Placenta-derived mesenchymal stem cells (PD-MSCs) have numerous advantages over other adult MSCs that make them an attractive cell source for regenerative medicine. Here, we demonstrate the therapeutic effect of PD-MSCs in ovariectomized (Ovx) rats and compare their efficacy when generated via a conventional monolayer culture system (2D, naïve) and a spheroid culture system (3D, spheroid). PD-MSC transplantation significantly increased the estradiol level in Ovx rats compared with the non-transplantation (NTx) group. In particular, the estradiol level in the Spheroid group was significantly higher than that in the Naïve group at 2 weeks. Spheroid PD-MSCs exhibited a significantly higher efficiency of engraftment onto ovarian tissues at 2 weeks. The mRNA and protein expression levels of Nanos3, Nobox, and Lhx8 were also significantly increased in the Spheroid group compared with those in the NTx group at 1 and 2 weeks. These results suggest that PD-MSC transplantation can restore ovarian function in Ovx rats by increasing estrogen production and enhancing folliculogenesis-related gene expression levels and further indicate that spheroid-cultured PD-MSCs have enhanced therapeutic potential via increased engraftment efficiency. These findings improve our understanding of stem-cell-based therapies for reproductive systems and may suggest new avenues for developing efficient therapies using 3D cultivation systems.

Asherman's syndrome (AS) is characterized by intrauterine adhesion or fibrosis resulting from damage to the endometrium, often leading to amenorrhea, infertility, or recurrent pregnancy loss. Although various therapeutic strategies for AS have been proposed, the options remain limited. New strategies such as bone marrow-derived mesenchymal stem cell (BM-MSC) therapy aim to potentiate the intrinsic capacity of endometrial regeneration. However, BM-MSC therapy has not been widely adopted mainly because it involves invasive and expensive procedures such as bone marrow biopsy and cell storing. On the other hand, platelet-rich plasma (PRP) is considered safe and affordable because it involves the less invasive procedure of blood collection from peripheral veins to produce PRP. To assess the effectiveness of human PRP infusion for endometrial regeneration, we established a murine model of injury-induced AS and evaluated endometrial morphology, expression of fibrosis-related factors, implantation sites (IS), and pregnancy outcomes associated with human PRP treatment. We found that treatment with human PRP was associated with improved endometrial morphology, reduced degree of fibrosis, and down-regulated expression of fibrosis-related factors in murine model of AS. Furthermore, human PRP treatment was associated with a higher number of IS and live-births. Our results suggest that human PRP treatment may become a valuable strategy to promote the regeneration of damaged endometrium and thus improve fertility and pregnancy outcomes in clinical practice.

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