Search Results (120)

Background: The worldwide prevalence of FGR is about 13% and can lead to various adverse perinatal outcomes, including preterm birth, stillbirth, and neonatal mortality. Hypoxia-Inducible Factor-1 (HIF-1) is an important regulator of oxygen homeostasis in humans and is crucial for placental development. The aim of this study is to determine the pattern of HIF-1A expression in placenta, and to correlate its association with preeclampsia, fetal growth restriction and adverse perinatal outcomes. Methods: This study comprised a total of 158 cases with 42 cases of mother having babies with fetal growth restriction (FGR), 39 cases of mother with preeclampsia (PE), 35 cases of mother with preeclampsia and fetal growth restriction and 42 controls. The expression of HIF-1A was evaluated in various placental cell types, including cytotrophoblasts, syncytiotrophoblasts, fetal endothelial cells, maternal endothelial cells, and decidual cells. Results: The expression of HIF-1A in placental decidual cells of mother with FGR (21/42, 50%, p < 0.0001), PE (25/39, 64.1%, p < 0.0001) and PE with FGR (12/35, 34.3%, p < 0.0001) were significantly increased compared to controls (1/42). Intriguingly, HIF-1A expression was significantly reduced in the placental cytotrophoblasts and syncytiotrophoblasts of mother with PE and FGR (2/35, 5.7%) compared to PE alone (11/39, 28.2%) (p = 0.0142). Conclusions: We found that increased HIF-1A expression in the nuclei of decidual cells was observed in the mothers of babies with FGR, both with and without PE. While HIF-1A expression in the cytotrophoblasts and syncytiotrophoblasts was significantly reduced between mothers with PE and mothers with PE and FGR. This suggests HIF-1A expression might play a role in the pathogenesis of FGR. Full article

Recurrent pregnancy loss (RPL) is a multifactorial condition affecting 1–5% of couples, often with unclear etiology. Idiopathic pregnancy losses (iPLs) are particularly challenging due to unknown molecular mechanisms. This study investigates the transcriptomic profiles of first-trimester products of conception (POC) from iPLs to uncover underlying molecular pathways. We performed RNA-sequencing on nine POC samples, identifying two distinct clusters enriched in trophoblast and decidual cells. Deconvolution analysis revealed reduced syncytiotrophoblast (STB) cells, with increased cytotrophoblast (CTB) and extravillous trophoblast (EVT) cells in iPLs. Gene Set Enrichment Analysis highlighted immune pathways enrichment in both villous trophoblasts and decidua. Gene ontology (GO) analysis of downregulated genes implicated hormonal and endocrine processes, consistent with STB reduction, while upregulated genes were associated with MHC protein complex and immune system processes, aligning with EVT increases. Histological analysis showed chronic histiocytic intervillositis (CHI) in iPL samples, supporting maternal immune dysregulation in unexplained RPL. Together, transcriptomic and histological analyses indicate that immune signaling dysregulation and impaired trophoblast differentiation may underlie unexplained iPLs. These findings bridge molecular and histopathological evidence, underscoring the interplay between trophoblast dysfunction and immune imbalance. Our results provide insights into iPL pathogenesis, highlighting potential biomarkers that may contribute to improved diagnosis and future research. Full article

Epidural-related maternal fever (ERMF) occurs with significant incidence in women receiving local anesthetics such as ropivacaine via epidural catheter for pain relief during labor. The causal mechanism behind this phenomenon is still not fully resolved, but evidence suggests that these anesthetics cause sterile inflammation. In this observational study, we investigated a possible contributory role of the dual-specificity phosphatase-9 (DUSP9) controlling the activity of mitogen-activated protein kinases (MAPK), and also PH-domain and Leucine-rich repeat phosphatase (PHLPP) regulating AKT kinases. The data show that ropivacaine differentially affects the expression of these phosphatases in distinct cell types of the umbilical cord and placenta. The gene expression of DUSP9 was almost completely switched off in the presence of ropivacaine in HUVECs and extravillous trophoblasts for up to 6 h, while the expression of PHLPP1 was upregulated in HUVECs and syncytiotrophoblasts. Extravillous trophoblasts were identified as a source of pro-inflammatory mediators and regulatory miRNAs in response to ropivacaine. Placentae at term exhibited a distinct DUSP9 expression pattern, whether the patients belonged to the control group or received epidural analgesia with or without elevated body temperature. The observed data imply that ropivacaine induces complex effects on the MAPK and AKT pathways at the feto–maternal interface, which contribute to the ERMF phenomenon. Full article

