HucMSC-Derived Exosomes Mitigate the Age-Related Retardation of Fertility in Female Mice

• Published in: Molecular therapy Vol. 28; no. 4; pp. 1200 - 1213
• Main Authors: Yang, Weijie, Zhang, Jing, Xu, Boqun, He, Yuanlin, Liu, Wei, Li, Jiazhao, Zhang, Songying, Lin, Xiaona, Su, Dongming, Wu, Tinghe, Li, Jing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.04.2020; American Society of Gene & Cell Therapy
• Subjects: Aging - physiology; Animals; exosomes; Exosomes - genetics; Exosomes - transplantation; Female; Infertility, Female - genetics; Infertility, Female - therapy; mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mice; MicroRNAs - genetics; Oocytes - metabolism; Original; ovarian aging; premature ovarian insufficiency; primordial follicle; Signal Transduction; Umbilical Cord - cytology; ovarian aging; premature ovarian insufficiency; primordial follicle; exosomes; mesenchymal stem cells
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2020.02.003

In mammals, resting primordial follicles serve as the ovarian reserve. The decline in ovarian function with aging is characterized by a gradual decrease in both the quantity and quality of the oocytes residing within the primordial follicles. Many reports show that mesenchymal stem cells have the ability to recover ovarian function in premature ovarian insufficiency (POI) or natural aging animal models; however, the underlying mechanism remains unclear. In this study, using exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-exos), we found the specific accumulation of exosomes in primordial oocytes. The stimulating effects of exosomes on primordial follicles were manifested as the activation of the oocyte phosphatidylinositol 3-kinase (PI3K)/mTOR signaling pathway and the acceleration of follicular development after kidney capsule transplantation. Further analysis revealed the stimulatory effects of HucMSC-exos on primordial follicles were through carrying functional microRNAs, such as miR-146a-5p or miR-21-5p. In aged female mice, the intrabursal injection of HucMSC-exos demonstrated the recovery of decreased fertility with increased oocyte production and improved oocyte quality. Although assisted reproductive technologies have been widely used to treat infertility, their overall success rates remain low, especially for women in advanced maternal age. We propose HucMSC-exos as a new approach to mitigate the age-related retardation of fertility in women. [Display omitted] Ovarian aging is characterized by a great decrease in the quantity and quality of primordial oocytes. Yang et al. report that exosomes derived from human umbilical stem cells stimulate follicular development and oocyte production in young and old mice. This is proposed as a new approach for patients with diminished ovarian reserve.