Mesenchymal stem cells derived extracellular vesicles ameliorate ovarian aging through inhibiting LGALS3BP/NF-κB induced inflammation

Ovarian aging can lead to early menopause, infertility, and even premature senility in female patients, seriously impairing the quality of life. Unfortunatly, it is still lack of effective protection strategies against ovarian aging. It has been emergingly recognized that mesenchymal stem cells (MSCs) play a pivotal role in the maintenance of organ and tissue homeostasis and extracellular vesicles (EVs) have been identified as significant contributors to the paracrine action of MSCs. Human umbilical cord derived MSCs (UCMSCs) are distinguished by their superior self-renewal potential, minimal immunogenicity, and plentiful supply, rendering them an excellent candidate for EV-based therapeutic transplantation. However, whether UCMSC-EVs improve ovarian aging though regulating inflammation is still uncertain. In this study, EVs derived from umbilical cord mesenchymal stem cells were isolated using ultracentrifugation. The protein markers and morphology of EVs were characterized. Their effect on human ovarian granulosa cells (GCs) and ovarian aging mice models were assessed using ROS assay, CCK-8 and AM/PI assay, HE staining, Masson staining, western blotting, RNA sequencing and bioinformatic analysis. The proteomic profiling of EVs was conducted via LC-MS/MS assay, with subsequent pathway analysis employing cell transfection and western blotting to evaluate the efficacy of UCMSC-EVs. Our research demonstrated that UCMSC-EVs markedly improved ovarian function, cellular apoptosis and inflammation of aging mice. Subsequently, our results further indicated that UCMSC-EVs facilitated the transport of LGALS3BP to injured ovarian granular cells, modulated NF-κB-mediated inflammatory pathway, and then mitigated ovarian senescence. Meanwhile, the absence of LGALS3BP in UCMSC-EVs impaired the amelioration of inflammatory and the functional improvement in ovarian senescence. MSC-EVs derived anti-inflammation and pro-regeneration effect confirmed their therapeutic potential in amelioration of ovarian aging, and further revel the underlying mechanisms by modulating the NF-κB-mediated inflammatory pathways will promote their clinical application.