Cell–cell communication is an essential mechanism for the maintenance and development of various organs, including the female reproductive system. Today, it is well-known that the function of the female reproductive system and successful pregnancy are related to appropriate follicular growth, oogenesis, implantation, embryo development, and proper fertilization, dependent on the main regulators of cellular crosstalk, exosomes. During exosome synthesis, selective packaging of different factors into these vesicles happens within the originating cells. Therefore, exosomes contain both genetic and proteomic data that could be applied as biomarkers or therapeutic targets in pregnancy-associated disorders or placental functions. In this context, the present review aims to compile information about the potential exosomes with key molecular cargos that are dysregulated in female reproductive diseases which lead to infertility, including polycystic ovary syndrome (PCOS), premature ovarian failure (POF), Asherman syndrome, endometriosis, endometrial cancer, cervical cancer, ovarian cancer, and preeclampsia, as well as signaling pathways related to the regulation of the reproductive system and pregnancy outcome during these pathological conditions. This review might help us realize the etiology of reproductive dysfunction and improve the early diagnosis and treatment of the related complications.

Regenerative medicine is a new and promising mode of therapy for patients who have limited or no other options for the treatment of their illness. Due to their pleotropic therapeutic potential through the inhibition of inflammation or apoptosis, cell recruitment, stimulation of angiogenesis, and differentiation, stem cells present a novel and effective approach to several challenging human diseases. In recent years, encouraging findings in preclinical studies have paved the way for many clinical trials using stem cells for the treatment of various diseases. The translation of these new therapeutic products from the laboratory to the market is conducted under highly defined regulations and directives provided by competent regulatory authorities. This review seeks to familiarize the reader with the process of translation from an idea to clinical practice, in the context of stem cell products. We address some required guidelines for clinical trial approval, including regulations and directives presented by the Food and Drug Administration (FDA) of the United States, as well as those of the European Medicine Agency (EMA). Moreover, we review, summarize, and discuss regenerative medicine clinical trial studies registered on the Clinicaltrials.gov website.

Polycystic ovary syndrome (PCOS) is known as the most common endocrine disorder in women. Previously, we suggested that human mesenchymal stem cells (MSCs) can reverse the PCOS condition by secreting factors. Here, we evaluated the therapeutic capability of MSC-derived extracellular vesicles (EVs), also known as exosomes, in both in vitro and in vivo PCOS models. Exosomes were used to treat androgen-producing H293R cells and injected in a mouse model through intraovarian and intravenous injection into a letrozole (LTZ)-induced PCOS mouse model. We assessed the effects of the exosomes on androgen-producing cells or the PCOS mouse model by analyzing steroidogenic gene expression (quantitative real-time polymerase chain reaction (qRT–PCR)), body weight change, serum hormone levels, and fertility by pup delivery. Our data show the therapeutic effect of MSC-derived EVs for reversing PCOS conditions, including fertility issues. Interestingly, intravenous injection was more effective for serum glucose regulation, and an intraovarian injection was more effective for ovary restoration. Our study suggests that MSC-derived exosomes can be promising biopharmaceutics for treating PCOS conditions as a novel therapeutic option. Despite the fact that we need more validation in human patients, we may evaluate this novel treatment option for PCOS with the following clinical trials.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. Previous studies have demonstrated the therapeutic efficacy of human bone marrow mesenchymal stem cells (BM-hMSCs) for PCOS; however, the regulatory mechanism remains unknown. Bone morphogenetic proteins (BMPs) secreted by BM-hMSCs may underlie the therapeutic effect of these cells on PCOS, based on the ability of BMPs to modulate androgen production and alter steroidogenesis pathway enzymes. In this study, we analyze the effect of BMP-2 on androgen production and steroidogenic pathway enzymes in H295R cells as a human PCOS in vitro cell model. In H295R cells, BMP-2 significantly suppressed cell proliferation, androgen production, and expression of androgen-synthesizing genes, as well as inflammatory gene expression. Furthermore, H295R cells treated with the BM-hMSCs secretome in the presence of neutralizing BMP-2 antibody or with BMP-2 gene knockdown showed augmented expression of androgen-producing genes. Taken together, these results indicate that BMP-2 is a key player mediating the favorable effects of the BM-hMSCs secretome in a human PCOS cell model. BMP-2 overexpression could increase the efficacy of BM-hMSC-based therapy, serving as a novel stem cell therapy for patients with intractable PCOS.

Primary ovarian insufficiency (POI), a condition in which there is a loss of ovarian function before the age of 40 years, leads to amenorrhea and infertility. In our previously published studies, we demonstrated recovery of POI, correction of serum sex hormone levels, increase in the granulosa cell population, and restoration of fertility in a chemotherapy-induced POI mouse model after intraovarian transplantation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). While hBM-MSC may be a promising cell source for treatment of POI, there are few reports on the safety of stem cell-based therapy for POI. For future clinical applications, the safety of allogenic hBM-MSCs for the treatment of POI through intraovarian engraftment needs to be addressed and verified in appropriate preclinical models. In this study, we induced POI in C57/BL6 mice using chemotherapy, then treated the mice with hBM-MSCs (500,000 cells/ovary) by intraovarian injection. After hBM-MSC treatment, we analyzed the migration of engrafted cells by genomic DNA polymerase chain reaction (PCR) using a human-specific ALU repeat and by whole-body sectioning on a cryo-imaging system. We examined the possibility of transfer of human DNA from the hBM-MSCs to the resulting offspring, and compared the growth rate of offspring to that of normal mice and hBM-MSC-treated mice. We found that engrafted hBM-MSCs were detected only in mouse ovaries and did not migrate into any other major organs including the heart, lungs, and liver. Further, we found that no human DNA was transferred into the fetus. Interestingly, the engrafted cells gradually decreased in number and had mostly disappeared after 4 weeks. Our study demonstrates that intraovarian transplantation of hBM-MSCs could be a safe stem cell-based therapy to restore fertility in POI patients.