Endometrial damage severely affects women's reproductive health and function. Although various treatments are available, their efficacy remains generally unsatisfactory. Mesenchymal stem cells (MSCs) possess multidirectional differentiation abilities and immunoregulation. To evaluate whether direct MSC transplantation into the uterine cavity enhances endometrial thickness, an animal model with thin endometrium was developed by administering ethanol into the uterine cavity. Our study aimed to observe and compare repair effects about three types of MSCs on endometrial injury, including menstrual blood-derived MSCs (MenSCs), bone marrow MSCs (BMSCs), and umbilical cord-derived mesenchymal stem cells (UC-MSCs). HE and Masson staining were used to assess endometrial morphology and fibrosis in the third estrous period post-operation. Immunohistochemistry and western blot were utilized to detect the expression of marker proteins in endometrial tissue. Endometrial thickness and protein expression in the MSC transplantation groups showed a notable improvement compared to the control group, though still below normal levels. Among MSC transplantation groups, no statistical difference was observed between MenSC and BMSC groups in endometrial thickness or ItgαVβ3 expression, but MenSCs showed higher levels than UC-MSCs, with statistical significance. CK18 and Vimentin expression in the MenSC and BMSC groups were similarly higher than UC-MSCs, with no significant difference. VEGF expression indicated that MenSCs outperformed both BMSCs and UC-MSCs. In conclusion, all three types of MSCs improved endometrial thickness and regeneration when transplanted into the injured endometrium. MenSCs demonstrated the greatest potential in promoting endometrial regeneration and improving receptivity, suggesting a promising new approach for treating endometrial injury.

Infertility affects 10-15 % of reproductive-age couples worldwide, with male infertility linked to sperm dysfunction and female infertility caused by ovulation disorders and reproductive abnormalities. Stem cell research presents a promising avenue for infertility treatment through germ cell differentiation. However, standardizing differentiation protocols and ensuring the functionality of in vitro-derived gametes remain significant challenges before clinical application becomes feasible.

Menopausal syndrome is characterized by a wide range of physical and psychological symptoms in women aged 40s-50s as a result of hormonal fluctuations and age-related decline. Various treatments have been used to manage the symptoms, including hormone replacement therapy, but no effective causal therapies have yet been identified. Regenerative medicine has gained considerable attention as a promising approach to age-related problems, and mesenchymal stem cell therapies have been extensively studied. Recently, menstrual blood has emerged as a novel cell source of stem cells, called menstrual blood-derived stem cells (MenSCs), due to its non-invasive, regular and consistent collection from women. In this study, we have investigated the therapeutic potential of intravenous administration of autologous MenSCs on female menopausal syndromes.

Menstrual blood was collected from 15 patients aged 30s-60s with ovarian dysfunction using a menstrual cup, and MenSCs were isolated, cultured and expanded. Patients received either 3 × 107 cells or 1 × 108 cells intravenously 1 to 5 times at intervals of more than 1 month. Patient-reported symptoms were assessed using the Simplified Menopausal Index at pre-treatment and after 1, 3, 6, and 12 months, and safety assessments were performed. Serum estradiol and follicle-stimulating hormone levels were also measured by immunoassay.

Almost all patients who received MenSCs experienced a sharp reduction in menopausal symptoms, including vasomotor, neuropsychiatric, and motor symptoms, one month after the first administration, and these symptoms remained low for 6 months. The Simplified Menopausal Index score was significantly reduced after treatment. The reducing potency of 1 × 108 MenSCs was greater than that of 3 × 107 MenSCs. Patients who received a higher number of MenSCs showed an increasing trend in estradiol levels and a decreasing trend in follicle-stimulating hormone levels. When MenSCs were administered to postmenopausal patients, this trend was more pronounced. Overall, no apparent serious adverse events were observed during these treatments.

The present results suggest that the administration of MenSCs improved menopausal symptoms and regulated hormonal balance without any serious adverse events. This is the first report on the promising therapeutic potential of cell-based therapy using autologous MenSCs for female menopausal syndrome.

Endometrium is vital to the establishment of pregnancy through its cyclical regeneration, which, when disrupted, can lead to endometrial thinning and Asherman's syndrome (AS). AS is characterized by infertility, pelvic pain, menstrual irregularities, and placental complications. Currently, treatments such as hysteroscopic adhesiolysis and hormone replacement therapy have demonstrated variable efficacy with limited clinical evidence. Recent developments in cell therapy have introduced menstrual blood-derived mesenchymal stem cells (MenSCs) as a promising alternative therapeutic strategy. Menstrual blood offers a noninvasive, periodically available source of mesenchymal stem cells, MenSCs for endometrial regeneration. This review comprehensively examines the endometrial regenerative process, pathophysiology of AS, and therapeutic prospects of MenSCs, underscoring the need for continued research to optimize treatment strategies.

Endometrial receptivity is crucial for embryo implantation success. Stem cell therapy shows promise for improving endometrial health. We developed a supramolecular hydrogel scaffold based on stereocomplexed triblock copolymers (MPEG-(sc-PLA)-PEI) and α-cyclodextrin for codelivering menstrual blood-derived endometrial stem cells (MenSCs) and siRNA targeting DNA methyl transferase 1 (DNMT1), enabling RNAi-mediated gene silencing to improve endometrial receptivity. The resulting α-CD/MPEG-(sc-PLA)-PEI hydrogels exhibited high mechanical stability, excellent self-healing capabilities, and sustained siRNA release via a dual-interaction mechanism involving host-guest interaction and stereocomplexation. In vitro studies indicated superior cellular uptake of DNMT1 siRNA encapsulated within MPEG-(sc-PLA)-PEI complexes, resulting in significant upregulation of endometrial receptivity markers, including HOXA10, ITGB3, and E-cadherin. In vivo experiments showed that DNMT1 siRNA-loaded hydrogels facilitated endometrial remodeling through therapeutic transgene expression in MenSCs. These findings suggest that this multifunctional hydrogel system may serve as an effective tool for stem cell-based therapies aimed at enhancing endometrial receptivity.

Stem cell therapy offers significant promise for tissue regeneration and repair. Traditionally, bone marrow- and adipose-derived stem cells have served as primary sources, but their clinical use is limited by invasiveness and low cell yield. This review focuses on body fluid-derived stem cells as an emerging, non-invasive, and readily accessible alternative. We examine stem cells isolated from amniotic fluid, peripheral blood, cord blood, menstrual fluid, urine, synovial fluid, breast milk, and cerebrospinal fluid, highlighting their unique biological properties and therapeutic potential. By comparing their characteristics and barriers to clinical translation, we propose body fluid-derived stem cells as a promising source for regenerative applications, with continued research needed to fully achieve their clinical utility.

