Search Results (39)

Background: Intrauterine adhesions, a leading cause of female infertility, frequently recur in 30–62.5% of patients despite hysteroscopic adhesiolysis and adjuvant therapies. Current intrauterine barriers, including injectable hydrogels, often lack sufficient bioactivity and tissue retention, failing to address the underlying pathological inflammation and oxidative stress driving abnormal fibrosis. Methods: Herein, we tailored a reactive oxygen species (ROS)-responsive, mussel-inspired adhesive injectable hydrogel (OHA-CP@TA) to intelligently modulate the inflammatory niche and promote normal endometrial regeneration. OHA-CP@TA was fabricated through Schiff base bonds between oxidized hyaluronic acid (OHA) and phenylboronic acid-modified carboxymethyl chitosan (CMCS-PBA), and boronate ester bonds between CMCS-PBA and tannic acid (TA). Results: OHA-CP@TA exhibited good mechanical strength, injectability, self-healing, and shear-thinning properties, and importantly, robust and stable adhesion to uterine tissue, overcoming endometrial mucus clearance. It also showed favorable in vivo uterine cavity retention for at least 7 days that covered the critical endometrial repair period. Within the postoperative inflammatory milieu, OHA-CP@TA intelligently released TA in a ROS-dependent manner, which effectively scavenged various ROS and significantly alleviated inflammation, and promoted M1 macrophage polarization into M2 phenotype. This targeted ROS scavenging and immunoregulation inhibited endometrium fibrosis progression, evidenced by downregulation of α-SMA and Col-1, and actively promoted endometrial repair and regeneration, demonstrated by enhanced angiogenesis, increased endometrial thickness, and restoration of glandular numbers. Furthermore, OHA-CP@TA exhibited good biocompatibility, in vivo biodegradability and safety. Conclusions: Therefore, OHA-CP@TA represents a promising, clinically translatable strategy for overcoming the limitations of current IUA management. Full article

Recurrent intrauterine adhesions (IUA) and refractory thin endometrium are associated with impaired endometrial regeneration, reduced implantation, and poor live birth outcomes. Regenerative therapy using mesenchymal stromal cells (MSCs) has shown promising results; however, factors associated with reproductive success remain unclear. In this prospective, single-centre, single-arm uncontrolled observational study, 35 women with recurrent IUA and thin endometrium (<7 mm) unresponsive to standard surgical and hormonal therapy received combined subendometrial and systemic administration of placenta-derived MSCs. The primary endpoint was live birth. Secondary endpoints included clinical pregnancy rate, time to pregnancy, endometrial thickness changes, uterine blood flow (resistance index, RI), and anti-Müllerian hormone (AMH) levels. Univariable logistic regression was performed to identify factors associated with live birth. Clinical pregnancy occurred in 13/35 patients (37.1%), and live birth was achieved in 11/35 (31.4%). Median time to pregnancy was 7 (5–8) months. Shorter duration of infertility or prior pregnancy loss (OR 1.55 per year; 95% CI 1.10–2.57), AFS stage I adhesions (OR 6.8; 95% CI 1.1–42; p = 0.04), lower baseline RI in uterine, arcuate and radial arteries, and higher baseline AMH (OR 2.59 per doubling; 95% CI 1.15–6.89) were significantly associated with live birth. Endometrial thickness increased after therapy but was not significantly associated with live birth. No severe adverse events were observed. Placenta-derived MSC therapy was followed by live birth in 31.4% of women with recurrent IUA and refractory thin endometrium. A shorter duration of reproductive disorders, less severe adhesions, lower baseline RI in uterine, arcuate and radial arteries, and higher AMH levels were associated with live birth after treatment and may help identify patients with a more favourable reproductive prognosis in future controlled studies. Full article

