HucMSC-EVs Facilitate In Vitro Development of Maternally Aged Preantral Follicles and Oocytes

Ying-Yi Zhang; Weijie Yang; Yi Zhang; Zhanhong Hu; Yingyan Chen; Yerong Ma; Anran Yang; Zhan Shi; Hanjing Zhou; Peipei Ren; Libing Shi; Jiamin Jin; Yan Rong; Xiaomei Tong; Yin-Li Zhang; Songying Zhang

doi:10.1007/s12015-022-10495-w

HucMSC-EVs Facilitate In Vitro Development of Maternally Aged Preantral Follicles and Oocytes

Stem Cell Rev Rep. 2023 Jul;19(5):1427-1448. doi: 10.1007/s12015-022-10495-w. Epub 2023 Mar 2.

Authors

Ying-Yi Zhang^#^{1

2}, Weijie Yang^#^{1

2}, Yi Zhang^{1

2}, Zhanhong Hu^{1

2}, Yingyan Chen^{1

2}, Yerong Ma^{1

2}, Anran Yang^{1

2}, Zhan Shi^{1

2}, Hanjing Zhou^{1

2}, Peipei Ren^{1

2}, Libing Shi^{1

2}, Jiamin Jin^{1

2}, Yan Rong^{1

2}, Xiaomei Tong^{1

2}, Yin-Li Zhang^{3

4}, Songying Zhang^{5

6}

Affiliations

¹ Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
² Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China.
³ Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. zhangyinli@zju.edu.cn.
⁴ Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China. zhangyinli@zju.edu.cn.
⁵ Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. zhangsongying@zju.edu.cn.
⁶ Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China. zhangsongying@zju.edu.cn.

^# Contributed equally.

Abstract

Follicle developmental capacity and oocyte quality decline with advanced maternal age. Extracellular vesicles from human umbilical cord mesenchymal stem cells (HucMSC-EVs) act as a potential therapeutic product in the treatment of age-related ovarian dysfunction. In vitro culture (IVC) of preantral follicles is a useful method for understanding the mechanism of follicle development and is a promising means for improving female fertility. However, whether HucMSC-EVs have beneficial effects on aged follicle development during IVC has not yet been reported. Our research demonstrated that follicular development with single-addition withdrawal of HucMSC-EVs was better than that with continuous treatment with HucMSC-EVs. HucMSC-EVs facilitated the survival and growth of follicles, promoted the proliferation of granulosa cells (GCs), and improved the steroid hormone secretion of GCs during IVC of aged follicles. Both GCs and oocytes could uptake HucMSC-EVs. Moreover, we observed elevated cellular transcription in GCs and oocytes after treatment with HucMSC-EVs. The RNA sequencing (RNA-seq) results further validated that the differentially expressed genes are related to the promotion of GC proliferation, cell communication, and oocyte spindle organization. Additionally, the aged oocytes displayed a higher maturation rate, presented less aberrant spindle morphology, and expressed a higher level of the antioxidant protein Sirtuin 1 (SIRT1) after treatment with HucMSC-EVs. Our findings suggested that HucMSC-EVs can improve the growth and quality of aged follicles and oocytes in vitro through the regulation of gene transcription, which provides evidence for HucMSC-EVs as potential therapeutic reagents to restore female fertility with advanced age.

Keywords: Advanced maternal age; Extracellular vesicles; Female fertility; Follicle development; Human umbilical cord mesenchymal stem cells; Oocyte maturation; Transcription.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Extracellular Vesicles*
Female
Granulosa Cells / metabolism
Humans
Mesenchymal Stem Cells*
Oocytes
Ovarian Follicle