In this single-center, double-blinded, randomized controlled trial, we investigated whether human umbilical cord-derived mesenchymal stromal cells loaded collagen scaffolds (hUC-MSC/CS) could improve the cumulative live-birth rate (cLBR) in infertile women with refractory thin endometrium (RTE). We randomly assigned 25 subfertile women with RTE, in a 1:1 ratio, to receive hysteroscopic adhesiolysis and plowing plus either hUC-MSC/CS or saline/CS (control) for intrauterine implantation. Uterine fluid was collected on the embryo transfer day for RNA-sequencing to explore the potential mechanisms by which hUC-MSCs exert their effects. The primary outcome was the cLBR. Live births occurred in 3 out of 11 women in the hUC-MSC/CS group and in 1 out of 13 women in the control group (27.3% vs 7.7%; relative risk [RR], 3.55; 95% confidence interval [CI], 0.43 to 29.42; P = .30). The cumulative frequencies of clinical pregnancy were 5/11 and 1/13 in the hUC-MSC/CS group and control group, respectively (45.5% vs. 7.7%; RR, 5.91; 95% CI, 0.81-43.28; P = .06). Two of 11 participants developed urticaria in the hUC-MSC/CS group. Enrichment analysis showed that T-cell activation had the largest proportion in the biological process category. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that most genes were related to cytokine-cytokine receptor interaction. In conclusion, there was a non-significant trend toward a higher cLBR with hUC-MSC/CS compared to controls, potentially through the cytokine-cytokine receptor interaction pathway. hUC-MSCs appeared to be relatively safe in a 1-year follow-up. Therefore, this novel therapy can be proposed to patients with RTE.

Intrauterine adhesions (IUA) and thin endometrium (TE) represent significant challenges in human reproduction. The condition arises frequently from damage to the endometrial basal layer, leading to fibrous tissue replacing the functional endometrium and impairing the uterus's ability to accept embryo implantation. Conventional treatments, mainly including hysteroscopic adhesiolysis and estrogen therapies, have shown limited success, particularly in severe cases. Regenerative medicine, with its focus on stem cell-based therapies and biomaterials, offers a promising avenue for restoring endometrial function and structure. This review synthesizes the current landscape of endometrial regeneration, focusing on the therapeutic potential of stem cells, the supportive role of biomaterials, and the importance of understanding molecular mechanisms to develop effective strategies for reconstruction of endometrial functional and fertility restoration.

This comprehensive review aimed to provide insights into the Asherman syndrome's historical background, clinical manifestations, classifications, obstetrical challenges, and current treatment approaches. The syndrome is characterized by intrauterine adhesions and fibrotic changes within the uterine tract as well as symptoms including menstrual irregularities, pelvic pain and infertility. The primary causes of Asherman syndrome are often associated with iatrogenic complications and congenital uterine defects. The syndrome results in certain obstetrical challenges, including recurrent pregnancy loss, placenta abnormalities, preterm birth, and intrauterine growth retardation, emphasizing the need for effective management. Hysteroscopic adhesiolysis represents the current gold standard treatment, but challenges persist because of adhesion recurrence and obstetrical complications. In this sense, emerging therapies were explored, including paracrine-acting factors, tissue-engineered scaffolds, and cell-based therapies. Autologous CD133+ bone marrow-derived stem cell therapy shows promise, with clinical trials demonstrating improved endometrial conditions and positive obstetrical outcomes. The review concludes by highlighting the potential of single-cell RNA sequencing to unravel the molecular mechanisms behind Asherman syndrome. This advanced technology offers insights into the gene expression profiles of individual cells, fostering a deeper understanding of Asherman syndrome pathogenesis and the development of innovative therapeutic strategies.

Uterine injuries, particularly damages to endometrium, are usually associated with abnormal menstruation, recurrent miscarriage, pregnancy complications, and infertility. Tissue engineering using cell-based, biomolecule-based, or biomaterial and scaffold-based strategies has emerged as a novel and promising approach for uterine regeneration. Stem cells, biomolecules, and porous scaffolds used alone or, very often, used in combination as a more effective treatment means have shown great potential in promoting uterine regeneration. The reported preclinical studies have indicated that appropriate tissue engineering strategies could safely and effectively reconstruct not only endometrium but also partial or even the whole uterine structure. However, the progress in the uterine regeneration area is slow in comparison to that of regenerating many other body tissues and hence it still remains a great challenge to apply uterine tissue engineering for clinical applications. In this review, conventional treatments for uterine-related diseases are briefly reviewed and discussed first. Subsequently, tissue engineering strategies (cell-based, biomolecule-based, biomaterial and scaffold-based, or their combinations) for uterine repair in preclinical studies and clinical trials are presented and analyzed. Finally, the challenges and perspectives in uterine regeneration are pointed and discussed. Despite various limitations and obstacles, the tissue engineering approach is viable and holds high promise for uterine regeneration.

The human endometrium is a highly regenerative tissue that contains mesenchymal stem/stromal cells (MSCs). These MSCs are sourced via office-based biopsies and menstrual fluid, providing a less invasive and readily available option for cell-based therapies. This review provides an update on endometrial-derived MSCs as a treatment option for gynecological diseases.

This narrative review covers the characterization and therapeutic mechanisms of endometrium biopsy-derived MSCs (eMSCs) and menstrual fluid-derived mesenchymal stromal cells (MenSCs), highlighting similarities and differences. It also covers studies of their application in preclinical animal models and in clinical trials as potential cell-based therapies for gynecological diseases.

eMSCs and MenSCs from a homologous tissue source have the potential to promote regenerative activity as a treatment for gynecological diseases. Both eMSCs and MenSCs demonstrate therapeutic benefits through their paracrine activity in tissue regeneration, immunomodulation, angiogenesis, and mitigating fibrosis. Further research is essential to establish standardized isolation and characterization protocols, particularly for heterogeneous MenSCs, and to fully understand their mechanisms of action. Implementing SUSD2 magnetic bead sorting for purifying eMSCs from endometrial tissues and menstrual fluid is crucial for their use in future cell-based therapies. Optimization of production, storage, and delivery methods will maximize their therapeutic effectiveness.

Intrauterine adhesions (IUAs) and Asherman's syndrome (AS) have been recognized medical conditions since the late 19th and mid-20th centuries. Multiple classification systems have been proposed to better understand their severity and implications. This article aims to provide a comprehensive overview of the existing classifications for IUAs and introduces the Loddo scoring system, a novel approach for classifying these conditions. The Loddo scoring system is unique in amalgamating the strengths of previous classifications while emphasizing the importance of ultrasonographic endometrial thickness. This new system integrates various clinical parameters, offering a holistic representation of IUAs in clinical presentation and underlying structural changes. The Loddo scoring system presents a refined approach to understand and manage IUAs, providing a precise prognosis evaluation. Bridging the diagnostic and therapeutic divide seen in past systems, it offers promise for reshaping the landscape of diagnosis and treatment in women's health. Further research and validation are essential to assess its broad clinical applicability.