Physiological hypoxia is a defining feature of early pregnancy, coordinating menstrual repair, implantation, decidualization, placental development, and fetoplacental adaptation. Hypoxia-inducible factors, HIF-1α and HIF-2α, act as master regulators of these processes by sensing oxygen tension and orchestrating cellular responses in metabolism, angiogenesis, immune regulation, and tissue remodeling. Although structurally related, HIF-1α and HIF-2α exhibit distinct spatial and temporal functions across reproductive stages. Embryonic HIF-1α is primarily involved in early embryonic development, whereas embryonic HIF-2α is required for later developmental stages. Furthermore, maternal HIF-1α acts early in pregnancy, coordinating metabolic adaptation, endometrial regeneration, decidualization, angiogenic expansion, placental organization, and maternal immune tolerance. In contrast, maternal HIF-2α regulates epithelial breakdown, trophoblast invasion, implantation mechanics, and vesicle-mediated trafficking. Mouse genetics demonstrate that disruption of either isoform leads to non-redundant defects in reproductive success, from failed implantation to placental insufficiency and fetal lethality. Pathological hypoxia or aberrant HIF signaling drives pregnancy disorders including preeclampsia, fetal growth restriction, recurrent pregnancy loss, and heavy menstrual bleeding. Defining the distinct roles of HIF-1α and HIF-2α supports the development of therapies targeting hypoxia-responsive pathways in infertility and obstetric disease. Full article

The uterus is a dynamic organ in which the endometrium undergoes cyclic processes of proliferation, shedding, and regeneration under the influence of estrogen and progesterone. In particular, estrogen regulates the proliferation and differentiation of the endometrium and plays an important role in the development of gynecological diseases such as endometrial cancer. Farnesyl diphosphate synthase (FDPS) is a key enzyme involved in the mevalonate pathway, catalyzing the synthesis of farnesyl pyrophosphate (FPP), which plays an essential role in cholesterol biosynthesis and protein prenylation. In this study, we demonstrated using an in vivo mouse model that the expression of FDPS is regulated by estrogen. FDPS expression was specifically elevated during the proestrus stage of the estrous cycle and subsequently decreased. In ovariectomized (OVX) mice, FDPS expression was significantly increased 24 h after estrogen treatment, whereas this response was suppressed by treatment with the estrogen receptor alpha (ERα) antagonist, ICI 182,780. Although FDPS expression has been reported in various cancers, its role in endometrial cancer remains unclear. Histological and cellular analyses revealed that FDPS is highly expressed in human endometrial cancer tissues and in the endometrial cancer cell line Ishikawa, where it contributes to cell proliferation. These findings suggest that FDPS may play a role in the survival and growth of endometrial cancer cells. This study provides new insights into the potential function of FDPS in the uterus and suggests that targeting FDPS may represent a promising therapeutic strategy for endometrial cancer. Full article

Background: Metabolic instability, encompassing fluctuations in body weight, glucose, insulin, and sex hormones, may create a pro-inflammatory and proliferative endometrial microenvironment even in women with normal BMI. Methods: A systematic literature review was performed in PubMed, Embase, and Google Scholar, including studies assessing the relationship between metabolic, endocrine, and inflammatory factors and the risk of endometrial cancer in non-obese women. Results: Variability in body weight and hormonal parameters was associated with chronic subclinical inflammation, altered leptin/adiponectin secretion, decreased sex hormone-binding globulin, and increased estrogen bioavailability. These changes disrupt the homeostatic rhythm of endometrial cell regeneration and increase the likelihood of neoplastic transformation. Conclusions: Metabolic instability represents a novel integrated risk factor for endometrial cancer among women without obesity and should be incorporated into future risk stratification and prevention models. Full article

