Fertility protection: a novel approach using pretreatment with mesenchymal stem cell exosomes to prevent chemotherapy–induced ovarian damage in a mouse model

Abstract

BackgroundPrimary ovarian insufficiency (POI) refers to the loss of ovarian functionbefore the age of 40 years and results in amenorrhea and infertility. POI has diverse causes, but a common cause is exposure to gonadotoxic chemotherapy for cancer treatment. Due to the risk of developing POI, patients who want to preserve their fertility may consider various procedures for fertility preservation. However, current fertility preservation options are highly invasive, carry substantial risks, and have uncertain success rates. Recent studies from our group and others reported that mesenchymal stem cells (MSCs) and MSC-derived exosomes can restore ovarian functions in preclinical models of POI by restoring damaged cells and inhibiting apoptosis. Although the restorative effect of MSC-derived exosomes has been well reported in previous studies, the potential of MSC-derived exosomes for preventing ovarian damage has not been fully elucidated. ObjectiveWe hypothesized that the antiapoptotic potential of MSC-derived exosomes may protect ovarian tissue from chemotherapy-induced damage. Study designIn this study, we delivered MSC-derived exosomes directly into mouse ovaries before chemotherapy. Sixty mice were divided into three groups (20 per group), which were labeled the control, CTx (chemotherapy), and FP (fertility protection) groups. Only the FP group mice received exosomes, while the control and CTx group mice received saline. After exosome injection, the CTx and FP groups of mice were subjected to chemotherapy treatment to induce ovarian damage. After chemotherapy, we evaluated the protective effects of exosome treatment on ovarian function, such as estrus cyclicity, serum hormone levels, and the fertility rate, by comparing these outcomes between the CTx and FP groups. These outcomes were also compared with those of the control group for comparison with outcomes under healthy conditions. ResultsAfter intraovarian injection of exosomes before chemotherapy, the mice were able to maintain their estrus cycle (4–5-day cyclicity), serum AMH level (66.06±26.40 ng/ml, not significantly different from that of the healthy controls), folliculogenesis (32.2±11.3 in the CTx group/46.4±14.1 in the FP group, p<0.05), steroidogenesis marker StAR gene expression (0.44±0.11-fold in the CTx group and 0.88±0.31-fold in the FP group, p<0.05), and fertility (2 of 8 in the CTx group and 5 of 8 in the FP group), preventing chemotherapy-induced damage. We found that exosome treatment before chemotherapy can preserve ovarian function and protect fertility through the overexpression of ABC transporters, such as ABCB1b (10.17±17.75-fold in the CTx group and 44.14±33.25-fold in the FP group; p<0.05), and ABCC10 (3.25±0.59-fold in the CTx group and 5.36±1.86-fold in the FP group; p<0.05). ConclusionIn this study, we present a novel fertility protection method using MSC-derived exosomes. We conclude that MSC-derived exosomes are a promising simple treatment option for fertility protection in reproductive-age patients receiving gonadotoxic chemotherapy.