Therapeutic Effects of Mesenchymal Stem Cell–Derived Extracellular Vesicles from Different Tissue Sources on Diminished Ovarian Reserve and the Related Mechanisms

Background Patients with diminished ovarian reserve (DOR) significantly reduced success rates in assisted reproduction, making DOR a major clinical challenge in assisted reproductive technologies. Recent studies have indicated that extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) hold promise for improving ovarian function, yet the impact of tissue origin on EV function remains unclear. Adipose tissue and the umbilical cord are common and easily accessible sources of MSCs. This study aimed to compare the therapeutic effects of adipose-derived MSC- EVs (A-EV) and umbilical cord MSC- EVs (U-EV) in a cyclophosphamide-induced DOR mouse model, investigate their underlying mechanisms and provide experimental evidence for selecting the most promising EVs source for clinical application. Results Proteomic analysis revealed differences protein composition between U-EV and A-EV. Both A-EV and U-EV significantly increased serum AMH levels and improved fertility, whereas U-EV produced more sustained reproductive benefits. Single-cell RNA sequencing and in vitro functional validation demonstrated that EV treatment reduced granulosa-cell apoptosis, oxidative stress, DNA-damage responses, and senescence signatures, with U-EV exerting broader regulatory effects. Conclusions In conclusion, both A-EV and U-EV improved ovarian function in DOR mice; however, U-EV demonstrated greater efficacy in promoting long-term fertility and inhibiting granulosa cell senescence, indicating greater potential for clinical translation.