Chen Juntong, Huo Xingyu, Qian Maojiao, Xue Qian, He Yu, Xu Pengzhan, Wang Yueming, Tang Xiaoxuan, Luo Qianqian, Bao Hongchu, Xiong Yanlian
Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai, People's Republic of China.
Reproductive Medicine Centre, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, People's Republic of China.
Int J Nanomedicine. 2025 Aug 22;20:10195-10212. doi: 10.2147/IJN.S532207. eCollection 2025.
Premature ovarian insufficiency (POI) is a persistent condition in young women characterized by early follicular development disorders and reduced fertility. Research has found that exosomes derived from human umbilical mesenchymal stem cells (hUCMSC-Exo) have significant tissue repair effects. This study aims to investigate the therapeutic effect and potential molecular mechanism of hUCMSC-Exo on POI.
In vivo experiments were conducted by intraperitoneally injecting the chemotherapy drug cyclophosphamide (CTX) to establish a 14-day POI rat model. Serum hormone levels were measured using an enzyme-linked immunosorbent assay, and changes in ovarian tissue structure were analyzed using hematoxylin-eosin (HE) staining. Perls staining and transmission electron microscopy were used to assess changes in ovarian ferroptosis. In vitro experiments involved exposing theca interna cells (TICs) treated with CTX to normal and miR-26a-5p inhibitor-treated hUCMSC-Exo. The expression changes of PTEN, Nrf2, and GPX4, which are associated with ferroptosis, were analyzed using immunofluorescence, Western blot, and quantitative reverse-transcription polymerase chain reaction.
hUCMSC-Exo intervention can significantly repair the ovarian tissue structure and functional abnormalities in the model rats, especially ferroptosis. Further bioinformatics analysis revealed that the inhibition of the PTEN/GPX4 pathway-mediated ferroptosis in TICs might be the main mechanism through which exosomes exert their regulatory/therapeutic effects. In vitro experiments, where exosome miR-26a-5p was inhibited, further confirmed that the delivery of miR-26a-5p is crucial for the regulatory effect of exosomes.
In conclusion, our results suggest that hUCMSC-Exos alleviates POI-related dysfunction of ovarian structure and function. The mechanism could be related to the transfers of miR-26a-5p and suppression of PTEN/GPX4 axis signaling-mediated autophagy of TICs. It provides a new perspective for developing treatment methods for patients with metabolic abnormalities related to POI.
卵巢早衰（POI）是年轻女性中的一种持续性疾病，其特征为早期卵泡发育障碍和生育力降低。研究发现，人脐间充质干细胞来源的外泌体（hUCMSC-Exo）具有显著的组织修复作用。本研究旨在探讨hUCMSC-Exo对POI的治疗效果及潜在分子机制。
通过腹腔注射化疗药物环磷酰胺（CTX）进行体内实验，建立为期14天的POI大鼠模型。采用酶联免疫吸附测定法测量血清激素水平，并用苏木精-伊红（HE）染色分析卵巢组织结构的变化。采用普鲁士蓝染色和透射电子显微镜评估卵巢铁死亡的变化。体外实验涉及将用CTX处理的卵泡膜细胞（TICs）暴露于正常的和经miR-26a-5p抑制剂处理的hUCMSC-Exo。使用免疫荧光、蛋白质免疫印迹和定量逆转录聚合酶链反应分析与铁死亡相关的PTEN、Nrf2和GPX4的表达变化。
hUCMSC-Exo干预可显著修复模型大鼠的卵巢组织结构和功能异常，尤其是铁死亡。进一步的生物信息学分析表明，抑制TICs中PTEN/GPX4途径介导的铁死亡可能是外泌体发挥调节/治疗作用的主要机制。在体外实验中，外泌体miR-26a-5p被抑制，进一步证实了miR-26a-5p的传递对于外泌体的调节作用至关重要。
总之，我们的结果表明hUCMSC-Exos可减轻POI相关的卵巢结构和功能障碍。其机制可能与miR-26a-5p的传递以及TICs中PTEN/GPX4轴信号介导的自噬抑制有关。它为开发与POI相关的代谢异常患者的治疗方法提供了新的视角。