Intrauterine adhesions (IUA), also known as Asherman's syndrome, arise from damage to the basal layer of the endometrium, frequently caused by intrauterine interventions. This damage leads to nonregenerative healing of endometrium resulting in replacement by fibrous connective tissue, which bring about the adherence of opposing endometrium to render the uterine cavity and/or cervical canal partially or completely obliterated. IUA is a common cause of the refractory uterine infertility. Hysteroscopy is the gold standard for diagnosis of IUA. However, the method of accurately predicting the likelihood of achieving a live birth in the future remains established. Classical treatments have shown limited success, particularly in severe cases. Therefore, utilizing new research methods to deepen the understanding of the pathogenesis of IUA will facilitate the new treatment approaches to be found. In this article we briefly described the advances in the pathogenesis of IUA, with focus on inflammation and parenchymal cellular homeostasis disruption, defects in autophagy and the role of ferroptosis, and we also outlined the progress in IUA therapy.

Intrauterine Adhesions (IUA) is a common gynecological disease which is seriously endangers the reproductive function of women without any ideal treatment. Some researchers found Menstrual Blood-derived Mesenchymal Stem Cells (MenSCs) can repair of damaged endometrium, however, has not been fully clarified. This study aims to evaluate the therapeutic effects of MenSCs in IUA and the repair mechanism in vivo.

This study is Laboratory-based study. To evaluate the therapeutic effects of MenSCs in IUA, We cultivated MenSCs, established mouse endometrial injury model, observed the uterine morphology and degree of endometrial fibrosis and compared the expression of CXC chemokine ligand-13 (CXCL13)、CXC chemokine receptor-5 (CXCR5)、Plasmin Activating Inhibitor-1(Pai-1), Transforming Growth Faction-β1(TGF- β1) and Matrix Metalloproteinase-9 (Mmp-9) among each groups. GraphPad Prism 8.0 was used for statistical processing. Data were expressed as mean ± SD. Statistical comparisons among groups were performed with one-way ANOVA. P < 0.05 were considered statistically significant.

We successfully cultured and identified MenSCs and established mice model of uterine adhesion. After treatment with MenSCs, endometrial morphology of mice was partially restored, endometrial thickness was increased, and glands were multipiled. The concentrations of CXCL13 and CXCR5 were significantly increased by immunofluorescence detection compared with the control group. The results of RT-qPCR showed that the expressions of Pai-1 and Mmp-9 were significantly lower than those of the control group.

MenSCs may reduce endometrial fibrosis and the down-regulating expression of Pai-1、Mmp-9 and CXCL13-CXCR5 axis were involved in the process of MenSCs repaired IUA.

The purpose of this study is to determine whether intrauterine infusion of autologous platelet-rich plasma (PRP) gel increases endometrial thickness (EMT) and improves the outcomes of frozen-thawed embryo transfer (FET) in women with thin endometrium.

This study included 111 women (aged 25-44 years) who had thin endometrium. All patients had at least one previous cycle canceled because of thin endometrium or previous embryo transfer cycles and an EMT < 7 mm. Forty-seven women underwent intrauterine infusion of autologous PRP gel on three occasions during endometrial preparation and the remaining women served as controls. The final EMT was measured by ultrasound before the start of the luteal phase, and FET-related outcome parameters were monitored.

Mean EMT was greater in women who received PRP gel than in those who did not (6.7 mm vs. 6.3 mm, respectively, p < 0.05). FET was attempted in all women. The 47 women who underwent infusion of PRP had a significantly higher pregnancy rate (18 pregnancies (38.3%), with 17 (36.2%) ongoing) compared with 64 control women (ten pregnancies (18.5%), nine (16.7%) ongoing). However, there was no significant reduction in the miscarriage rate.

Intrauterine infusion of autologous PRP gel during endometrial preparation for FET cycles can improve the EMT, clinical pregnancy rate, and ongoing pregnancy rate in women with thin endometrium.

The establishment and maintenance of pregnancy depend on endometrial competence. Asherman syndrome (AS) and intrauterine adhesions (IUA), or endometrial atrophy (EA) and thin endometrium (TE), can either originate autonomously or arise as a result from conditions (i.e. endometritis or congenital hypoplasia), or medical interventions (e.g. surgeries, hormonal therapies, uterine curettage or radiotherapy). Affected patients may present an altered or inadequate endometrial lining that hinders embryo implantation and increases the risk of poor pregnancy outcomes and miscarriage. In humans, AS/IUA and EA/TE are mainly treated with surgeries or pharmacotherapy, however the reported efficacy of these therapeutic approaches remains unclear. Thus, novel regenerative techniques utilizing stem cells, growth factors, or tissue engineering have emerged to improve reproductive outcomes.

This review comprehensively summarizes the methodologies and outcomes of emerging biotechnologies (cellular, acellular, and bioengineering approaches) to treat human endometrial pathologies. Regenerative therapies derived from human tissues or blood which were studied in preclinical models (in vitro and in vivo) and clinical trials are discussed.

A systematic search of full-text articles available in PubMed and Embase was conducted to identify original peer-reviewed studies published in English between January 2000 and September 2023. The search terms included: human, uterus, endometrium, Asherman syndrome, intrauterine adhesions, endometrial atrophy, thin endometrium, endometritis, congenital hypoplasia, curettage, radiotherapy, regenerative therapy, bioengineering, stem cells, vesicles, platelet-rich plasma, biomaterials, microfluidic, bioprinting, organoids, hydrogel, scaffold, sheet, miRNA, sildenafil, nitroglycerine, aspirin, growth hormone, progesterone, and estrogen. Preclinical and clinical studies on cellular, acellular, and bioengineering strategies to repair or regenerate the human endometrium were included. Additional studies were identified through manual searches.

From a total of 4366 records identified, 164 studies (3.8%) were included for systematic review. Due to heterogeneity in the study design and measured outcome parameters in both preclinical and clinical studies, the findings were evaluated qualitatively and quantitatively without meta-analysis. Groups using stem cell-based treatments for endometrial pathologies commonly employed mesenchymal stem cells (MSCs) derived from the human bone marrow or umbilical cord. Alternatively, acellular therapies based on platelet-rich plasma (PRP) or extracellular vesicles are gaining popularity. These are accompanied by the emergence of bioengineering strategies based on extracellular matrix (ECM)-derived hydrogels or synthetic biosimilars that sustain local delivery of cells and growth factors, reporting promising results. Combined therapies that target multiple aspects of tissue repair and regeneration remain in preclinical testing but have shown translational value. This review highlights the myriad of therapeutic material sources, administration methods, and carriers that have been tested.

