BDNF secreted by mesenchymal stem cells ameliorates the accelerated meiotic progression in aged mouse oocytes by activating the PI3K/AKT pathway

BACKGROUND: Oocyte aneuploidy is a major contributor to age-related fertility decline, but the effective treatments are still unavailable. The spindle assembly checkpoint (SAC), which functions to maintain chromosomal euploidy in oocytes, may become impaired with aging, manifesting primarily as an aberrant acceleration of meiotic progression. In the present study, we investigated the effects, effective components, and molecular mechanisms of the secretome of mesenchymal stem cells (MSC-sec) in reducing aneuploidy by alleviating the accelerated meiotic progression of aged mouse oocytes. METHODS: MSC-sec was added to oocyte culture medium and its effects on aged oocytes were evaluated through analysis of meiotic process, chromosome alignment, the expression and localization of SAC proteins BubR1 and ZW10. The critical role of the PI3K/AKT pathway was confirmed by application of the inhibitor LY294002. Exogenous brain-derived neurotrophic factor (BDNF) or BDNF neutralizing antibodies were used to identify the effective components of MSC-sec. The in vitro effects of 7,8-dihydroxyflavone (7,8-DHF), a BDNF receptor agonist, were validated through PI3K/AKT and ERK1/2 pathway activity, meiotic progression and aneuploidy assays, while its in vivo effects were assessed by oocyte quality and early embryo development following intraperitoneal injection. RESULTS: MSC-sec could ameliorate age-related accelerated meiotic progression and increase the expression of BubR1 and ZW10 at the kinetochore in mouse oocyte. MSC-sec treatment activates the PI3K/AKT pathway in aged oocytes, and its effect on meiotic progression can be blocked by the PI3K inhibitor LY294002. BDNF is identified as the effective component of MSC-sec in decelerating the meiotic progression. In vitro application of 7,8-DHF ameliorated the accelerated meiotic progression and reduced the aneuploidy rate in aged oocytes, effectively mimicking the effects of BDNF. In vivo administration of 7,8-DHF significantly enhanced oocyte quality and early embryo development in aged mice. CONCLUSIONS: We found that BDNF secreted by MSCs ameliorates the accelerated meiotic progression in aged mouse oocytes by activating the PI3K/AKT pathway, which may be attributed to an improvement in SAC function. Our study elucidates the molecular mechanism and effective component of MSC-sec to alleviate aneuploidy of aged oocytes, providing an experimental foundation for the clinical translation of BDNF or its alternative 7,8-DHF in improving the quality and development potential of oocytes from aged women.