Human Pluripotent Stem Cell–Mesenchymal Stem Cell-Derived Exosomes Promote Ovarian Granulosa Cell Proliferation and Attenuate Cell Apoptosis Induced by Cyclophosphamide in a POI-Like Mouse Model

Abstract

Premature ovarian insufficiency (POI) is a complex disease which causes amenorrhea, hypergonadotropism and infertility in patients no more than 40 years old. Recently, several studies have reported that exosomes have the potential to protect ovarian function using a POI-like mouse model induced by chemotherapy drugs. In this study, the therapeutic potential of exosomes derived from human pluripotent stem cell–mesenchymal stem cells (hiMSC exosomes) was evaluated through a cyclophosphamide (CTX)-induced POI-like mouse model. POI-like pathological changes in mice were determined by serum sex-hormones levels and the available number of ovarian follicles. The expression levels of cellular proliferation proteins and apoptosis-related proteins in mouse ovarian granulosa cells were measured using immunofluorescence, immunohistochemistry and Western blotting. Notably, a positive effect on the preservation of ovarian function was evidenced, since the loss of follicles in the POI-like mouse ovaries was slowed. Additionally, hiMSC exosomes not only restored the levels of serum sex hormones, but also significantly promoted the proliferation of granulosa cells and inhibited cell apoptosis. The current study suggests that the administration of hiMSC exosomes in the ovaries can preserve female-mouse fertility.

miRNA profiling of granulosa cell‐derived exosomes reveals their role in promoting follicle development

“…Studies have shown that exosomes secreted by brown adipose tissue can improve the fertility decline of mice, and exosomes secreted by stromal cells in menstrual blood can improve the ovarian function of mice with premature ovarian failure (Zhang, Fang, et al, 2023;Zhang et al, 2021). Similarly, exosomes derived from mesenchymal stem cells promote the proliferation of GCs and reduce apoptosis in mice with ovarian insufficiency (Zhang, Ma, et al, 2023). et al, 2015;Yuan, Li, et al, 2021).…”

Preservation of ovarian function using human pluripotent stem cell-derived mesenchymal progenitor cells

“…Furthermore, a previous study indicated that the secretome of hESC-MPCs could prevent ovarian dehttps://doi.org/10.5653/cerm.2024.07003 generation and help maintain female fecundity when these cells were locally administered in a chemotherapy-induced mouse model [42]. Therefore, the ongoing administration of secretome or extracellular vesicles from hPSC-MPCs and adult tissue-derived-MPCs may aid in the functional recovery or preservation of damaged or aging ovaries [42,[52][53][54][55][56]. These studies also suggest that such interventions could play a pivotal role in overcoming challenges associated with the clinical application of hPSC-MPCs.…”

“…Recent studies have reported that various substances secreted by hPSC-MPCs and adult tissue-derived MPCs play key roles in suppressing ovarian and biological aging by preventing inflammation and fibrosis (Tables 1 and 2) [34,42,[50][51][52][53][54][55][56][57][58][59]. Therefore, defining their functions and uncovering their precise mechanisms could greatly contribute to the advancement of regenerative medicine, which seeks to treat aging-related diseases in various organs, as well as to the field of reproductive medicine.…”

Biological therapies for premature ovarian insufficiency: what is the evidence?

“…By releasing non-coding RNA, mRNA, growth factors and proteins, exos are active in influencing cellular communication as well as the fate of recipient cells, via regulation of proliferation and apoptosis (14,(59)(60)(61)(62). In rodent models of POI, the administration of exos from various human MSCs, such as bone marrow-derived MSCs (BMSCs) (63), umbilical cord MSCs (UC-MSCs) (64), and adipose tissue-derived MSCs (ADSCs) (65), as well as from human embryonic stem cells (ESC) (66) and human pluripotent stem cell-mesenchymal stem cells (hiMSC) (67) is demonstrated to recover the oestrous cycle (63), to increase the hormone levels, the AMH level and the number of follicles (63,(65)(66)(67), as well as to prevent follicular atresia (63,67) and to enhance the fertility rate by reducing the time of impregnation (64).…”