PDF(Pubmed)
Abstract：
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 H2O2 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 FOXO3 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/FOXO3 axis regulation, providing a possible therapeutic target for patients with POF.
摘要：
卵巢早衰（POF）影响许多40岁以下的成年女性，并导致不孕。间充质干细胞来源的小细胞外囊泡（MSCs-sEV）由于其安全性和有效性而成为POF卵巢功能恢复和卵泡发生的有吸引力的候选者。然而,MSCs-sEV中调节这种反应和潜在机制的关键介质仍然难以捉摸。在这里，我们报道了YB-1蛋白在H2O2和CTX诱导的POF体外和体内模型中显著下调,伴有颗粒细胞（GC）衰老表型。值得注意的是,BMSCs-sEV移植上调YB-1，减轻GCs氧化损伤诱导的细胞衰老，显著改善POF大鼠卵巢功能,但这被YB-1耗尽所逆转。此外，YB-1在POF患者血清和GCs中显示明显下降。机械上,YB-1作为一种RNA结合蛋白（RBP），与长的非编码RNA发生物理相互作用，MALAT1，并增加其稳定性，进一步,MALAT1充当竞争性内源性RNA（ceRNA），通过螯合miR-211-5p来防止其降解来提高FOXO3水平，导致卵巢功能修复。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/FOXO3轴的调节，为POF患者提供可能的治疗靶点。
