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The placenta is the interface between mother and fetus in all eutherian species. However, our understanding of this essential organ remains incomplete. A substantial challenge has been the syncytial cells of the placenta, which have made dissociation and independent evaluation of the different cell types of this organ difficult. Here, we address questions concerning the ontogeny, specification, and function of the cell types of a representative hemochorial placenta by performing single nuclei RNA sequencing (snRNA-seq) at multiple stages of mouse embryonic development focusing on the exchange interface, the labyrinth. Timepoints extended from progenitor-driven expansion through terminal differentiation. Analysis by snRNA-seq identified transcript profiles and inferred functions, cell trajectories, signaling interactions, and transcriptional drivers of all but the most highly polyploid cell types of the placenta. These data profile placental development at an unprecedented resolution, provide insights into differentiation and function across time, and provide a resource for future study.

Simple Summary: Autophagy, a fundamental mechanism for maintaining homeostasis, has been studied in the field of reproductive health. Accurate evaluation of autophagy activity is possible in cells and experimental animals, but it is difficult for fixed tissues, including human samples. In this review, we introduce some studies related to autophagy in this field and provide a tip for interpreting experimental results and understanding autophagy. Autophagy is a fundamental process involved in regulating cellular homeostasis. Autophagy has been classically discovered as a cellular process that degrades cytoplasmic components non-selectively to produce energy. Over the past few decades, this process has been shown to work in energy production, as well as in the reduction of excessive proteins, damaged organelles, and membrane trafficking. It contributes to many human diseases, such as neurodegenerative diseases, carcinogenesis, diabetes mellitus, development, longevity, and reproduction. In this review, we provide important information for interpreting results related to autophagic experiments and present the role of autophagy in this field. [ABSTRACT FROM AUTHOR]

Purpose: Multidrug resistance protein 1 (MDR1) is located at the interface between two syncytiotrophoblast layers in rodent placenta, and may influence fetal drug distribution. Here, we quantitatively compare the functional impact per single MDR1 molecule of MDR1 at the placental barrier and blood-brain barrier in mice. Methods: MDR1A and MDR1B proteins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Paclitaxel or digoxin was continuously administered to pregnant Mdr1a−/−/Mdr1b−/− or wild-type mice, and the drug concentrations in the maternal and fetal plasma and maternal brain were quantified by LC-MS/MS. Results: MDR1A and MDR1B proteins are expressed in the membrane of mouse placental labyrinth, and total MDR1 at the placental barrier amounts to about 30% of that at the blood-brain barrier. The fetal-to-maternal plasma concentration ratio of digoxin was only marginally affected in Mdr1a−/−/Mdr1b−/− mice, while that of paclitaxel showed a several-fold increase. No such difference between the two drugs was found in the maternal brain distribution. The impact per single MDR1 molecule on the fetal distribution of digoxin was calculated to be much lower than that on the brain distribution, but this was not the case for paclitaxel. Our pharmacokinetic model indicates that the impact of placental MDR1 is inversely correlated to the ratio of permeability through gap junctions connecting the two syncytiotrophoblast layers to passive diffusion permeability. Conclusion: Our findings indicate that murine placental MDR1 has a minimal influence on the fetal concentration of certain substrates, such as digoxin, due to bypass transfer, probably via connexin26 gap junctions. [ABSTRACT FROM AUTHOR]

During placentation, cytotrophoblasts differentiate and fuse to form multinucleated cells (syncytiotrophoblasts) in a process that involves autophagy. Appropriate syncytial differentiation is essential for establishing a healthy pregnancy. In this study, we evaluated the effect of two chloroquine compounds, hydroxychloroquine (HCQ) and chloroquine (CQ), on syncytial differentiation and autophagy in cultured primary human trophoblasts (PHTs). PHT cells were isolated from the human term placenta. Bafilomycin, a well-known autophagy inhibitor, was used as a positive control. Biochemical and morphological differentiation was assessed in syncytiotrophoblasts, and autophagy-related proteins and genes were evaluated. Affymetrix Human Gene 2.0 ST Array profiling was used to identify genes affected by HCQ during syncytial differentiation. Chloroquine compounds lowered the production of beta-human chorionic gonadotropin (β-hCG) and the fusion index in PHTs. Syncytial differentiation in PHT was associated with the increased expression of ATG4C mRNA (autophagy-related gene), and this expression was affected by CQ but not by HCQ. Microarray analysis revealed that HCQ or CQ affected several genes (MMP15, GPC3, CXCL10, TET-1, and S100A7) during syncytial differentiation, which were different from that of the syncytial differentiation suppression (Ham’s/Waymouth media) or autophagy inhibition (bafilomycin treatment). Using Kyoto Encyclopedia of Genes and Genomes analysis we identified that HCQ might affect JAK2 signaling in the syncytial differentiation of PHT. In conclusion, chloroquine compounds could mitigate biochemical and morphological syncytial trophoblast differentiation in cultured PHT cells through the JAK signaling pathway rather than the inhibition of autophagic activity.

