Zhou Jing, Li Cheng, Mi Xin, Zhou Jiali, Chen Caiyi, Ren Jiayi, Liu Ran, Liu Gang, Chen Zi-Jiang, Qin Yingying, Wu Keliang, Zhao Shidou
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China.
National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China.
Cell Commun Signal. 2025 Mar 23;23(1):150. doi: 10.1186/s12964-025-02137-8.
Reduced oocyte quality is a key factor in age-related fertility decline, and there are no effective treatments available. The secretome of mesenchymal stem cells (MSC-sec) contains various bioactive factors and has the potential to improve oocyte quality. This study aimed to investigate the effective component and molecular mechanism of MSC-sec involved in improving oocyte quality from aged mice and humans.
Immunofluorescence and chromosome spread were performed to investigate the effects of secretome from human umbilical cord-MSC on spindle assembly and aneuploidy in aged mouse oocytes. Brain-derived neurotrophic factor (BDNF) and its neutralization antibody was supplemented in both in vitro and in vivo experiments to verify the effective component in MSC-sec. RNA-seq analysis was used to reveal the alterations in maternal mRNA degradation in aged mouse oocytes after MSC-sec treatment. In vitro culture of oocytes from aged women was also used to verify the effectiveness of BDNF in improving oocyte quality.
MSC-sec treatment significantly increased first polar body emission, improved spindle assembly, promoted maternal RNA degradation, and reduced aneuploidy rate in aged mouse oocytes. While the addition of BDNF neutralization antibody blocked the effects of MSC-sec, BDNF alone also increased the oocyte quality from aged mice. Mechanistically, both MSC-sec and BDNF rescued the quality of aged mouse oocytes by activating the ERK1/2 signaling pathway to increase the expression of DAZL and BTG4. In situ injection of MSC-sec or BDNF into aged mouse ovaries significantly improved oocyte quality and early embryonic development. Finally, we demonstrated that BDNF treatment increased both the fertilization rate and blastocyst formation rate of aged human oocytes.
These findings demonstrate that BDNF secreted by mesenchymal stem cells can improve the quality and development potential of oocytes from both aged mice and humans by activating the ERK1/2 signaling pathway, suggesting that it has the potential to mitigate age-related declines in oocyte quality.
卵母细胞质量下降是年龄相关生育力下降的关键因素，且目前尚无有效的治疗方法。间充质干细胞分泌组（MSC-sec）含有多种生物活性因子，具有改善卵母细胞质量的潜力。本研究旨在探讨MSC-sec改善老年小鼠和人类卵母细胞质量的有效成分及分子机制。
采用免疫荧光和染色体铺展技术，研究人脐带间充质干细胞分泌组对老年小鼠卵母细胞纺锤体组装和非整倍体的影响。在体外和体内实验中补充脑源性神经营养因子（BDNF）及其中和抗体，以验证MSC-sec中的有效成分。RNA测序分析用于揭示MSC-sec处理后老年小鼠卵母细胞中母体mRNA降解的变化。还通过体外培养老年女性的卵母细胞来验证BDNF改善卵母细胞质量的有效性。
MSC-sec处理显著提高了老年小鼠卵母细胞的第一极体排出率，改善了纺锤体组装，促进了母体RNA降解，并降低了非整倍体率。虽然添加BDNF中和抗体可阻断MSC-sec的作用，但单独使用BDNF也可提高老年小鼠的卵母细胞质量。机制上，MSC-sec和BDNF均通过激活ERK1/2信号通路来增加DAZL和BTG4的表达，从而挽救老年小鼠卵母细胞的质量。将MSC-sec或BDNF原位注射到老年小鼠卵巢中可显著改善卵母细胞质量和早期胚胎发育。最后，我们证明BDNF处理可提高老年人类卵母细胞的受精率和囊胚形成率。
这些发现表明，间充质干细胞分泌的BDNF可通过激活ERK1/2信号通路来改善老年小鼠和人类卵母细胞的质量和发育潜力，提示其具有减轻年龄相关卵母细胞质量下降的潜力。