Therapies that promote endometrial proliferation, vascular development, and tissue repair may help restore endometrial function and, ultimately, fertility. Based on the existing evidence, cost, accessibility, and availability of the therapies, we propose the development of triple-hit regenerative strategies, potentially combining high-yield MSCs (e.g. from bone marrow or umbilical cord) with acellular treatments (PRP), possibly integrated in ECM hydrogels. Advances in biotechnologies together with insights from preclinical models will pave the way for developing personalized treatment regimens for patients with infertility-causing endometrial disorders such as AS/IUA, EA/TE, and endometritis.

https://osf.io/th8yf/.

Infertility is a global phenomenon that impacts people of both the male and the female sex; it is related to multiple factors affecting an individual's overall systemic health. Recently, investigators have been using mesenchymal stem cell (MSC) therapy for female-fertility-related disorders such as polycystic ovarian syndrome (PCOS), premature ovarian failure (POF), endometriosis, preeclampsia, and Asherman syndrome (AS). Studies have shown promising results, indicating that MSCs can enhance ovarian function and restore fertility for affected individuals. Due to their regenerative effects and their participation in several paracrine pathways, MSCs can improve the fertility outcome. However, their beneficial effects are dependent on the methodologies and materials used from isolation to reimplantation. In this review, we provide an overview of the protocols and methods used in applications of MSCs. Moreover, we summarize the findings of published preclinical studies on infertility treatments and discuss the multiple properties of these studies, depending on the isolation source of the MSCs used.

Intrauterine adhesions (IUAs) jeopardise uterine function in women, which is a great challenge in the clinic. Previous studies have shown that endometrial perivascular cells (En-PSCs) can improve the healing of scarred uteri and that hydroxysafflor yellow A (HSYA) promotes angiogenesis. The purpose of this study was to observe whether the combination of En-PSCs with HSYA could improve the blood supply and fertility in the rat uterus after full-thickness injury.

En-PSCs were sorted by flow cytometry, and the effect of HSYA on the proliferation and angiogenesis of the En-PSCs was detected using CCK-8 and tube formation assays. Based on a previously reported rat IUA model, the rat uteri were sham-operated, spontaneously regenerated, or treated with collagen-loaded PBS, collagen-loaded HSYA, collagen-loaded En-PSCs, or collagen-loaded En-PSCs with HSYA, and then collected at both 30 and 90 days postsurgery. HE staining and Masson staining were used to evaluate uterine structure and collagen fibre deposition, and immunohistochemical staining for α-SMA and vWF was used to evaluate myometrial regeneration and neovascularization in each group. A fertility assay was performed to detect the recovery of pregnancy function in each group. RNA-seq was performed to determine the potential mechanism underlying En-PSCs/HSYA treatment. Immunofluorescence, tube formation assays, and Western blot were used to validate the molecular mechanism involved.

The transplantation of Collagen/En-PSCs/HSYA markedly promoted uterine repair in rats with full-thickness injury by reducing fibrosis, increasing endometrial thickness, regenerating myometrium, promoting angiogenesis, and facilitated live births. RNA sequencing results suggested that En-PSCs/HSYA activated the NRG1/ErbB4 signaling pathway. In vitro tube formation experiments revealed that the addition of an ErbB inhibitor diminished the tube formation ability of cocultured En-PSCs and HUVECs. Western blot results further showed that elevated levels of NRG1 and ErbB4 proteins were detected in the Collagen/En-PSCs/HSYA group compared to the Collagen/En-PSCs group. These collective results suggested that the beneficial effects of the transplantation of Collagen/En-PSCs/HSYA might be attributed to the modulation of the NRG1/ErbB4 signaling pathway.

The combination of En-PSCs/HSYA facilitated morphological and functional repair in rats with full-thickness uterine injury and may promote endometrial angiogenesis by regulating the NRG1/ErbB4 signaling pathway.

Mesenchymal stem cells (MSCs) have attracted more and more attention because of their multidirectional differentiation potential, immune regulatory abilities and self-renewal capacity. In recent years, their use has become prominent in the domains of regenerative medicine and tissue engineering. MSCs have shown promise in therapeutic studies for a variety of diseases and have become a new source of innovative solutions for the treatment of some obstetric and gynecological diseases. This review systematically presents the latest research on the use of MSCs in the treatment of obstetrics- and gynecology-related diseases. Specifically, this review encompasses the latest findings related to the role of MSCs in premature ovarian failure, polycystic ovary syndrome, ovarian cancer, fallopian tube-related diseases, uterine adhesions, endometriosis, cesarean scar defects, postmenopausal osteoporosis, and pelvic floor dysfunction. The shortcomings and challenges of the future use of MSCs in disease treatment are also discussed, with the intent to motivate improvements in MSC applications in clinical therapy. It is believed that with further research, MSCs will play a more important role in the treatment of obstetrics- and gynecology-related diseases.

While the provision of unapproved regenerative medicine has been problematic worldwide, few studies have examined the implementation status of regenerative medicine (RM) in the specific field. This study aimed to determine the current status of therapy and clinical research in the obstetrics and gynecology (OBGYN) in Japan under the Act on the Safety of Regenerative Medicine (RM Act).

Detailed data were extracted from publicly available websites provided by the Ministry of Health, Labour, and Welfare. We extracted descriptive details, including risk classification of the RM Act, modality, target disease, locality, institution, and administration route. For therapy, the price for each modality was evaluated.

The total number of therapeutic provision plans in OBGYN (1.9% of RM in Japan) are classified as Class II (moderate) risk. Most were administered in clinics in urban areas for treating endometrial or ovarian infertility by locally administering platelet-rich plasma (PRP) or autologous mesenchymal stem cells (MSCs). The price using MSCs is approximately eight times more expensive that of those involving PRP (1832.1 ± 1139.8 vs 240.8 ± 106.5 thousand yen, p < 0.0001). Regarding research, four plans (2.2%) were submitted to target implantation failure and advanced gynecological cancer using autologous lymphocytes, dendritic cells, or MSCs.

The RM Act permits knowledge of the current status of regenerative medicine even for unapproved uses in a specific clinical field. The study findings shall prompt a worldwide discussion regarding the required regulations for therapy and clinical research of RM.

Mesenchymal stromal cell (MSC)-based advanced therapy medicinal products (ATMPs) are being tried in a vast range of clinical applications. These cells can be isolated from different donor tissues by using several methods, or they can even be derived from induced pluripotent stem cells or embryonic stem cells. However, ATMP heterogeneity may impact product identity and potency, and, consequently, clinical trial outcomes. In this review, we discuss these topics and the need to establish minimal criteria regarding the manufacturing of MSCs so that these innovative therapeutics may be better positioned to contribute to the advancement of regenerative medicine.

