Abstract
BackgroundPremature ovarian insufficiency (POI) is one of the major causes of infertility. We previously demonstrated that transplantation of menstrual blood-derived stromal cells (MenSCs) effectively improved ovarian function in a murine model of POI. Recent studies indicated that mesenchymal stem cell-derived exosomes were important components in tissue repair. In this study, we investigated the therapeutic effects of MenSCs-derived exosomes (MenSCs-Exos) in a rat model of POI and its mechanism in restoring ovulation.MethodsOvaries of 4.5-day-old Sprague Dawley rats (SD rats) were cultured in vitro to evaluate the effects of MenSCs-Exos exposure on early follicle development. Furthermore, POI in rats was induced by intraperitoneal administration of 4-vinylcyclohexene diepoxide (VCD). Forty-eight POI rats were randomly assigned to four groups, each receiving a different treatment: PBS, MenSCs, MenSCs-Exos, and Exo-free culture supernatant of MenSCs. Estrous cyclicity, ovarian morphology, follicle dynamics, serum hormones, pregnancy outcomes, and molecular changes were investigated.ResultsExposure to MenSCs-Exos promoted the proliferation of granulosa cells in primordial and primary follicles in vitro and increased the expression of early follicle markers Deleted In Azoospermia Like (DAZL) and Forkhead Box L2 (FOXL2) while inhibiting follicle apoptosis. In vivo, MenSCs-Exos transplantation effectively promoted follicle development in the rat model of POI and restored the estrous cyclicity and serum sex hormone levels, followed by improving the live birth outcome. In addition, transplantation of MenSCs-Exos regulated the composition of the ovarian extracellular matrix and accelerated the recruitment of dormant follicles in the ovarian cortex and increased proliferation of granulosa cells in these follicles.ConclusionMenSCs-Exos markedly promoted follicle development in vitro and in vivo and restored fertility in POI rats, suggesting a restorative effect on ovarian functions. The therapeutic effect of MenSCs-Exos transplantation was sustainable, consistent with that of MenSCs transplantation. Our results suggested that MenSCs-Exos transplantation may be a promising cell-free bioresource in the treatment of POI.
Highlights
Premature ovarian insufficiency (POI) is one of the major causes of infertility
menstrual blood-derived stromal cells (MenSCs)-Exos treatment promoted early follicular development and inhibited apoptosis in vitro The ovaries of 4.5-day-old rats were cultured in culture medium containing 0, 2 μg/ml, or 20 μg/ml of MenSCs-Exos for 2, 4, and 6 days
This study demonstrated that MenSCs-Exos treatment is effective in restoring ovarian functions and fertility in a rodent model of POI
Summary
Premature ovarian insufficiency (POI) is one of the major causes of infertility. We previously demonstrated that transplantation of menstrual blood-derived stromal cells (MenSCs) effectively improved ovarian function in a murine model of POI. We investigated the therapeutic effects of MenSCs-derived exosomes (MenSCs-Exos) in a rat model of POI and its mechanism in restoring ovulation. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before the age of 40 and is characterized by hormone imbalances, menstrual disorders (amenorrhea or oligomenorrhea), anovulation, and infertility [1]. The majority of POI patients are diagnosed with diminished ovarian reserve (DOR), which is manifested by the rapid depletion of primordial follicle pool [7]. Restoring ovarian reserve and activating dormant follicles are potential strategies for POI treatment
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