The heart and placenta have simultaneous embryologic development, the interactions between the two organs representing the heart–placental axis. They both share key developmental pathways, one of which involves the placental growth factor (PlGF) and its receptor, vascular endothelial growth factor receptor-1 (VEGFR-1). The aim of this study was to evaluate the placental pathology and the expression patterns of PlGF and VEGFR-1 in pregnancies with fetuses with congenital heart defects (CHDs). We analyzed placental gross and microscopic alterations between placentas from pregnancies with CHD fetuses and pregnancies with structurally normal heart fetuses. We also performed the immunohistochemical (IHC) assessment of the placental expression of PlGF and VEGFR-1 in the two groups. We discovered significant gross placental abnormalities in pregnancies with CHD fetuses, including a shorter umbilical cord, marginal or velamentous umbilical cord insertion, and a lower fetal-to-placental weight ratio. Also, 88.2% of the placentas in the CHD group displayed microscopic pathologic aspects. We demonstrated significant placental immunostaining for PlGF and VEGFR-1 in the syncytiotrophoblast and decidual cells compared to villous endothelial cells. We identified a lower placental IHC expression of PlGF in pregnancies with CHD fetuses compared to controls but no differences in the placental immunostaining pattern for VEGFR-1 between the two groups. Our study uncovered a potential role played by the PlGF/VEGFR-1 pathway in the development of CHDs through placental-mediated mechanisms. Full article

The human (h) growth hormone (GH)/placental lactogen (PL) gene family has served as an important model to study tissue-specific expression. The two GH genes (hGH-N/GH1 and GH-V/GH2) and three PL or chorionic somatomammotropin hormone (CSH) genes (hPL-L/CSL1, hPL-A/CSH1 and hPL-B/CSH2) are clustered together at a single locus. Although they share >90% sequence similarity, hGH-N is expressed by somatotrophs of the anterior pituitary while the remaining four hGH/PL genes are expressed by the villous syncytiotrophoblast of the placenta. Efficient pituitary expression depends on a locus control region (LCR) that includes nuclease hypersensitive sites I-V (HS I-V). For activation, data indicate that HS III facilitates the initial access of pituitary-specific transcription factor Pit-1 to the locus, where it is required to bind Pit-1 sites at HS I/II and the hGH-N promoter. This is associated with histone acetylation and tri-methylation modifications that are consistent with active chromatin. However, all five hGH/PL genes share similar nuclease sensitivity in human pituitary chromatin, suggesting similar levels of accessibility and thus potential for transcription. Furthermore, hPL-A and hPL-B promoters contain Pit-1 binding sites, and the hPL-A promoter, like hGH-N, will support expression in transfected pituitary tumor GC cells in culture. These observations suggest the possibility of a transcriptional repressor mechanism that prevents hPL gene expression in the pituitary. P sequences were identified as a candidate. They are located upstream of all four placental hGH/PL genes but not hGH-N, repress hPL-A promoter activity in transfected pituitary GC cells, and bind a forkhead box A1/nuclear factor-1 transcription, which is proposed to act as a repressor complex in human pituitary chromatin. In spite of this, the inability to limit hGH-N expression when tested in transgenic mice brought the role of P sequences in pituitary repression into question. These observations are re-examined here in light of new evidence that the LCR (HS III) interacts with P sequences in the human pituitary. Full article

Trophoblast fusion into the multinucleated syncytiotrophoblast (SCT) appears as an inescapable feature of placentation in mammals and other viviparous species. The trophoblast cells underlying the syncytium are considered a reservoir for the restoration of the aging peripheric structure. The transition from trophoblasts to SCTs has to be tightly regulated, and could be altered by genetic anomalies or environmental exposure. The resulting defective placental function could be one of the causes of the major placental diseases, such as preeclampsia (PE) and Intra-Uterine Growth Restriction (IUGR). This review attempts to take stock of the current knowledge about fusion mechanisms and their deregulations. Full article