Thin endometrium (TE) is defined as a mid-luteal endometrial thickness ≤7mm. TE can affect endometrial tolerance, leading to lower embryo implantation rates and clinical pregnancy rates, and is also associated with impaired outcomes from assisted reproductive treatment. Herein, we systematically review TE causes, mechanisms, and treatments. TE pathogenesis has multiple causes, with the endometrium becoming thinner with age under hormonal influence. In addition, uterine cavity factors are important, as the inflammatory environment may affect expressions of certain genes thereby inhibiting endometrial stromal cell proliferation and promoting apoptosis. Long-term oral contraceptive use or the use of ovulation-promoting drugs are also definite factors contributing to endometrial thinning. Other patients have primary factors, for which the clinical etiology remains unknown. The main therapeutic strategies available for TE are pharmacological (including hormonal and vasoactive drugs), regenerative medicine, intrauterine infusion of growth factor-granulocyte colony-stimulating factor, autologous platelet-rich plasma, and complementary alternative therapies (including traditional Chinese herbal medicine and acupuncture). However, the associated mechanisms of action are currently unclear. Clinical scholars have proposed various approaches to improve treatment outcomes in patients with TE, and are exploring the principles of efficacy, offering potentials for novel treatments. It is hoped that this will improve TE tolerance, increase embryo implantation rates, and help more couples with infertility with effective treatments.

Annulus fibrosis (AF) defects have been identified as the primary cause of disc herniation relapse and subsequent disc degeneration following discectomy. Stem cell-based tissue engineering offers a promising approach for structural repair. Menstrual blood-derived mesenchymal stem cells (MenSCs), a type of adult stem cell, have gained attention as an appealing source for clinical applications due to their potential for structure regeneration, with ease of acquisition and regardless of ethical issues.

The differential potential of MenSCs cocultured with AF cells was examined by the expression of collagen I, SCX, and CD146 using immunofluorescence. Western blot and ELISA were used to examine the expression of TGF-β and IGF-I in coculture system. An AF defect animal model was established in tail disc of Sprague-Dawley rats (males, 8 weeks old). An injectable gel containing MenSCs (about 1*106/ml) was fabricated and transplanted into the AF defects immediately after the animal model establishment, to evaluate its repairment properties. Disc degeneration was assessed via magnetic resonance (MR) imaging and histological staining. Immunohistochemical analysis was performed to assess the expression of aggrecan, MMP13, TGF-β and IGF-I in discs with different treatments. Apoptosis in the discs was evaluated using TUNEL, caspase3, and caspase 8 immunofluorescence staining.

Coculturing MenSCs with AF cells demonstrated ability to express collagen I and biomarkers of AF cells. Moreover, the coculture system presented upregulation of the growth factors TGF-β and IGF-I. After 12 weeks, discs treated with MenSCs gel exhibited significantly lower Pffirrmann scores (2.29 ± 0.18), compared to discs treated with MenSCs (3.43 ± 0.37, p < 0.05) or gel (3.71 ± 0.29, p < 0.01) alone. There is significant higher MR index in disc treated with MenSCs gel than that treated with MenSCs (0.51 ± 0.05 vs. 0.24 ± 0.04, p < 0.01) or gel (0.51 ± 0.05 vs. 0.26 ± 0.06, p < 0.01) alone. Additionally, MenSCs gel demonstrated preservation of the structure of degenerated discs, as indicated by histological scoring (5.43 ± 0.43 vs. 9.71 ± 1.04 in MenSCs group and 10.86 ± 0.63 in gel group, both p < 0.01), increased aggrecan expression, and decreased MMP13 expression in vivo. Furthermore, the percentage of TUNEL and caspase 3-positive cells in the disc treated with MenSCs Gel was significantly lower than those treated with gel alone and MenSCs alone. The expression of TGF-β and IGF-I was higher in discs treated with MenSCs gel or MenSCs alone than in those treated with gel alone.

MenSCs embedded in collagen I gel has the potential to preserve the disc structure and prevent disc degeneration after discectomy, which was probably attributed to the paracrine of growth factors of MenSCs.

The monthly regeneration of human endometrial tissue is maintained by the presence of human endometrial mesenchymal stromal/stem cells (eMSC), a cell population co-expressing the perivascular markers CD140b and CD146. Endometrial regeneration is impaired in the presence of intrauterine adhesions, leading to infertility, recurrent pregnancy loss and placental abnormalities. Several types of somatic stem cells have been used to repair the damaged endometrium in animal models, reporting successful pregnancy. However, the ability of endometrial stem cells to repair the damaged endometrium remains unknown.

Electrocoagulation was applied to the left uterine horn of NOD/SCID mice causing endometrial injury. Human eMSC or PBS was then injected into the left injured horn while the right normal horn served as controls. Mice were sacrificed at different timepoints (Day 3, 7 and 14) and the endometrial morphological changes as well as the degree of endometrial injury and repair were observed by histological staining. Gene expression of various inflammatory markers was assessed using qPCR. The functionality of the repaired endometrium was evaluated by fertility test.

Human eMSC successfully incorporated into the injured uterine horn, which displayed significant morphological restoration. Also, endometrium in the eMSC group showed better cell proliferation and glands formation than the PBS group. Although the number of blood vessels were similar between the two groups, gene expression of VEGF-α significantly increased in the eMSC group. Moreover, eMSC had a positive impact on the regeneration of both stromal and epithelial components of the mouse endometrium, indicated by significantly higher vimentin and CK19 protein expression. Reduced endometrial fibrosis and down-regulation of fibrosis markers were also observed in the eMSC group. The eMSC group had a significantly higher gene expression of anti-inflammatory factor Il-10 and lower mRNA level of pro-inflammatory factors Ifng and Il-2, indicating the role of eMSC in regulation of inflammatory reactions. The eMSC group showed higher implantation sites than the PBS group, suggesting better endometrial receptivity with the presence of newly emerged endometrial lining.

Our findings suggest eMSC improves regeneration of injured endometrium in mice.

The endometrium is a resilient and highly dynamic tissue, undergoing cyclic renewal in preparation for embryo implantation. Cyclic endometrial regeneration depends on the intact function of several cell types, including parenchymal, endothelial, and immune cells, as well as adult stem cells that can arise from endometrial or extrauterine sources. The ability of the endometrium to undergo rapid, repeated regeneration without scarring is unique to this tissue. However, if this tissue renewal process is disrupted or dysfunctional, women may present clinically with infertility due to endometrial scarring or persistent atrophic/thin endometrium. Such disorders are rate-limiting in the treatment of female infertility and in the success of in vitro fertilization because of a dearth of treatment options specifically targeting the endometrium. A growing number of studies have explored the potential of adult stem cells, including mesenchymal stem cells (MSCs), to treat women with disorders of endometrial regeneration. MSCs are multipotent adult stem cells with capacity to differentiate into cells such as adipocytes, chondrocytes, and osteoblasts. In addition to their differentiation capacity, MSCs migrate toward injured sites where they secrete bioactive factors (e.g. cytokines, chemokines, growth factors, proteins and extracellular vesicles) to aid in tissue repair. These factors modulate biological processes critical for tissue regeneration, such as angiogenesis, cell migration and immunomodulation. The MSC secretome has therefore attracted significant attention for its therapeutic potential. In the uterus, studies utilizing rodent models and limited human trials have shown a potential benefit of MSCs and the MSC secretome in treatment of endometrial infertility. This review will explore the potential of MSCs to treat women with impaired endometrial receptivity due to a thin endometrium or endometrial scarring. We will provide context supporting leveraging MSCs for this purpose by including a review of mechanisms by which the MSC secretome promotes regeneration and repair of nonreproductive tissues.