Platelet-rich plasma (PRP) is an autologous blood-derived concentrate increasingly utilized in regenerative medicine for its ability to accelerate healing and tissue repair. PRP is broadly classified by leukocyte content, fibrin architecture, and platelet concentration, with classification systems developed to standardize characterization. Preparation methods, including single- or double-spin centrifugation and buffy coat techniques, influence the final composition of PRP, determining the relative proportions of platelets, leukocytes, plasma proteins, and extracellular vesicles. These components act synergistically, with platelets releasing growth factors (e.g., VEGF, PDGF, TGF-β) that stimulate angiogenesis and matrix synthesis, leukocytes providing immunomodulation, plasma proteins facilitating scaffolding, and exosomes regulating intercellular signaling. Mechanistically, PRP enhances tissue repair through four key pathways: platelet adhesion molecules promote hemostasis and cell recruitment; immunomodulation reduces pro-inflammatory cytokines and favors M2 macrophage polarization; angiogenesis supports vascular remodeling and nutrient delivery; and serotonin-mediated pathways contribute to analgesia. These processes establish a regenerative microenvironment that supports both structural repair and functional recovery. Clinically, PRP has been applied across multiple specialties. In orthopedics, it promotes tendon, cartilage, and bone healing in conditions such as tendinopathy and osteoarthritis. In dermatology, PRP enhances skin rejuvenation, scar remodeling, and hair restoration. Gynecology has adopted PRP for ovarian rejuvenation, endometrial repair, and vulvovaginal atrophy. In dentistry and oral surgery, PRP accelerates wound closure and osseointegration, while chronic wound care benefits from its angiogenic and anti-inflammatory effects. PRP has also favored gingival recession coverage, regeneration of intrabony periodontal defects, and sinus grafting. Although preparation heterogeneity remains a challenge, PRP offers a versatile, biologically active therapy with expanding clinical utility. Full article

The human endometrium is unique in that it has a high potential for regeneration after menstruation without scarring. Although growth factors are thought to be responsible for scar formation, it has recently been shown for foetal skin that CD26-negative fibroblasts are essential. Thus, we investigated whether CD26 might be involved in scar formation. Primary human endometrial stromal cells (HPESCs) were stimulated with interleukin-1 alpha (IL1α) to induce CD26 protein expression, and secretion of the scar-associated proteins collagen 1 alpha 1 (COL1A1) and TGF-β3 was measured using ELISAs. The contribution of CD26 to wound closure was analysed using a wound healing assay. The CD26 inhibitor diprotin A (DPA) was used to attenuate CD26 activity. Immunohistochemistry of human uterine samples showed negligible stromal staining of CD26, but CD26 was abundant in the endometrial glands. Treatment of CD26-negative HPESCs with IL1α induced CD26 protein expression, strongly stimulated wound healing in vitro, and increased secretion of COL1A1, but decreased TGF-β3 secretion. DPA effectively attenuated all IL1α-induced effects. We suggest that the stromal non-expression of the scar-associated protein CD26 might contribute to non-scarring during endometrial wound healing. Full article

The endometrium is a highly dynamic tissue central to female reproductive function, undergoing nearly 500 cycles of proliferation, differentiation, shedding, and regeneration throughout a woman’s reproductive life. This remarkable regenerative capacity is driven by a reservoir of endometrial stem/progenitor cells (ESCs), which are crucial for maintaining tissue homeostasis. Dysregulation of these cells is linked to a variety of clinical disorders, including menstrual abnormalities, infertility, recurrent pregnancy loss, and serious gynecological conditions such as endometriosis and endometrial cancer. Recent advancements in organoid technology and lineage-tracing models have provided insights into the complex cellular hierarchy that underlies endometrial regeneration and differentiation. This review highlights the latest breakthroughs in endometrial stem cell biology, focusing particularly on 3D in vitro platforms that replicate endometrial physiology and disease states. By integrating these cutting-edge approaches, we aim to offer new perspectives on the pathogenesis of endometrial disorders and establish a comprehensive framework for developing precision regenerative therapies. Full article