Introduction: Equine chorionic girdle cells can give rise to the endometrial cup, a structure that secretes equine chorionic gonadotropin (eCG). To date, the mechanisms underlying the proliferation, differentiation, invasion, and hormone secretion of equine chorionic girdle cells are not fully understood. During human pregnancy, interleukin-6 (IL-6) is maternally expressed to stimulate the invasion and migration of human syncytiotrophoblast cells and influence the synthesis of human chorionic gonadotropin. Although many previous studies reported the same upregulation of IL-6 during equine placentation, its effects on equine chorionic girdle cells have never been tested. Methods: In this study, we tested the effects of different concentrations of IL-6 on the morphology, differentiation, proliferation, hormone production, invasion, migration, and gene expression profiles of equine chorionic girdle cells. Results: We found that, with respect to morphology and proliferation, IL-6 had no significant effect; with respect to eCG production, 30 ng/mL IL-6 significantly increased the expression of genes related to eCG production, whereas treatment with 70 ng/mL IL-6 downregulated these genes. However, no significant increase in intracellular protein levels or eCG secretion was observed following treatment with any concentration of IL-6. Regarding cell migration and invasion, we found that IL-6 treatment had no significant effect on the migration capability of equine chorionic girdle cells but did enhance the invasion capability of equine chorionic girdle cells and upregulated the expression of the invasion-related genes, Mmp2 and Mmp9. Finally, our transcriptomic study revealed that in equine chorionic girdle cells, IL-6 treatment mainly affected the expression of genes related to the NOD-like receptor signaling pathway and the JAK–STAT signaling pathways, which are involved in immune and inflammatory responses. Conclusions: In summary, this study demonstrates the positive effects of IL-6 on the cytokine secretion and invasive ability of equine chorionic girdle cells. Full article

The villous trophoblast cells are of fundamental importance because they fulfill a variety of functions that are vital for the growth of the fetus and the maintenance of pregnancy. A simple in vitro villous trophoblast cell model that grows on standard tissue culture plates has been utilized for various functional studies on villous trophoblast cells. Despite the potential value of incorporating electron microscopy analysis in reports on functional analysis of primary human trophoblast cells, electron microscopy analysis is exclusively ancillary to functional analysis in previous publications. In the context of autophagy research of villous trophoblast cells using primary trophoblast cells, a detailed ultrastructural analysis of autophagy flux using electron microscopy is imperative; however, it has not been conducted to date. In this study, we isolated term villous trophoblast cells (i.e., cytotrophoblast cells, CTB cells) using the most up-to-date isolation method for isolating pure CTB cells from human term placenta and investigated the ultrastructural dynamic process of autophagy of cultured CTB cells by means of transmission electron microscopy. The initial 6 h culture resulted in CTB cell aggregation; however, the majority of CTB cells did not differentiate into syncytial cells. In contrast, after 72 h, CTB cells exhibited a promotion of differentiation into syncytial cells. The electron microscopy analysis revealed the upregulation of autophagy and visualized unique autophagic profiles during differentiation into syncytial cells, which exhibited perinuclear accumulation of extremely large autophagosomes/autolysosomes. This study provides novel insights into the reproductive biology of primary trophoblast cells, thereby demonstrating the substantial value of primary trophoblast cells as research resources. Full article

Placentation disorders, including severe preeclampsia and fetal growth restriction, have their origins in early pregnancy, whereas symptoms typically present later on. To investigate the pathogenesis of these diseases, there is a need for a reliable in vitro model system of early placenta development with known pregnancy outcomes. Therefore, we optimized the generation of human induced trophoblast stem cells (iTSCs) from term umbilical cord, enabling non-invasive collection of patient-derived material immediately after birth. Using a direct reprogramming approach previously described for dermal fibroblasts, we investigated the effects of three supplements (A-485, BMP4, and EPZ-6438) to assess their potential to enhance iTSC induction. The generated iTSCs fulfilled the criteria for bona fide first-trimester trophoblasts and exhibited key functional capacities, including long-term self-renewal, differentiation into hormone-producing syncytiotrophoblasts and invasive extravillous trophoblasts, and the formation of organoids. Furthermore, transcriptomic analysis revealed high similarity between the generated iTSCs and trophoblast stem cells derived from first-trimester placental tissue. The supplements did not improve the generation of iTSCs. In conclusion, we successfully generated bona fide iTSCs from term umbilical cord using a direct reprogramming approach, providing a robust and clinically relevant model to study early placentation mechanisms in patient-derived trophoblasts. Full article

