Tang Yu, He Yu, Huo Xingyu, Chen Juntong, Qian Maojiao, Huang Haoyu, Meng Yixuan, Zhang Lianshuang, Xu Feibo, Zhang Yukun, Bao Hongchu, Xiong Yanlian
Xu Rongxiang Regenerative Medicine Research Center, School of Basic Medicine, Binzhou Medical University, Yantai, P.R. China.
Department of Physiology, School of Medicine, Shandong College of Traditional Chinese Medicine, Yantai, P.R. China.
Stem Cell Res Ther. 2025 Jun 7;16(1):291. doi: 10.1186/s13287-025-04396-1.
One major factor contributing to infertility in women of childbearing age is premature ovarian insufficiency (POI). Exosomes produced from human umbilical cord mesenchymal stem cells (hUMSC-Exos) have drawn a lot of attention lately as a potential treatment for ovarian dysfunction brought on by POI. However, its therapeutic mechanism is still unclear and needs further exploration.
POI model was established by intraperitoneal injection of cyclophosphamide (CTX) in female Wistar rats. These POI rats were treated with hUMSC-Exos for one week. In addition to in vivo experiments, in vitro POI models were also established. In vitro experiments, theca interstitial cells (TICs) treated with CTX were exposed to normal as well as let-7a-5p inhibitory hUMSC-Exos. The ovary structure, morphology, endocrine function, and reproductive ability of POI rats were observed by H&E staining and ELISA. Western blot, immunofluorescence staining (IF), and quantitative real-time polymerase chain reaction (qRT-PCR) were used to evaluate the autophagy-related indexes in ovary and TICs of POI rats in each group.
CTX induced abnormalities of ovarian morphology, structure, endocrine, and reproductive function in rats, and accompanied by autophagy of TICs. Notably, hUMSC-Exos diminishes ovarian structural and functional damage in POI rats and TICs autophagy via targeting the AMPK/mTOR pathway. Furthermore, downregulating let-7a-5p in hUMSC-Exos weakened their ability to prevent TICs autophagy.
Overall, the findings suggested that hUMSC-Exos improves ovarian function in POI rats by inhibiting TICs autophagy via the let-7a-5p/AMPK/mTOR pathway. Our study provided further evidence that POI patients can benefit from hUMSC-Exos-mediated therapy.
育龄期女性不孕的一个主要因素是卵巢早衰（POI）。人脐带间充质干细胞来源的外泌体（hUMSC-Exos）作为一种可能治疗POI所致卵巢功能障碍的方法，近来备受关注。然而，其治疗机制仍不清楚，需要进一步探索。
通过腹腔注射环磷酰胺（CTX）建立雌性Wistar大鼠POI模型。用hUMSC-Exos对这些POI大鼠进行为期一周的治疗。除体内实验外，还建立了体外POI模型。在体外实验中，用CTX处理的卵泡膜间质细胞（TICs）分别暴露于正常的以及let-7a-5p抑制型hUMSC-Exos。通过苏木精-伊红染色（H&E）和酶联免疫吸附测定（ELISA）观察POI大鼠的卵巢结构、形态、内分泌功能和生殖能力。采用蛋白质免疫印迹法（Western blot）、免疫荧光染色（IF）和定量实时聚合酶链反应（qRT-PCR）评估各组POI大鼠卵巢和TICs中的自噬相关指标。
CTX诱导大鼠卵巢形态、结构、内分泌和生殖功能异常，并伴有TICs自噬。值得注意的是，hUMSC-Exos通过靶向AMPK/mTOR途径减轻POI大鼠的卵巢结构和功能损伤以及TICs自噬。此外，下调hUMSC-Exos中的let-7a-5p会削弱其预防TICs自噬的能力。
总体而言，研究结果表明hUMSC-Exos通过let-7a-5p/AMPK/mTOR途径抑制TICs自噬，从而改善POI大鼠的卵巢功能。我们的研究提供了进一步的证据，表明POI患者可从hUMSC-Exos介导的治疗中获益。