Background: Infertility remains a significant global health challenge, affecting approximately 15% of couples worldwide. In vitro fertilization (IVF) has transformed reproductive medicine; however, challenges such as low success rates in older patients, ovarian insufficiency, endometrial dysfunction, and male infertility continue to limit outcomes. Objective: This review aims to summarize the principles of IVF and explore the potential role of stem cells in enhancing IVF outcomes, with particular attention to applications in both women and men, as well as the accompanying ethical considerations. Summary: Stem cell research has introduced novel therapeutic opportunities, including ovarian rejuvenation, endometrial regeneration, sperm quality enhancement, and the development of synthetic embryo models. Mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs) demonstrate regenerative properties that may help to overcome current reproductive limitations. Despite encouraging findings from preclinical and early clinical studies, challenges such as tumorigenesis, genetic instability, and ethical controversies remain major barriers to translation. Conclusions: IVF continues to serve as a cornerstone of assisted reproductive technology (ART). Stem cell-based approaches represent an exciting frontier that could expand the therapeutic possibilities of IVF. Careful clinical validation, international regulatory harmonization, and robust ethical oversight will be essential to ensuring safe and equitable implementation. Full article

Mesenchymal stromal/stem cells (MSCs) are known to secrete a wide range of pleiotropic molecules promoting tissue repair and regeneration. Recent advances in cell sheet technology have demonstrated significant improvements in the regenerative capacity of MSCs within the sheet, retaining appropriate microenvironmental cues, and have suggested an instructing role of extracellular matrix (ECM). We previously found that the secretome of MSCs cultured on a decellularized MSC-derived ECM (dECM) was significantly enriched in dozens of cytokines, chemokines and growth factors compared to the secretome of MSCs grown on standard plastic dishes. The enriched secretome has been shown to have enhanced chemotactic and angiogenic properties, stimulate C2C12 myoblast proliferation and promote skeletal muscle regeneration in a murine in vivo model. Here, we report novel findings about dECM-induced changes in the miRNA profile of MSCs. We performed miRNA-seq and found 17 differentially expressed miRNAs in endometrial MSCs (MESCs) with miR-146a-5p being the most upregulated. Additionally, we investigated miR-146a-5p expression in MSCs of various origins after exposure to dECM, and found a correlation between miR-146a-5p upregulation and the general dECM-induced paracrine response. Furthermore, we demonstrated that miR-146a-5p mimics, transfected into C2C12 myoblasts, promoted their proliferation, suggesting a role for miR-146a-5p in myotropic effects mediated by the enriched secretome. These findings provide new insights into how ECM as a component of the MSC niche influences the secretory phenotype and modulates therapeutic properties of MSCs. Full article

The endometrium is essential for reproductive function, supporting implantation and pregnancy through mechanisms such as hormonal responsiveness, immune regulation, and tissue regeneration. Aging disrupts these processes, with cellular senescence—marked by irreversible cell cycle arrest due to DNA damage and oxidative stress—being a key contributor. While senescence aids in tumor suppression and tissue repair, its dysregulation impairs endometrial function. Central to this regulation are p53, AMPK, and mTOR, which coordinate stress responses, metabolic regulation, and proliferation control. p53 activates AMPK and inhibits mTOR, promoting energy conservation and limiting senescence. AMPK also suppresses mTOR, reducing age-related dysfunction. This p53–AMPK–mTOR axis, along with autophagy, governs cell fate in response to stress and nutrient status. Although moderate senescence supports endometrial function, excessive accumulation can hinder fertility. Understanding these molecular interactions may advance fertility treatments and strategies to counteract reproductive aging. Full article

