BDNF secreted by mesenchymal stem cells improves aged oocyte quality and development potential by activating the ERK1/2 pathway.

Summary

Human umbilical cord MSC secretome improves key hallmarks of aged oocyte quality in mice and identifies BDNF as the active component. BDNF activates ERK1/2 to upregulate DAZL and BTG4, improving spindle integrity, maternal RNA clearance, and reducing aneuploidy; it also enhanced fertilization and blastocyst rates in aged human oocytes.

Key Findings

• MSC secretome improved first polar body emission, spindle assembly, maternal mRNA degradation, and reduced aneuploidy in aged mouse oocytes.
• Neutralizing BDNF abrogated MSC-secretome effects; recombinant BDNF replicated benefits.
• Mechanism: ERK1/2 activation increased DAZL and BTG4 expression in aged oocytes.
• In situ ovarian injection of MSC-secretome or BDNF enhanced oocyte quality and early embryonic development in aged mice.
• BDNF increased fertilization and blastocyst formation rates in aged human oocytes in vitro.

Clinical Implications

BDNF or MSC-derived biologics could be explored as adjuncts to improve oocyte competence in older patients undergoing IVF; pathway markers (ERK1/2 activation, DAZL/BTG4) may guide responder selection.

Limitations

• Preclinical; clinical safety, dosing, and delivery methods for ovarian administration remain to be established.
• Sample sizes and long-term offspring outcomes were not reported.

Future Directions

Optimize dosing and delivery (local vs systemic), assess safety and efficacy in large animals, and design early-phase clinical trials integrating molecular response biomarkers.