外，POF患者血清和GCs中的YB-1明显下降。机制上，YB-1作为一种RNA结合蛋白（RBP）与长链非编码RNA MALAT1发生物理相互作用并增加其稳定性，此外，MALAT1作为一种竞争性内源RNA（ceRNA），通过螯合miR-211-5p以防止其降解来提高FOXO水平，从而导致卵巢功能的修复。总之，我们证明BMSCs-sEVs通过释放YB-1来改善卵巢功能，YB-1介导MALAT1/miR-211-5p/FOXO轴的调节，为POF患者提供了一个可能的治疗靶点。