Intrauterine adhesion (IUA) is characterized by endometrial fibrosis. S100A8/A9 plays an important role in inflammation and fibroblast activation. However, the role of S100A8/A9 in IUA remains unclear. In this study, we collect normal and IUA endometrium to verify the expression of S100A8/A9. Human endometrial stromal cells (hEnSCs) are isolated to evaluate fibrosis progression after S100A8/A9 treatment. A porcine IUA model is established by electrocautery injury to confirm the therapeutic effect of menstrual blood-derived stromal cells (MenSCs) on IUA. Our study reveals increased S100A8/A9 expression in IUA endometrium. S100A8/A9 significantly enhances hEnSCs proliferation and upregulates fibrosis-related and inflammation-associated markers. Furthermore, S100A8/A9 induces hEnSCs fibrosis through the RAGE-JAK2-STAT3 pathway. Transplantation of MenSCs in a porcine IUA model notably enhances angiogenesis, mitigates endometrial fibrosis and downregulates S100A8/A9 expression. In summary, S100A8/A9 induces hEnSCs fibrosis via the RAGE-JAK2-STAT3 pathway, and MenSCs exhibit marked effects on endometrial restoration in the porcine IUA model.

Introduction: Intrauterine adhesions (IUA), also known as Asherman's syndrome, is caused by trauma to the pregnant or non-pregnant uterus, which leads to damaged endometrial basal lining and partial or total occlusion of the uterine chambers, resulting in abnormal menstruation, infertility, or recurrent miscarriage. The essence of this syndrome is endometrial fibrosis. And there is no effective treatment for IUA to stimulate endometrial regeneration currently. Recently, menstrual blood-derived stem cells (MenSCs) have been proved to hold therapeutic promise in various diseases, such as myocardial infarction, stroke, diabetes, and liver cirrhosis. Methods: In this study, we examined the effects of MenSCs on the repair of uterine adhesions in a rat model, and more importantly, promoted such therapeutic effects via a xeno-free VitroGel MMP carrier. Results: This combined treatment reduced the expression of inflammatory factors, increased the expression of anti-inflammatory factors, restricted the area of endometrial fibrosis, diminished uterine adhesions, and partially restored fertility, showing stronger effectiveness than each component alone and almost resembling the sham group. Discussion: Our findings suggest a highly promising strategy for IUA treatment.

Thin endometrium (TE) is a significant factor contributing to fertility challenges, and addressing this condition remains a central challenge in reproductive medicine. Menstrual blood-derived mesenchymal stem cells (MenSCs) play a crucial role in tissue repair and regeneration, including that of TE. The Wnt signaling pathway, which is highly conserved and prevalent in eukaryotes, is essential for cell proliferation, tissue development, and reproductive functions. MALAT1 is implicated in various transcriptional and molecular functions, including cell proliferation and metastasis. However, the combined effects of the Wnt signaling pathway and the long non-coding RNA (lncRNA) MALAT1 on the regulation of MenSCs' regenerative capabilities in tissue engineering have not yet been explored. To elucidate the regulatory mechanism of MALAT1 in TE, we analyzed its expression levels in normal endometrium and TE tissues, finding that low expression of MALAT1 was associated with poor clinical prognosis. In addition, we conducted both in vitro and in vivo functional assays to examine the role of the MALAT1/miR-7-5p/TCF4 axis in cell proliferation and migration. Techniques such as dual-luciferase reporter assay, fluorescent in situ hybridization, and immunoblot experiments were utilized to clarify the molecular mechanism. To corroborate these findings, we established a TE model and conducted pregnancy experiments, demonstrating a strong association between MALAT1 expression and endometrial fertility. In conclusion, our comprehensive study provides strong evidence supporting that lncRNA MALAT1 modulates TCF4 expression in the Wnt signaling pathway through interaction with miR-7-5p, thus enhancing MenSCs-mediated improvement of TE and improving fertility.

Intrauterine adhesion (IUA) results from serious complications of intrauterine surgery or infection and mostly remains incurable. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have emerged as a potential new approach for the treatment of IUA; however, their impact is not fully understood. Here, we performed a meta-analysis summarizing the effects of sEVs on IUA in preclinical rodent models.

This meta-analysis included searches of PubMed, EMBASE, Cochrane, and the Web of Science databases from January 1, 1997, to April 1, 2022, to identify studies reporting the therapeutic effect of sEVs on rodent preclinical animal models of IUA. We compared improvements in endometrial thickness, endometrial gland number, fibrosis area, embryo number, vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGFβ1), and leukemia inhibitory factor (LIF) levels after treatment.

Our search included 100 citations, of which 7 met the inclusion criteria, representing 231 animals. Compared with that in the control group, the fibrosis area in the sEV-treated group was significantly reduced (standardized mean difference (SMD) = -6.87，95 % confidence interval (CI) = -9.67 to -4.07). The number of glands increased after the intervention (95 % CI, 3.72-7.68; P = 0.000). Endometrial thickness was significantly improved in the sEV-treated group (SMD = 2.57, 95 % CI, 1.62-3.52).

This meta-analysis is highlighting that sEV treatment can improve the area of endometrial fibrosis, as well as VEGF, and LIF level, in a mouse IUA model. This knowledge of these findings will provide new insights into future preclinical research.

Endometrial fibrosis may cause infertility. Accurate evaluation of endometrial fibrosis helps clinicians to schedule timely therapy.

To explore T2 mapping for assessing endometrial fibrosis.

Prospective.

Ninety-seven women with severe endometrial fibrosis (SEF) and 21 patients with mild to moderate endometrial fibrosis (MMEF), diagnosed by hysteroscopy, and 37 healthy women.

3T, T2-weighted turbo spin echo (T2-weighted imaging) and multi-echo turbo spin echo (T2 mapping) sequences.

Endometrial MRI parameters (T2, thickness [ET], area [EA], and volume [EV]) were measured by N.Z. and Q.H. (9- and 4-years' experience in pelvic MRI) and compared between the three subgroups. A multivariable model including MRI parameters and clinical variables (including age and body mass index [BMI]) was developed to predict endometrial fibrosis assessed by hysteroscopy.

