Small extracellular vesicles (sEVs) secreted by human umbilical cord have therapeutic effects on various degenerative diseases. However, the characteristics and potential functions of human umbilical cord mesenchymal stem cells (huMSCs)‐derived sEVs, especially the role of premature ovarian failure (POF), are poorly understood. Here, we isolated and characterized huMSCs and their sEVs. huMSCs highly expressed CD73, CD90, and CD105. huMSC‐sEVs showed typical exosomal features, highly expressing CD9, TSG101, and CD63. It was shown that huMSC‐sEVs could be taken up by granulosa cells (GCs) and damaged ovarian tissue, which increased the levels of hormone secretion and reduced GCs apoptosis. We further confirmed that the levels of follicle‐stimulating hormone in rat serum decreased dramatically, while the levels of estrogen (E2）and anti‐mullerian hormone (AMH) increased significantly with the treatment of huMSC‐sEVs. Meanwhile, huMSC‐sEVs treatment greatly reduced cell apoptosis and autophagy, while increased the phosphorylation levels of p‐PI3K and p‐Akt. Therefore, treatment with huMSC‐sEVs significantly inhibited GCs apoptosis, improved ovarian morphology, promoted follicular development, inhibited follicular over‐atresia, and improved ovarian reserve capacity in POF rats. Our study verified that activation of PI3K/Akt signaling pathway and regulation of cellular autophagy, thus reducing GCs death, are the mechanisms by which huMSC‐sEVs restore ovarian tissue function.

中文翻译：

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人脐带间充质干细胞来源的小细胞外囊泡对顺铂所致卵巢损伤的修复作用

人类脐带分泌的小细胞外囊泡（sEV）对多种退行性疾病具有治疗作用。然而，人们对人脐带间充质干细胞（huMSCs）衍生的 sEV 的特征和潜在功能，尤其是卵巢早衰（POF）的作用知之甚少。在这里，我们分离并表征了 huMSC 及其 sEV。 huMSC 高表达 CD73、CD90 和 CD105。 huMSC-sEVs 显示出典型的外泌体特征，高表达 CD9、TSG101 和 CD63。结果表明，huMSC-sEV 可以被颗粒细胞 (GC) 和受损的卵巢组织摄取，从而增加激素分泌水平并减少 GC 凋亡。我们进一步证实，大鼠血清中促卵泡激素的水平急剧下降，而雌激素（E2）和抗苗勒氏管激素（AMH）随着 huMSC-sEV 的治疗而显着增加。同时，huMSC-sEVs处理大大减少了细胞凋亡和自噬，同时增加了p-PI3K和p-Akt的磷酸化水平。因此，huMSC-sEVs治疗显着抑制POF大鼠GCs凋亡，改善卵巢形态，促进卵泡发育，抑制卵泡过度闭锁，提高卵巢储备能力。我们的研究证实，PI3K/Akt信号通路的激活和细胞自噬的调节，从而减少GCs死亡，是huMSC-sEVs恢复卵巢组织功能的机制。