The placenta plays a critical role in nutrient and oxygen exchange during pregnancy, yet the effects of medicinal drugs on this selective barrier remain poorly understood. To overcome this, this study presents a cost-effective bioimpedance spectroscopy (BIS) system to assess tight junction integrity and monolayer formation in BeWo b30 cells, a widely used model of the multinucleated maternal–fetal exchange surface of the placental barrier. Cells were cultured on collagen-coated porous membranes and treated with forskolin to induce controlled syncytialization. Electrical impedance was measured using an entry level impedance analyzer, while immunofluorescence staining was used to confirm monolayer formation and syncytialization. The measurements and staining confirmed the formation of a confluent monolayer on day 4. In fact, the electrical resistance tripled for treated samples indicating a more electrically restrictive barrier. This resistance remained constant for treated samples reflecting the intact barrier’s integrity over the next 3 days. The measurements show that, on day 4, the electrical capacitance of the cells decreased for the treated samples as opposed to the untreated samples. This reflects that the surface area of the BeWo b30 cells decreased when the samples were treated with forskolin. Finally, a COMSOL model was developed to explore the effects of electrode positioning, depth, and distance on TEER measurements, explaining discrepancies in the literature. In fact, there was a substantial 97% and 39.4% difference in the obtained TEER values. This study demonstrates the AD2 device’s feasibility for monitoring placental barrier integrity and emphasizes the need for standardized setups for comparable results. The system can hence be used to analyze drug effects and nutrient transfer across the placental barrier. Full article

Human chorionic gonadotropin is a glycoprotein hormone produced by human or humanoid syncytiotrophoblasts that differentiate during pregnancy. Due to its superior stability and long-lasting effects compared to luteinizing hormone, it is often used to replace luteinizing hormone to regulate reproductive performance in sows. Human chorionic gonadotropin promotes oocyte maturation, follicle development, and luteinization, thereby increasing conception rates and supporting early embryonic development. In sow reproductive management, the application of human chorionic gonadotropin not only enhances ovulation synchrony but also improves the success rate of embryo implantation by regulating endometrial receptivity and immune mechanisms, significantly enhancing overall reproductive performance. This article primarily reviews the application of human chorionic gonadotropin in sow follicle development, luteal maintenance, and embryo implantation, providing theoretical support for its use in improving reproductive performance in sows. Full article

Intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin are cell adhesion molecules that play a significant role in inflammation and are implicated in the pathophysiology of preeclampsia development and HIV infection. More specifically, the immune expression of ICAM-1, VCAM-1, and E-selectin within cyto- and syncytiotrophoblast cells are dysregulated in preeclampsia, indicating their role in defective placentation. This study investigates the associations of ICAM-1, VCAM-1, and E-selectin gene variants (rs3093030, rs3783605, and rs1805193, respectively) with preeclampsia comorbid with HIV infection in women of African ancestry. It also examines the susceptibility to preeclampsia development and the effect of highly active antiretroviral therapy (HAART). A total of 405 women were enrolled in this study. Out of these women, 204 were preeclamptic and 201 were normotensive. Clinical characteristics were maternal age, weight, blood pressure (systolic and diastolic), and gestational age. Whole blood was collected, DNA was extracted, and genotyping of the ICAM-1 (rs3093030 C>T), VCAM-1(rs3783605 A>G), and E-selectin (rs1805193 A>C) gene polymorphisms was performed. Comparisons were made using the Chi-squared test. Our results demonstrated that preeclamptic women exhibited a higher frequency of analyzed variants, in contrast to those with the duality of preeclampsia and HIV infection. Additionally, the C allele of the ICAM-1 (rs3093030 C>T) and G allele of the VCAM-1 (rs3783605 A>G) genes were found to have a greater role in the co-morbidity and may be considered as a risk factor for preeclampsia development in women of African ancestry. In contrast, the SNP of rs1805193 of the E-selectin gene indicated that A>C was only significantly associated with HIV infection and not with preeclampsia. These findings highlight a strong association of the rs3093030 SNP of the ICAM-1 gene and of the VCAM-1 rs3783605 gene with the development of preeclampsia, indicating their role in the defective trophoblast invasion of preeclampsia. Sub-group analysis further reveals an association of the AA genotype with late-onset preeclampsia, a less severe form of disease indicating differing genetic predispositions between early and late-onset forms. Full article

