hUCMSC-derived extracellular vesicles relieve cisplatin-induced granulosa cell apoptosis in mice by transferring anti-apoptotic miRNAs.

Premature ovarian insufficiency (POI) caused by chemotherapy is a common complication in female cancer survivors of childbearing age. Traditional methods, including mesenchymal stem cell (MSC) transplant and hormone replacement therapy, have limited clinical application because of their drawbacks, and more methods need to be developed. In the current study, the potential effects and underlying mechanisms of human umbilical cord MSC-derived extracellular vesicles (hUCMSC-EVs) were investigated in a cisplatin (CDDP)-induced POI mouse model and a human granulosa cell (GC) line. The results showed that hUCMSC-EVs significantly attenuated body weight loss, ovarian weight loss, ovary atrophy, and follicle loss in moderate-dose (1.5 mg/kg) CDDP-induced POI mice, similar to the effects observed with hUCMSCs. We further found that the hUCMSC-EVs inhibited CDDP-induced ovarian GC apoptosis by upregulating anti-apoptotic miRNA levels in GCs, thereby downregulating the mRNA levels of multiple pro-apoptotic genes. In general, our findings indicate that the moderate-dose chemotherapy may be a better choice for clinical oncotherapy, considering effective rescue of the oncotherapy-induced ovarian damage with hUCMSC-EVs. Additionally, multiple miRNAs in hUCMSC-EVs may potentially be used to inhibit the chemotherapy-induced ovarian GC apoptosis, thereby restoring ovarian function and improving the life quality of female cancer patients.