Drug-free in vitro activation combined with ADSCs-derived exosomes restores ovarian function of rats with premature ovarian insufficiency.

ABSTRACT

BACKGROUND: Drug-free in vitro activation (IVA) is a new protocol to activate residual dormant follicles for fertility restoration in patients with premature ovarian insufficiency (POI). However, several deficiencies have reduced its clinical efficacy rate. Our previous studies have confirmed that the combination of adipose-derived stem cells (ADSCs) and drug-free IVA can improve the effectiveness of drug-free IVA and restore ovarian function of rats with POI. Increasing evidence has demonstrated that mesenchymal stem cell-derived exosomes have similar therapeutic effects as their source cells. Here, we performed a preclinical study to evaluate the therapeutic effects of ADSCs-derived exosomes (ADSCs-Exos) combined with drug-free IVA in the POI rats and the mechanism in restoring ovarian function. RESULTS: In vivo, the effects of ADSCs-Exos were comparable to those of ADSCs, and the ADSCs-Exos combined with drug-free IVA was better than ADSCs-Exos alone therapy in promoting follicular development. Moreover, transplantation of ADSCs/ADSCs-Exos lead to up-regulation of BCL-2 expression and down-regulation of the expression of Bax and Cleaved Caspase-3, thus reducing the apoptosis of chemotherapy-induced follicle cells, and further promoting the development of the follicles and rescuing ovarian function in POI-damaged ovary. In vitro, ovarian fragmentation could activate follicular growth and development, and in combination with ADSCs-Exos could prevent the loss of follicles, promote follicular proliferation and inhibit apoptosis. CONCLUSIONS: ADSCs-Exos combined drug-free IVA had remarkable therapeutic effects in restoring ovarian function of POI rats, and markedly promoted follicular development and inhibited apoptosis of ovarian cells in vitro. Our study confirmed that the combination therapy might be a promising and effective treatment for POI.