Kruskal-Wallis; ANOVA; Spearman's correlation coefficient (rho); area under the receiver operating characteristic curve (AUC); binary logistic regression; intraclass correlation coefficient (ICC). P value <0.05 for statistical significance.

Endometrial T2, ET, EA, and EV of MMEF patients (185 msec, 8.2 mm, 168 mm2 , and 2181 mm3 ) and SEF patients (164 msec, 6.7 mm, 120 mm2 , and 1762 mm3 ) were significantly lower than those of healthy women (222 msec, 11.7 mm, 316 mm2 , and 3960 mm3 ). Endometrial T2 and ET of SEF patients were significantly lower than those of MMEF patients. Endometrial T2, ET, EA, and EV were significantly correlated to the degree of endometrial fibrosis (rho = -0.623, -0.695, -0.694, -0.595). There were significant strong correlations between ET, EA, and EV in healthy women and MMEF patients (rho = 0.850-0.908). Endometrial MRI parameters and the multivariable model accurately distinguished MMEF or SEF from normal endometrium (AUCs >0.800). Age, BMI, and MRI parameters in univariable analysis and age and T2 in multivariable analysis significantly predicted endometrial fibrosis. The reproducibility of MRI parameters was excellent (ICC, 0.859-0.980).

T2 mapping has potential to noninvasively and quantitatively evaluate the degree of endometrial fibrosis.

2 Technical Efficacy: Stage 2.

Assisted reproduction faces a significant obstacle in the form of poor ovarian response (POR) to controlled ovarian stimulation. To address this challenge, mesenchymal stem cell therapy has been proposed as a potential treatment for female infertility and/or restoration of ovarian function in POR women. Our previous research has demonstrated that menstrual blood-derived-mesenchymal stromal cells (MenSCs) injected into the ovaries of women with POR can increase pregnancy rates. The objective of this study was to examine whether MenSC therapy could enhance ovarian reserve parameters and pregnancy outcomes in a larger population of individuals with POR.

This study consisted of 180 infertile individuals with POR who declined oocyte donation. Participants were divided into two groups: those who received bilateral MenSCs intraovarian injection and those who received no intervention. Our primary aim was to compare the rates of spontaneous pregnancy between the two groups, followed by an investigation of any alterations in the ovarian reserve parameters, such as serum FSH, AMH, and AFC levels, as well as the ICSI/IVF outcomes, in both groups of participants.

The MenSC therapy exhibited a favourable tolerability profile and did not raise any safety concerns. Following the 2-month follow-up period, women who received MenSC treatment demonstrated a significantly higher rate of spontaneous pregnancy (P < 0.005) and an improvement in anti-Müllerian hormone (AMH) levels (P = 0.0007) and antral follicle count (AFC) (P < 0.001), whereas the control group demonstrated a considerable decline in these parameters (Both P < 0.001). The MenSC therapy led to a greater number of mature oocytes and embryos among women who underwent ICSI/IVF. Our age subgroup analysis demonstrated a significant difference in the number of spontaneous pregnancies and ICSI/IVF outcomes between the treatment and control groups only among individuals below 40 years of age.

The results of our study indicate that MenSCs treatment may be a viable option for treating women experiencing POR. However, in order to be widely implemented in clinical practice, the clinical effectiveness of MenSCs therapy will need to be established through rigorous prospective randomized clinical trials.

ClinicalTrials.gov Identifier: NCT05703308. Registered 01/26/2023, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05703308 . IRCT, IRCT20180619040147N4. Registered 08/01/2020.

Endometrial injury is one of the leading causes of female infertility and is caused by intrauterine surgery, endometrial infection, repeated abortion, or genital tuberculosis. Currently, there is little effective treatment to restore the fertility of patients with severe intrauterine adhesions and thin endometrium. Recent studies have confirmed the promising therapeutic effects of mesenchymal stem cell transplantation on various diseases with definite tissue injury. The aim of this study is to investigate the improvements of menstrual blood-derived endometrial stem cells (MenSCs) transplantation on functional restoration in the endometrium of mouse model. Therefore, ethanol-induced endometrial injury mouse models were randomly divided into two groups: the PBS-treated group, and the MenSCs-treated group. As expected, the endometrial thickness and gland number in the endometrium of MenSCs-treated mice were significantly improved compared to those of PBS-treated mice (P < 0.05), and fibrosis levels were significantly reduced (P < 0.05). Subsequent results revealed that MenSCs treatment significantly promoted angiogenesis in the injured endometrium. Simultaneously, MenSCs enhance the proliferation and antiapoptotic capacity of endometrial cells, which is likely contributed by activating the PI3K/Akt signaling pathway. Further tests also confirmed the chemotaxis of GFP-labeled MenSCs towards the injured uterus. Consequently, MenSCs treatment significantly improved the pregnant mice and the number of embryos in pregnant mice. This study confirmed the superior improvements of MenSCs transplantation on the injured endometrium and uncovered the potential therapeutic mechanism, which provides a promising alternative for patients with serious endometrial injury.

Menstrual blood-derived cells show regenerative potential as a mesenchymal stem cell and may therefore be a novel stem cell source of treatment for refractory infertility with injured endometrium. However, there have been few pre-clinical studies using cells from infertile patients, which need to be addressed before establishing an autologous transplantation. Herein, we aimed to investigate the therapeutic capacity of menstrual blood-derived cells from infertile patients on endometrial infertility.

We collected menstrual blood-derived cells from volunteers and infertile patients and confirmed their mesenchymal stem cell phenotype by flow cytometry and induction of tri-lineage differentiation. We compared the proliferative and paracrine capacities of these cells. Furthermore, we also investigated the regenerative potential and safety concerns of the intrauterine transplantation of infertile patient-derived cells using a mouse model with mechanically injured endometrium.

Menstrual blood-derived cells from both infertile patients and volunteers showed phenotypic characteristics of mesenchymal stem cells. In vitro proliferative and paracrine capacities for wound healing and angiogenesis were equal for both samples. Furthermore, the transplantation of infertile patient-derived cells into uterine horns of the mouse model ameliorated endometrial thickness, prevented fibrosis, and improved fertility outcomes without any apparent complications.

In our pre-clinical study, intrauterine transplantation of menstrual blood-derived cells may be a novel and attractive stem cell source for the curative and prophylactic therapy for injured endometrium. Further studies will be warranted for future clinical application.

