Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Reprod Sci. 2024 Aug;31(8):2392-2408. doi: 10.1007/s43032-024-01509-8. Epub 2024 Mar 26.
Ovarian aging reduced the quality of oocytes, resulting in age-related female infertility. It is reported that mesenchymal stem cells (MSCs) therapy can improve age-related ovarian function decline and the success rate of in vitro maturation (IVM) in assisted reproductive therapy. In order to investigate the effectiveness and mechanisms of MSCs to enhance oocyte quality of cumulus oocyte complexes (COCs) in advanced age, this study focus on the respective functional improvement of oocytes and granulosa cells (GCs) from aging mice and further to explore and verify the possible mechanisms. Here, we studied a popular but significant protein of follicular development, Forkhead box O-3a (FOXO3a), which is a transcription factor that mediates a variety of cellular processes, but the functions of which in regulating oocyte quality in MSCs therapy still remain inconclusive. In this study, the RNA-seq data of metaphase II (MII) oocytes and GCs isolated from COCs confirmed that, GCs of immature follicles show the most potential to be the targeted cells of bone marrow mesenchymal stem cells (BMSCs) by FOXO3a signaling pathway. Furthermore, we demonstrated the effectiveness of BMSCs co-culture with aging COCs to enhance oocyte quality and found its mechanism to function via ameliorating the biological function of GCs by alleviating FOXO3a levels. These results provide significant fundamental research on MSCs therapy on ovarian aging, as well as offering guidance for raising the success rate of assisted reproductive technology such IVM in clinical and non-clinical settings.
卵巢衰老降低了卵母细胞的质量，导致与年龄相关的女性不孕。有报道称，间充质干细胞（MSCs）治疗可以改善与年龄相关的卵巢功能下降和辅助生殖治疗中体外成熟（IVM）的成功率。为了研究 MSCs 增强高龄小鼠卵丘卵母细胞复合物（COCs）中卵母细胞质量的有效性和机制，本研究重点关注衰老小鼠卵母细胞和颗粒细胞（GCs）的各自功能改善，并进一步探索和验证可能的机制。在这里，我们研究了一个流行但重要的卵泡发育蛋白，叉头框 O-3a（FOXO3a），它是一种转录因子，介导多种细胞过程，但在调节 MSCs 治疗中卵母细胞质量的功能仍不清楚。在这项研究中，从中期 II（MII）卵母细胞和从 COCs 分离的 GCs 的 RNA-seq 数据证实，不成熟卵泡的 GCs 通过 FOXO3a 信号通路显示出最有潜力成为骨髓间充质干细胞（BMSCs）的靶向细胞。此外，我们证明了 BMSCs 与衰老 COCs 共培养以提高卵母细胞质量的有效性，并发现其通过减轻 FOXO3a 水平来改善 GCs 的生物学功能来发挥作用的机制。这些结果为卵巢衰老的 MSCs 治疗提供了重要的基础研究，并为提高临床和非临床环境中 IVM 等辅助生殖技术的成功率提供了指导。
