Rejuvenation of aged oocyte through exposure to young follicular microenvironment

Abstract Reproductive aging is a major cause of fertility decline, attributed to decreased oocyte quantity and competence. Follicular somatic cells play crucial roles in the growth and development of the oocyte by providing nutrients and regulatory factors. Here we investigated how oocyte quality is affected by its somatic cell environment by creating chimeric follicles, whereby an oocyte from one follicle was transplanted into and cultured within another follicle whose native oocyte was removed. Somatic cells within the chimeric follicle re-establish connections with the oocyte and support oocyte growth and maturation in a three-dimensional (3D) culture system. We show that young oocytes transplanted into aged follicles exhibited reduced meiotic maturation and developmental potential, whereas the young follicular environment significantly improved the rates of maturation, blastocyst formation and live birth of aged oocytes. Aged oocytes cultured within young follicles exhibited enhanced interaction with somatic cells, more youth-like transcriptome, remodelled metabolome, improved mitochondrial function, and enhanced fidelity of meiotic chromosome segregation. These findings provide the basis for a future follicular somatic cell-based therapy to treat age-associated female infertility. Competing Interest Statement We would like to disclose that we have filed a patent for this study. The applicants and inventors for this patent are Rong Li and HaiYang Wang. This patent application, titled 'Somatic Cell-Based Therapy to Treat Female Infertility', was filed under the following numbers: PCT/SG2023/050339 and has been published with the Publication Number: WO 2023/224556 A1. The remaining authors declare no competing interests.