Exosomes derived from hypoxic mesenchymal stem cell ameliorate premature ovarian insufficiency by reducing mitochondrial oxidative stress
Abstract Cyclophosphamide (CTX) exposure causes premature ovarian insufficiency (POI). The therapeutic potential of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) is not fully understood, especially regarding whether hypoxic preconditioning enhances their efficacy in POI...
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Nature Portfolio
2025-03-01
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| Online Access: | https://doi.org/10.1038/s41598-025-90879-3 |
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| author | Shanshan Zhang Xinfeng Zou Xiaona Feng Shuai Shi Yanyun Zheng Qun Li Yanqun Wu |
| author_facet | Shanshan Zhang Xinfeng Zou Xiaona Feng Shuai Shi Yanyun Zheng Qun Li Yanqun Wu |
| author_sort | Shanshan Zhang |
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| description | Abstract Cyclophosphamide (CTX) exposure causes premature ovarian insufficiency (POI). The therapeutic potential of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) is not fully understood, especially regarding whether hypoxic preconditioning enhances their efficacy in POI. In this study, exosomes were isolated and identified from hucMSCs (hucMSCs-Exos) under hypoxic (HExos) and normoxic (NExos) conditions. Cyclophosphamide (CTX) was used to develop the POI rat model, and NExos or HExos was injected into the tail vein to investigate its therapeutic effect on POI. In addition, CTX-treated KGN cell lines were used to investigate the effects of NExos and HExos on cell proliferation, apoptosis, oxidative stress and mitochondrial membrane potential.The results indicated that hucMSCs-Exos transplantation substantially improved body weight, ovarian weight coefficient, estrous cycles, ovarian morphology, ovulation count, and sex hormone levels in POI rats. Further, HExos showed a higher level of therapeutic efficiency than NExos. In vitro experiments demonstrated that NExos and HExos may be phagocytosed by KGN cell line, decrease cell apoptosis, and enhance cell growth. After NExos or HExos transplantation, the reactive oxygen species level was reduced, mitochondrial membrane potential enhanced, and the levels of mitochondrial oxidative stress-associated factors returned to their basal level. Notably, the improvement of oxidative stress by NExos or HExos was blocked by the SIRT3 selective inhibitor 3-TYP. In conclusion, hypoxia-induced hucMSCs-Exos protected the ovarian reserve against CXT-induced ovarian damage by rectifying mitochondrial malfunction via the SIRT3/PGC1-α pathway, establishing a solid basis for developing specific ovarian protection therapies. |
| format | Article |
| id | doaj-art-5d4d1f5a76454aaf9b2592a5291cd8ca |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-5d4d1f5a76454aaf9b2592a5291cd8ca2025-08-20T04:02:45ZengNature PortfolioScientific Reports2045-23222025-03-0115111410.1038/s41598-025-90879-3Exosomes derived from hypoxic mesenchymal stem cell ameliorate premature ovarian insufficiency by reducing mitochondrial oxidative stressShanshan Zhang0Xinfeng Zou1Xiaona Feng2Shuai Shi3Yanyun Zheng4Qun Li5Yanqun Wu6School of Life sciences, Jining Medical UniversityShandong Xinchao Biotechnology Co., Ltd.School of Life sciences, Jining Medical UniversityIVF center, Jinhua People’s HospitalSchool of Life sciences, Jining Medical UniversitySchool of Life sciences, Jining Medical UniversitySchool of Life sciences, Jining Medical UniversityAbstract Cyclophosphamide (CTX) exposure causes premature ovarian insufficiency (POI). The therapeutic potential of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) is not fully understood, especially regarding whether hypoxic preconditioning enhances their efficacy in POI. In this study, exosomes were isolated and identified from hucMSCs (hucMSCs-Exos) under hypoxic (HExos) and normoxic (NExos) conditions. Cyclophosphamide (CTX) was used to develop the POI rat model, and NExos or HExos was injected into the tail vein to investigate its therapeutic effect on POI. In addition, CTX-treated KGN cell lines were used to investigate the effects of NExos and HExos on cell proliferation, apoptosis, oxidative stress and mitochondrial membrane potential.The results indicated that hucMSCs-Exos transplantation substantially improved body weight, ovarian weight coefficient, estrous cycles, ovarian morphology, ovulation count, and sex hormone levels in POI rats. Further, HExos showed a higher level of therapeutic efficiency than NExos. In vitro experiments demonstrated that NExos and HExos may be phagocytosed by KGN cell line, decrease cell apoptosis, and enhance cell growth. After NExos or HExos transplantation, the reactive oxygen species level was reduced, mitochondrial membrane potential enhanced, and the levels of mitochondrial oxidative stress-associated factors returned to their basal level. Notably, the improvement of oxidative stress by NExos or HExos was blocked by the SIRT3 selective inhibitor 3-TYP. In conclusion, hypoxia-induced hucMSCs-Exos protected the ovarian reserve against CXT-induced ovarian damage by rectifying mitochondrial malfunction via the SIRT3/PGC1-α pathway, establishing a solid basis for developing specific ovarian protection therapies.https://doi.org/10.1038/s41598-025-90879-3Mesenchymal stem cellsPremature ovarian insufficiencyExosomesReactive oxygen speciesHypoxic |
| spellingShingle | Shanshan Zhang Xinfeng Zou Xiaona Feng Shuai Shi Yanyun Zheng Qun Li Yanqun Wu Exosomes derived from hypoxic mesenchymal stem cell ameliorate premature ovarian insufficiency by reducing mitochondrial oxidative stress Scientific Reports Mesenchymal stem cells Premature ovarian insufficiency Exosomes Reactive oxygen species Hypoxic |
| title | Exosomes derived from hypoxic mesenchymal stem cell ameliorate premature ovarian insufficiency by reducing mitochondrial oxidative stress |
| title_full | Exosomes derived from hypoxic mesenchymal stem cell ameliorate premature ovarian insufficiency by reducing mitochondrial oxidative stress |
| title_fullStr | Exosomes derived from hypoxic mesenchymal stem cell ameliorate premature ovarian insufficiency by reducing mitochondrial oxidative stress |
| title_full_unstemmed | Exosomes derived from hypoxic mesenchymal stem cell ameliorate premature ovarian insufficiency by reducing mitochondrial oxidative stress |
| title_short | Exosomes derived from hypoxic mesenchymal stem cell ameliorate premature ovarian insufficiency by reducing mitochondrial oxidative stress |
| title_sort | exosomes derived from hypoxic mesenchymal stem cell ameliorate premature ovarian insufficiency by reducing mitochondrial oxidative stress |
| topic | Mesenchymal stem cells Premature ovarian insufficiency Exosomes Reactive oxygen species Hypoxic |
| url | https://doi.org/10.1038/s41598-025-90879-3 |
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