Adapted Exosomes for Addressing Chemotherapy-induced Premature Ovarian Insufficiency

Background: Premature ovarian insufficiency (POI) presents a multifaceted challenge with limited treatment options. This study explored the therapeutic potential of exosome-based interventions for chemotherapy-induced POI. Methods: Adapted exosomes were engineered from umbilical cord mesenchymal stem cells (UC-MSCs) under a specific co-culture system and used for treating in vitro and in vivo models of chemotherapy-induced premature ovarian insufficiency. Results: In vitro models revealed the significant impact of adapted exosomes, which promoted granulosa cell proliferation, decrease apoptosis, and enhanced ovarian functional markers. The findings in an in vivo chemotherapy-induced POI mouse model indicated the restoration of ovarian morphology, follicle numbers, and fertility in both the naïve and adapted exosome-treated groups. Notably, the adapted exosome group demonstrated a heightened pregnancy rate, increased numbers of primary follicles, and a significant reduction in ovarian apoptosis. MiRNA profiling revealed distinctive cargo in the adapted exosomes, among which miR-20b-5p played a pivotal role in regulating apoptosis and inflammation; this finding is especially important given that apoptosis is one of the primary complications of chemotherapy-induced POI. Furthermore, cells treated with adapted exosomes demonstrated significant overexpression of miR-20b-5p, resulting in decreased PTEN expression and the activation of the PI3K-AKT pathway—a crucial mechanism in mitigating chemotherapy-induced POI. Conclusions: This study introduces an exosome-based therapeutic approach, emphasizing the importance of exosome cargo composition in treating disorders. Further investigation into the identified miRNA profile in adapted exosomes is necessary to clarify the underlying mechanisms, potentially leading to the development of a new treatment for clinical premature ovarian insufficiency.