Exosomes derived from mesenchymal stem cells repair ovarian function by suppressing NLRP3-mediated pyroptosis in cyclophosphamide-induced premature ovarian failure
Xiangrong Cui, Huihui Li, Xia Huang, Tingting Xue, Shu Wang, Xinyu Zhu, Xuan Jing
Abstract
BACKGROUND: Premature ovarian failure (POF) is a debilitating condition impairing fertility and health in women. Mesenchymal stem cell-derived exosomes (MSC-EVs) have emerged as a promising therapeutic option for POF due to their regenerative capabilities. This study explores the effectiveness of human umbilical cord mesenchymal stem cell-derived exosomes (HuMSCs-Exos) in counteracting NLRP3-mediated pyroptosis and restoring ovarian function in a cyclophosphamide (CTX)-induced POF model. METHODS: HuMSCs-Exos were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blot for exosomal markers. A CTX-induced POF mouse model was treated with HuMSCs-Exos to assess their impact on ovarian morphology, function, and fertility. Additionally, in vitro studies on granulosa cells (GCs) evaluated the effects of HuMSCs-Exos on cell viability, apoptosis, oxidative stress, and NLRP3 inflammasome pathway components. RESULTS: In the CTX-induced POF model, HuMSCs-Exos treatment significantly improved ovarian structure, increased follicle counts, restored estrous cycles, and enhanced fertility outcomes. Hormonal balance was also achieved, with a notable reduction in NLRP3 inflammasome activation and oxidative stress markers. In vitro, HuMSCs-Exos promoted GCs viability and reduced apoptosis and oxidative damage, further inhibiting the NLRP3 inflammasome pathway. CONCLUSION: HuMSCs-Exos effectively mitigate CTX-induced POF through the suppression of NLRP3-mediated pyroptosis, enhancing ovarian function and fertility. This study underscores the potential of MSC-EV-based therapies for treating POF and possibly other inflammatory and degenerative reproductive disorders.