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BDNF secreted by mesenchymal stem cells ameliorates the accelerated meiotic progression in aged mouse oocytes by
Xin Mi1,2,3,4,5,6,7, Jiali Zhou1,2,3,4,5,6,7, Caiyi Chen1,2,3,4,5,6,7
1State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, Shandong, China.
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.
Insights
Mesenchymal stem cell secretome (MSC-sec) improves aged oocyte quality by decelerating meiotic progression via brain-derived neurotrophic factor (BDNF). This treatment alleviates aneuploidy and enhances early embryo development, offering potential for fertility treatments.
Area of Science:
- Reproductive biology and stem cell therapy
- Oocyte aging and aneuploidy research
- Molecular mechanisms of meiosis regulation
Background:
- Oocyte aneuploidy is a primary cause of age-related fertility decline, with limited treatment options.
- Aging impairs the spindle assembly checkpoint (SAC), accelerating meiotic progression and increasing aneuploidy.
- Investigating mesenchymal stem cell secretome (MSC-sec) for potential therapeutic effects on aged oocytes.
Purpose of the Study:
- To investigate the effects of MSC-sec on reducing aneuploidy in aged mouse oocytes.
- To identify the effective components and molecular mechanisms underlying MSC-sec's action.
- To evaluate the potential of MSC-sec components for clinical translation in improving oocyte quality.
Main Methods:
- Cultured aged mouse oocytes with MSC-sec, assessing meiotic progression and chromosome alignment.
- Analyzed expression/localization of SAC proteins (BubR1, ZW10) and PI3K/AKT pathway activity.
- Identified brain-derived neurotrophic factor (BDNF) as key component; tested BDNF receptor agonist 7,8-dihydroxyflavone (7,8-DHF) in vitro and in vivo.
Main Results:
- MSC-sec ameliorated accelerated meiotic progression and increased SAC protein expression in aged oocytes.
- MSC-sec activated the PI3K/AKT pathway, with effects blocked by LY294002; BDNF was identified as the active component.
- 7,8-DHF mimicked MSC-sec effects in vitro, reducing aneuploidy, and improved oocyte quality and embryo development in vivo.
Conclusions:
- BDNF from MSCs activates PI3K/AKT, improving SAC function and decelerating meiotic progression in aged oocytes.
- MSC-sec alleviates oocyte aneuploidy through BDNF-mediated PI3K/AKT pathway activation.
- BDNF or its agonist 7,8-DHF show promise for clinical applications to enhance oocyte quality in aged women.
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