The bovine uterus is susceptible to bacterial infections after calving, particularly from Escherichia coli (E. coli), which often results in endometritis. Additionally, postpartum stress in cows can elevate cortisol levels in the body, inhibiting endometrial regeneration and reducing immune function, thereby further increasing the risk of infection. Selenium (Se) is a common feed additive in dairy farming, known for its anti-inflammatory and antioxidant effects. The aim of this study was to investigate the regulatory role of Se in the growth of bovine endometrial stromal cells (BESCs) under the conditions of LPS-induced inflammatory damage at high cortisol levels. BESCs were treated with 1, 2, 4 μM Se in combination with co-treatment of LPS and cortisol. The results indicated that LPS inhibited the cell viability and reduced the mRNA expression of CTGF, TGF-β1, and TGF-β3. Additionally, LPS increased apoptosis, hindered the cell cycle progression by blocking it in the G0/G1 phase, and suppressed the PI3K/AKT/GSK-3β and Wnt/β-catenin signaling pathways. Furthermore, increased concentrations of cortisol can exacerbate the impacts of LPS on cell proliferation and apoptosis. Conversely, the supplementation of Se promoted cell viability, increased the mRNA expression of TGF-β1 and TGF-β3, and enhanced cell cycle progression, while simultaneously repressing cell apoptosis as well as activating the PI3K/AKT/GSK-3β and Wnt/β-catenin signaling pathways. The above findings demonstrated that Se can promote cell proliferation, reduce cell apoptosis, and aid in the growth of BESCs damaged by LPS under high levels of cortisol. The potential mechanisms may be associated with the regulation of the PI3K/AKT/GSK-3β and Wnt/β-catenin signaling pathways. Full article

Background and Objectives: This article investigates the transformative impact of 3D and bio 3D printing technologies in assisted reproductive technology (ART), offering a comprehensive review of their applications in improving reproductive outcomes. Materials and Methods: Following PRISMA guidelines, we conducted a thorough literature search focusing on the intersection of ART and additive manufacturing, resulting in the inclusion of 48 research papers. Results: The study highlights bio 3D printing’s potential in revolutionizing female infertility treatments, especially in follicle complex culture and ovary printing. We explore the use of decellularized extracellular matrix (dECM) as bioink, demonstrating its efficacy in replicating the ovarian microenvironment for in vitro maturation of primordial oocytes. Furthermore, advancements in endometrial cavity interventions are discussed, including the application of sustained-release systems for growth factors and stem cell integration for endometrial regeneration, showing promise in addressing conditions like Asherman’s syndrome and thin endometrium. We also examine the role of conventional 3D printing in reproductive medicine, including its use in educational simulators, personalized IVF instruments, and microfluidic platforms, enhancing training and precision in reproductive procedures. Conclusions: Our review underscores both 3D printing technologies’ contribution to the dynamic landscape of reproductive medicine. They offer innovative solutions for individualized patient care, augmenting success rates in fertility treatments. This research not only presents current achievements but also anticipates future advancements in these domains, promising to expand the horizons for individuals and families seeking assistance in their reproductive journeys. Full article

Pericytes are versatile cells integral to the blood vessel walls of the microcirculation, where they exhibit specific stem cell traits. They are essential in modulating blood flow, ensuring vascular permeability, and maintaining homeostasis and are involved in the tissue repair process. The human endometrium is a unique and complex tissue that serves as a natural scar-free healing model with its cyclical repair and regeneration process every month. The regulation of pericytes has gained increasing attention due to their involvement in various physiological and pathological processes. However, endometrial pericytes are less well studied compared to the pericytes in other organs. This review aims to provide a comprehensive overview of endometrial pericytes, with a focus on elucidating their physiological function and potential implications in uterine disorders. Full article

Infertility caused by a thin endometrium remains a significant challenge in assisted reproduction and is often associated with a low success rate after treatment with assisted reproductive technology. There is a lack of consensus in the field concerning both its diagnostic criteria and clinical management. The currently available treatment options are few with limited efficacy. Recent advances in cell therapy and bioengineering have, however, shown promising results for the treatment of a thin endometrium. Notably, these novel interventions have demonstrated the ability to increase endometrial thickness, restore endometrial function, and improve reproductive outcomes. In this comprehensive review, we focus on a critical evaluation of these emerging therapeutic strategies for a thin endometrium including platelet-rich plasma, exosomes derived from stem cells, and bioengineering-based techniques. By synthesizing the findings from available clinical trials, we highlight the promising outcomes achieved so far and underscore the importance of robust clinical trials in assessing the safety and efficacy of these interventions in the future. Continued research efforts to unravel the intricate mechanisms involved in endometrial repair and regeneration will also be essential to enhance our understanding of this multifactorial condition and to identify novel treatment targets for future therapeutic interventions. Full article