Abstract
BackgroundTranslational studies have explored the therapeutic potential and feasibility of mesenchymal stem cells (MSCs) in several degenerative diseases; however, mechanistic studies of the function of these cells have been insufficient. As ovarian failure causes anovulation as well as ovarian steroid hormonal imbalances, the specific aims of this study were to analyze the therapeutic role of placenta-derived MSCs (PD-MSCs) in an ovarian failure ovariectomy (OVX) rat model and evaluate whether PD-MSC transplantation (Tx) improved folliculogenesis and oocyte maturation in the injured ovary through PI3K/Akt and FOXO signaling.MethodsBlood and ovary tissue were collected and analyzed after various PD-MSC Tx treatments in an ovariectomized rat model. Changes in the expression of folliculogenesis- and ovary regeneration-related genes induced by PD-MSC treatments were analyzed by qRT-PCR, Western blotting, and histological analysis.ResultsThe levels of hormones related to ovary function were significantly increased in the PD-MSC Tx groups compared with those in the nontransplantation group (NTx). The follicle numbers in the ovarian tissues were increased along with the increased expression of genes related to folliculogenesis in the PD-MSC Tx groups compared with the NTx groups. Furthermore, Tx PD-MSCs induced follicle maturation by increasing the phosphorylation of GSK3 beta and FOXO3 (p < 0.05) and shifting the balance of growth and apoptosis in oocytes.ConclusionsTaken together, these results show that PD-MSC Tx can restore ovarian function and induce ovarian folliculogenesis via the PI3K/Akt and FOXO signaling pathway.
Highlights
Translational studies have explored the therapeutic potential and feasibility of mesenchymal stem cells (MSCs) in several degenerative diseases; mechanistic studies of the function of these cells have been insufficient
placenta-derived MSCs (PD-MSCs) transplantation increased the serum levels of hormones involved in ovarian function To investigate whether the effect of PD-MSCs on the levels of hormones related to ovarian function depends on the transplantation route, we measured the levels of estradiol (E2), anti-Mullerian hormone (AMH), and folliclestimulating hormone (FSH) in the serum of rats in the NTx, DTx, and TTx groups at 1, 2, 3, and 5 weeks after PD-MSC transplantation (Fig. 1)
PD-MSCs engrafted into the ovary increased the number of follicles To confirm that the engraftment of PD-MSCs in a rat model of ovarian failure depends on the transplantation route, we analyzed the expression of the human Alu gene as a human-specific marker in the ovary tissues of rats using qRT-PCR
Summary
Translational studies have explored the therapeutic potential and feasibility of mesenchymal stem cells (MSCs) in several degenerative diseases; mechanistic studies of the function of these cells have been insufficient. For causes other than chemotherapy or radiation, polycystic ovary syndrome (PCOS) in particular is a common female pathology that affects 5~10% of women of reproductive age. These women become infertile because of the aberrant follicle growth of immature follicles [2]. These irregularities in folliculogenesis are further defined by an abnormal relationship between the growth of oocytes and the surrounding granulosa cells [3] in terms of several hormones, including anti-Mullerian hormone (AMH), folliclestimulating hormone (FSH), and estrogen. The most common treatment for the induction of ovulation is hormone replacement therapy; this approach can increase the risk of ovarian and breast cancer [4, 5]
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