Gestational diabetes mellitus (GDM) is a common condition during pregnancy. The prevalence of GDM is continuously increasing worldwide. Due to accessible diagnostic methods and a clear understanding of risk factors, GDM can be effectively diagnosed and managed. Galectins may influence immunomodulatory and inflammatory processes. This study examines the expression of galectin-7 in the placentas of women with gestational diabetes (GDM), compares it to its expression in healthy pregnancies, and evaluates the associated clinical outcomes. The placentas of 40 healthy women and 40 GDM placentas were included in the cohort. The expression level of galecin-7 was measured in the syncytiotrophoblast (SCT) and in the decidua of the placenta by immunohistochemistry and double immunofluorescence staining. The evaluation was performed by an immunoreactivity score (IRS). The study results show an increased expression of galectin-7 in the SCT and the decidua of GDM placentas as compared to the placentas of the control group. Elevated levels of galectin-7 were observed in both the nucleus and the cytoplasm. This study investigated the hypothesis that galectins are involved in pathophysiological processes of gestational diabetes. Statistical analysis of gene expression patterns confirmed that galectin-7 is indeed upregulated in GDM placentas. Further studies are needed to show the correlation of galectin-7 and the development and maintenance of gestational diabetes mellitus. Full article

Malaria during pregnancy has been associated with significant risks to both the mother and the fetus, leading to complications such as anemia, low birth weight, and increased infant mortality. The trophoblast cells, a key component of the placenta, are crucial for nutrient and oxygen exchange between mother and fetus. The differentiation of cytotrophoblasts (CTBs) into syncytiotrophoblasts (STBs) is critical for proper pregnancy development. These cells form the bi-stratified epithelium surrounding the placental villi. While previous studies have described an inflammatory activation of STB cells exposed to Plasmodium falciparum-infected erythrocytes (P. falciparum-IE) or components such as hemozoin (HZ), little is known about the direct effect this parasite may have on the epithelial turnover and function of trophoblast cells. This study aims to contribute to understanding mechanisms leading to placental damage during placental malaria using a BeWo cell line as a differentiation model. It was found that P. falciparum-IE interferes with the fusion of BeWo cells, affecting the differentiation process of trophoblast. A reduction in syncytialization could be associated with the adverse effects of infection in fetal health, altering the remodeling of the trophoblast epithelial barrier and reducing their capacity to exchange substances. However, further studies are necessary to assess alterations in the functionality of this epithelium. Full article

Background and Objectives: Preeclampsia has been linked to an inflammatory response that may be brought on by endothelial cell dysfunction. This paper investigates the pathomechanism of syncytiotrophoblast basement membrane (STBM) damage and Placental Protein 13 (PP13) release, which may have a role in systemic endothelial dysfunction in preeclampsia. Materials and Methods: This comparative cross-sectional study involves 54 preeclampsia patients (27 early-onset preeclampsia and 27 late-onset preeclampsia) and 27 pregnant women with normal blood pressure. An enzyme-linked immunosorbent assay was performed to evaluate maternal blood levels of PP13. Following birth, a portion of the placenta was collected for transmission electron microscope (TEM) and immunohistochemical (IHC) analysis. The data were analyzed using STATA version 15. Results: PP13 expression in the placental syncytiotrophoblast was significantly lower in the early-onset preeclampsia, compared to late-onset preeclampsia and normotensive pregnancy, group (p < 0.001). In contrast, serum PP13 levels were found to be the highest in the early-onset preeclampsia group, although no significant difference were found in mean maternal serum levels of PP13 between the three groups. The decreased PP13 expression in placental syncytiotrophoblast can be attributed to the greater extent of damage in the STBM in early-onset preeclampsia that leads to the release of a larger amount of PP13 into maternal circulation. The hypothesis aligns with the TEM analysis results. Preeclamptic pregnancies showed placental syncytiotrophoblast aponeurosis, whereas normotensive pregnancies did not. Placental lesions and STBM shedding were found to be more pronounced in early-onset preeclampsia compared to late-onset preeclampsia. Conclusions: PP13 and STBM damage may play a role in systemic endothelial dysfunction in preeclampsia. Full article