Abstract
BackgroundPremature ovarian failure (POF) has a great impact on reproductive endocrine function in females, and it is an important cause of infertility. Previous studies have demonstrated that small extracellular vesicles (sEVs) derived from stem cells play an important role in tissue regeneration. This study aimed to investigate the therapeutic effect of sEVs derived from embryonic stem cells (ESCs-sEVs) on damaged ovaries and explore the underlying molecular mechanisms.MethodsMice POF models were established by injecting mice with cyclophosphamide and busulfan. Then, ESCs-sEVs were intravenously transplanted into POF mice. The plasma of mice was harvested at 1 and 2 weeks after treatment to analyze the levels of anti-Mullerian hormone (AMH), estradiol (E2), and follicle stimulating hormone (FSH) by ELISA. The morphology of ovaries and follicles was observed by H&E staining, and apoptosis of granulosa cells was detected by TUNEL. In vitro, EdU and CCK-8 tests were used to evaluate the proliferation of cultured granulosa cells stimulated by ESCs-sEVs. Western blotting was used to determine the expression of PI3K/AKT and apoptotic-related proteins.ResultsAfter transplantation of ESCs-sEVs, the levels of serum sex hormones recovered to normal levels. In addition, the number of follicles was significantly increased, and the number of apoptotic cells was decreased. The results in vitro revealed that ESCs-sEVs could significantly improve the proliferation rate of granulosa cells and increase the expression of phosphorylated PI3K and AKT. Meanwhile, the positive effect on proliferation and the negative effect on apoptosis observed in granulosa cells were obviously decreased when the PI3K/AKT signaling pathway was inhibited.ConclusionOur findings suggested that ESCs-sEVs could improve ovarian function by regulating the PI3K/AKT signaling pathway, which could provide a promising clinical therapy for POF.
Highlights
Premature ovarian failure (POF) is a gynecological disease that is associated with a myriad of complex etiologies, and it has a serious impact on women’s fertility and quality of life
Western blotting demonstrated that the Embryonic stem cells (ESCs)-small extracellular vesicles (sEVs) were positive for CD9, CD63, and TSG101, and they were negative for Golgi membrane bound protein GM130, Actin, and Lamin A/ C (Fig. 1c)
All the results demonstrated that the ESCs-sEVs play a similar role in both chemotherapy-induced POF mice and naturally aging mice
Summary
Premature ovarian failure (POF) is a gynecological disease that is associated with a myriad of complex etiologies, and it has a serious impact on women’s fertility and quality of life. With the development of regenerative medicine, mesenchymal stem cells (MSCs) have been reported to play a vital therapeutic role in the treatment of POF [2,3,4]. Embryonic stem cells (ESCs) have the unique ability to proliferate indefinitely and are pluripotent, making them a promising therapeutic candidate in aging-related disease [5]. Previous studies have demonstrated that small extracellular vesicles (sEVs) derived from stem cells play an important role in tissue regeneration. This study aimed to investigate the therapeutic effect of sEVs derived from embryonic stem cells (ESCs-sEVs) on damaged ovaries and explore the underlying molecular mechanisms
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