Human placenta-derived mesenchymal stem cells induce trophoblast invasion via dynamic effects on mitochondrial function.

The trophoblast is a critical cell for placental development and embryo implantation in the placenta. We previously reported that placenta-derived mesenchymal stem cells (PD-MSCs) increase trophoblast invasion through several signaling pathways. However, the paracrine effects of PD-MSCs on mitochondrial function in trophoblasts are still unclear. Therefore, the objective of the study was to analyze the mitochondrial function of trophoblasts in response to cocultivation with PD-MSCs. The results showed that PD-MSCs regulate the balance between cell survival and death and protect damaged mitochondria in trophoblasts from oxidative stress. Moreover, PD-MSCs upregulate factors involved in mitochondrial autophagy in trophoblast cells. Finally, PD-MSCs improve trophoblast invasion. Taken together, the data indicate that PD-MSCs can regulate trophoblast invasion through dynamic effects on mitochondrial energy metabolism. These results support the fundamental role of mitochondrial energy mechanism in trophoblast invasion and suggest a new therapeutic strategy for infertility.

Vascular remodeling by placenta-derived mesenchymal stem cells restores ovarian function in ovariectomized rat model via the VEGF pathway.

Angiogenesis 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 GSK3ß/ß-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.