Exosomes Derived From Human Mesenchymal Stem Cells Mitigate Follicular Interstitial Cell Ferroptosis via the miR-26a-5p/PTEN/GPX4 Axis in Rats with Chemotherapy-Induced Premature Ovarian Insufficiency

Abstract

Juntong Chen,1,* Xingyu Huo,1,* Maojiao Qian,1 Qian Xue,1 Yu He,1 Pengzhan Xu,1 Yueming Wang,1 Xiaoxuan Tang,1 Qianqian Luo,1 Hongchu Bao,2,3 Yanlian Xiong1 1Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai, People’s Republic of China; 2Reproductive Medicine Centre, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, People’s Republic of China; 3Shandong Provincial Key Medical and Health Laboratory of Reproductive Health and Genetics, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanlian Xiong; Hongchu Bao, Email [email protected]; [email protected]: 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.Methods: 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.Results: 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.Conclusion: 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. Keywords: POI, miR-26a-5p, GPX4, TICs, ferroptosis, hUCMSC-Exo

Keywords

• POI
• miR-26a-5p
• GPX4
• TICs
• ferroptosis
• hUCMSC-Exo