Women's infertility impacts the quality of life of both patients and couples and has multifaceted dimensions that increase the number of challenges associated with female infertility and how to face them. Female reproductive disorders, such as premature ovarian failure (POF), endometriosis, Asherman syndrome (AS), polycystic ovary syndrome (PCOS), and preeclampsia, can stimulate infertility. In the last decade, translational medicine has advanced, and scientists are focusing on infertility therapy with innovative attitudes. Recent investigations have suggested that stem cell treatments could be safe and effective. Stem cell therapy has established a novel method for treating women's infertility as part of a regeneration approach. The chief properties and potential of mesenchymal stem/stromal cells (MSCs) in the future of women's infertility should be considered by researchers. Due to their high abundance, great ability to self-renew, and high differentiation capacity, as well as less ethical concerns, MSC-based therapy has been found to be an effective alternative strategy to the previous methods for treating female infertility, such as intrauterine insemination, in vitro fertilization, medicines, and surgical procedures. These types of stem cells exert their beneficial role by releasing active mediators, promoting cell homing, and contributing to immune modulation. Here we first provide an overview of MSCs and their crucial roles in both biological and immunological processes. The next large chapter covers current preclinical and clinical studies on the application of MSCs to treat various female reproductive disorders. Finally, we deliberate on the extant challenges that hinder the application of MSCs in female infertility and suggest plausible measures to alleviate these impediments.

Asherman syndrome is characterized by a triad of symptoms including pain, menstrual abnormalities, and infertility and is a result of intrauterine scar tissue after instrumentation of a gravid uterus. Saline sonohysterogram is typically the most sensitive diagnostic tool; however, hysteroscopy is the criterion standard for diagnosis. Treatment includes hysteroscopic-guided lysis of adhesion, with restoration of the anatomy of the uterine cavity. Several modalities are used in an attempt to reduce the reformation of scar tissue after surgery; however, there is no consensus on the ideal method. Stem cells and platelet-rich plasma are being explored as means of regenerative therapy for the endometrium, but data remain limited. At present, most individuals can have restoration of menstrual function; however, lower pregnancy rates and obstetric complications are not uncommon. These complications are worse for patients with a higher grade of disease. Efforts are needed in standardizing classification, reducing uterine instrumentation of the gravid uterus, and referring patients to health care professionals with clinical expertise in this area.

Intrauterine adhesion (IUA) is a recurrent and refractory reproductive dysfunction disorder for which menstrual blood-derived stromal cells (MenSCs) might be a promising intervention. We reported that administration of MenSCs-derived exosomes (MenSCs-EXO) could achieve similar therapeutic effects to MenSCs transplantation, including alleviating endometrial fibrosis and improving fertility in IUA rats. The mass spectrometry sequencing result suggested that UBR4, a member of the proteasome family, was abundantly enriched in MenSCs-EXO. This study aimed to investigate the key role of UBR4 in MenSCs-EXO for the treatment of IUA and the specific molecular mechanism.

UBR4 was lowly expressed in the endometrial stromal cells (EndoSCs) of IUA patients. MenSCs-EXO treatment could restore the morphology of IUA endometrium, reduce the extent of fibrosis, and promote endometrial and vascular proliferation. Knockdown of UBR4 in MenSCs did not affect the characteristics of exosomes but attenuated the therapeutic effect of exosomes. UBR4 in MenSCs-EXO could alleviate endometrial fibrosis by boosting YAP ubiquitination degradation and promoting YAP nuclear-cytoplasmic translocation. Moreover, P65 could bind to the UBR4 promoter region to transcriptionally promote the expression level of UBR4 in MenSCs.

Our study clarified that MenSCs-EXO ameliorated endometrial fibrosis in IUA primarily by affecting YAP activity mediated through UBR4, while inflammatory signaling P65 may affect UBR4 expression in MenSCs to enhance MenSCs-EXO therapeutic effects. This revealed a novel mechanism for the treatment of IUA with MenSCs-EXO, proposing a potential option for the clinical treatment of endometrial injury.

Stem cells, with their remarkable capacity for differentiation into diverse cell types, are vital for the development as well as maintenance of health and homeostasis. Two unique abilities set them apart from other cells: self-renewal and the capacity for differentiation. They play important roles in embryogenesis, development, regeneration, and various other processes. Over the last decade, there has been increased interest in their potential use in the treatment of numerous diseases and disorders across multiple fields of medicine in acute, chronic, innate, and acquired diseases. Stem cells are key to maintaining the body's homeostasis and regulating growth and tissue functions. There are several types of stem cells-embryonic, adult, and human-induced pluripotent cells. Currently, mesenchymal stem cells are of great interest due to their regenerative, immunomodulatory, analgesic, and antimicrobial (anti-inflammatory) effects. Recent studies have shown the potent regenerative effect of stem cell therapy in gynecologic diseases such as infertility, Asherman syndrome, lichen sclerosus, polycystic ovary syndrome, premature ovarian insufficiency, genitourinary syndrome of menopause, and rectovaginal fistulas. Moreover, the successful isolation of oogonial stem cells could lead to a revolution in the field of gynecology and the potential treatment of the conditions discussed. This review aims to provide a better understanding of the latest therapeutic options involving stem cells and raise awareness of this promising yet not widely known topic in gynecology and medicine in general.

Postoperative adhesions remain a clinical challenge to both patients and providers, as they are associated with significant complications and a high economic burden. This article provides a clinical review of currently available antiadhesive agents and promising new therapies that have advanced past animal studies.

Several agents have been investigated on their ability to reduce adhesion formation; however, there is no widely acceptable option. The few available interventions are barrier agents and while low-quality evidence suggests that they may be more effective than no treatment, there is no general agreement on their overall efficacy. There is an abundance of research on new solutions; however, their clinical efficacy is yet to be determined.

Although a wide range of therapeutics have been investigated, majority are halted in animal models with only a select few being studied in humans and ultimately available in the market. Many agents have shown effectiveness in reducing adhesion formation, however, that has not been translated to improvement in clinically relevant outcomes; hence the need for high-quality large randomized trials.

Intrauterine adhesion (IUA) is a common cause of uterine infertility and its histopathologic characteristic is endometrial fibrosis. A shortage of stem cells in the endometrial basalis has been recognized as a common cause of IUA development because approximately 90% of patients suffer from IUA after endometrial injury. In this study, we provide evidence that persistent inflammation is the main contributor to endometrial fibrosis in IUA patients. We further found that treating an IUA-like mouse model with ITI-hUC-MSCs (hUC-MSCs reprogrammed by IL-1β, TNF-α and IFN-γ) significantly decreased endometrial inflammation and fibrosis. Mechanistically, high levels of complement 1 inhibitor (C1INH) secreted by ITI-hUC-MSCs prevented inflammation from inducing profibrotic CD301+ macrophage polarization by downregulating the JAK-STAT signaling pathway. In conclusion, persistent inflammation in the endometria of IUA patients provides macrophage polarization with a profibrotic niche to promote endometrial fibrosis, and the powerful immunomodulatory effects of ITI-hUC-MSCs improve the immune microenvironment of endometrial regeneration.