Ovarian extracellular matrix hydrogel microspheres increase the efficacy of stem cell treatment in premature ovarian insufficiency

Premature ovarian insufficiency (POI) affects approximately 1-2% of reproductive-aged women, significantly impacting their reproductive potential and systemic health. Stem cell-based therapy has demonstrated promising therapeutic efficacy in restoring ovarian function through promoting neovascularization, attenuating fibrosis, and suppressing ovarian cell apoptosis. However, conventional cell transplantation approaches are limited by poor cell viability and retention. Here, we developed a novel therapeutic strategy utilizing hydrogel microspheres (OG-HMPs) fabricated from decellularized ovarian extracellular matrix (OECM) and gelatin as delivery vehicles for bone marrow mesenchymal stem cells (BMSCs) to treat POI. OG-HMPs effectively supported BMSCs attachment and proliferation, facilitating the formation of high-density cellular spheroids. The retained ovary-specific bioactive components in OECM recapitulate the native ovarian microenvironment, enhancing cell survival and significantly elevating the expression of angiogenic factors including VEGF and HGF. Moreover, OG-HMPs@BMSCs demonstrate immunomodulatory effects on activated macrophages and cytoprotective properties against chemically-induced granulosa cell apoptosis. In vivo studies using POI mouse models confirmed that OG-HMPs@BMSCs transplantation significantly enhanced BMSCs retention within ovarian tissue and improved both endocrine function, estrous cycle pattern, and reproductive outcomes compared to conventional cell delivery. Collectively, OG-HMPs, exhibiting excellent biocompatibility and biological activity, represent a promising therapeutic platform for POI treatment through enhanced stem cell-mediated tissue regeneration.