BDNF secreted by mesenchymal stem cells improves the quality and development potential of aged oocytes by activating the ERK1/2 signaling pathway

Decreased oocyte quality is a major determinant of age-associated fertility decline which lacks an effective treatment strategy. The secretome of mesenchymal stem cells (MSC-sec) contains various bioactive factors and has the potential to improve oocyte quality. In this study, MSC-sec treatment significantly increased first polar body emission, improved spindle assembly, reduced aneuploidy rate, and promoted maternal mRNA degradation in aged mouse oocytes, whereas the addition of BDNF antibody blocked the effects of MSC-sec. Furthermore, BDNF treatment alone also improved the oocyte quality from aged mice. Mechanistically, both MSC-sec and BDNF activated the ERK1/2 signaling pathway to increase the expression of DAZL and BTG4 in aged oocytes. Furthermore, injection of MSC-sec or BDNF into aged mouse ovaries significantly improved oocyte quality and early embryonic development. Finally, we demonstrated that BDNF treatment increased both the fertilization rate and blastocyst formation of aged human oocytes. Our study identified BDNF as the functional component of MSC-sec to improve the quality and development potential of aged oocytes by activating the ERK1/2 signaling pathway, suggesting that BDNF has the potential to mitigate age-related decline in oocyte quality. To detect the maternal mRNA degradation, we subjected young, aged and aged-sec(aged+MSC-sec) oocytes in MⅡ stage to global RNA-seq analyses. Following the administration of IVM with or without hUC-MSC-sec, RNA sequencing was conducted on 20 MII stage oocytes obtained from four mice in each group, which were classified as young, aged, or aged with hUC-MSC-sec(aged-sec). The high throughput sequencing and subsequent data analysis was performed by BGI Genomics Co., Ltd (Shenzhen, China) using the DNBSEQ platform.