Abstract
AbstractAngiogenesis plays an important role in damaged organ or tissue and cell regeneration and ovarian development and function. Primary ovarian insufficiency (POI) is a prevalent pathology in women under 40. Conventional treatment for POI involves hormone therapy. However, due to its side effects, an alternative approach is desirable. Human mesenchymal stem cells (MSCs) from various sources restore ovarian function; however, they have many limitations as stem cell sources. Therefore, it is desirable to study the efficacy of placenta-derived MSCs (PD-MSCs), which possess many advantages over other MSCs, in a rat model of ovarian dysfunction. Here, we investigated the restorative effect of PD-MSCs on injured ovaries in ovariectomized (OVX) rats and the ability of intravenous transplantation (Tx) of PD-MSCs (5 × 105) to enhance ovarian vasculature and follicular development. ELISA analysis of serum revealed that compared to the non-transplantation (NTx) group, the Tx group showed significantly increased levels of anti-Müllerian hormone, follicle stimulating hormone, and estradiol (E2) (*P < 0.05). In addition, histological analysis showed more mature follicles and less atresia and restoration of expanded blood vessels in the ovaries of the OVX PD-MSC Tx group than those of the NTx group (*P < 0.05). Furthermore, folliculogenesis-related gene expression was also significantly increased in the PD-MSC Tx group (*P < 0.05). Vascular endothelial growth factor (VEGF) and VEGF receptor 2 expressions were increased in the ovaries of the OVX PD-MSC Tx group compared to the NTx group through PI3K/AKT/mTOR and GSK3β/β-catenin pathway activation. Interestingly, ex vivo cocultivation of damaged ovaries and PD-MSCs or treatment with recombinant VEGF (50 ng/ml) increased folliculogenic factors and VEGF signaling pathways. Notably, compared to recombinant VEGF, PD-MSCs significantly increased folliculogenesis and angiogenesis (*P < 0.05). These findings suggest that VEGF secreted by PD-MSCs promotes follicular development and ovarian function after OVX through vascular remodeling. Therefore, these results provide fundamental data for understanding the therapeutic effects and mechanism of stem cell therapy based on PD-MSCs and provide a theoretical foundation for their application for obstetrical and gynecological diseases, including infertility and menopause.Vascular endothelial growth factor secreted by placenta-derived mesenchymal stem cells (PD-MSCs) promotes follicular development and ovarian function after ovariectomy through vascular remodeling. These results provide fundamental data for understanding the therapeutic mechanisms of stem cell therapy based on placenta-derived mesenchymal stem cells PD-MSCs and provide a theoretical foundation for their application for obstetrical and gynecological diseases, including infertility and menopause.
Highlights
These authors contributed : Jinki Cho, Tae-Hee Kim
We demonstrated the proangiogenic effects of PD-mesenchymal stem cells (MSCs) on ovarian function and the close relationship between the ovarian vasculature and ovarian function in an OVX model and an ex vivo experimental scheme
Among the many mechanisms underlying the therapeutic effects of MSCs, recent studies have focused on the paracrine mechanism of the proangiogenic effects of MSCs, which involves the secretion of bioactive molecules [39,40,41,42]
Summary
Many studies have reported the etiological factors that cause various types of ovarian dysfunction, including genetic alterations, toxins, and autoimmunity, which contribute to the disruption of folliculogenesis, the follicle maturation process, the exact mechanisms of POI are not fully understood [6,7,8]. Transplanted MSCs improve ovarian function, including by changing hormone levels in the blood and altering folliculogenesis-related genes, further study on how transplanted stem cells regulate the therapeutic mechanism and which factors are involved is needed. Placenta-derived mesenchymal stem cells (PD-MSCs), which have recently attracted much attention, are derived from the human placenta and are known to promote angiogenesis and have therapeutic effects in liver regeneration. We determined which factors of PD-MSCs are involved in improving the ovarian vasculature and follicular development and the regulatory mechanism
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