Aim: Azithromycin (AZM) is widely used to treat mycoplasma infection in pregnancy. However, there is no adequate evaluation of its side effect on the placenta. In this study, using human placental syncytiotrophoblasts and a mouse model, we investigated whether AZM use in pregnancy might adversely affect placental function and pregnancy outcome. Results: Transcriptomic analysis of AZM-treated human placental syncytiotrophoblasts showed increased expression of endoplasmic reticulum (ER) stress-related genes and decreased expression of genes for hormone production and growth factor processing. Verification studies showed that AZM increased the abundance of ER stress mediators (phosphorylated eIF2α, activating transcription factor 4 [ATF4], and C/EBP Homologous Protein [CHOP]) and decreased the abundance of enzymes involved in progesterone and estradiol synthesis ( STS , CYP11A1 , and CYP19A1 ) and insulin-like growth factor binding protein (IGFBP) cleavage ( PAPPA and ADAM12 ) in human placental syncytiotrophoblasts. Inhibition of ER stress blocked AZM-induced decreases in the expression of CYP19A1, CYP11A1, PAPPA, and ADAM12, suggesting that the inhibition of AZM on those genes' expression was secondary to AZM-induced ER stress. Further mechanism study showed that increased ATF4 in ER stress might repressively interact with C/EBPα to suppress the expression of those genes, including CEBPA itself. Mouse studies showed that AZM administration decreased fetal weights along with increased ER stress mediators and decreased levels of insulin-like growth factor, estrogen, and progesterone in the maternal blood, which could be alleviated by inhibition of ER stress. Innovation and Conclusion: These findings first support the fact that AZM, often used during pregnancy, may affect fetal growth by inhibiting crucial enzymes for estrogen and progesterone synthesis and disrupting crucial proteases for IGFBP cleavage via inducing ER stress in placental syncytiotrophoblasts.

The placenta is the interface between mother and fetus in all eutherian species. However, our understanding of this essential organ remains incomplete. A substantial challenge has been the syncytial cells of the placenta, which have made dissociation and independent evaluation of the different cell types of this organ difficult. Here, we address questions concerning the ontogeny, specification, and function of the cell types of a representative hemochorial placenta by performing single nuclei RNA sequencing (snRNA-seq) at multiple stages of mouse embryonic development focusing on the exchange interface, the labyrinth. Timepoints extended from progenitor-driven expansion through terminal differentiation. Analysis by snRNA-seq identified transcript profiles and inferred functions, cell trajectories, signaling interactions, and transcriptional drivers of all but the most highly polyploid cell types of the placenta. These data profile placental development at an unprecedented resolution, provide insights into differentiation and function across time, and provide a resource for future study.

Since its emergence in Wuhan as a novel coronavirus disease, it has taken only a few months since January 2020 for it to be recognized as a widespread COVID‐19 pandemic which has contributed to global health devastation. As pointed out by health experts, it is a once in a century pandemic of our times. Clinical observations so far indicate that the older population and immune compromised individuals, particularly in African American and Hispanic/Latino communities, are at much higher risk for infection with this novel coronavirus. In this regard, pregnancy offers an altered immunity scenario which may allow severe COVID‐19 disease. The literature is so far highly conflicting on this issue. This review will offer a conceptual basis for severe or controlled disease and address trepidations for pregnant women associated with COVID‐19 pandemic, particularly in the comparative context of clinical consequences of other coronaviruses such as SARS and MERS. We will highlight the possible consequences of COVID‐19 on the general health of pregnant women as well as its possible effects at the maternal‐fetal interface. For the placenta‐related pathology, we will focus our discussion on the temporal expression of ACE2 throughout gestation for possible propagation of SARS‐CoV‐2 in the placenta in infected women and ensuing consequences. [ABSTRACT FROM AUTHOR]

Objective: Chorionic syncytiotrophoblasts (STB) function as an essential regulator of feto-maternal exchange. Therefore, STB actively differentiate to maintain their continuity for barrier function. However, the placental pathology reported in disorders such as pre-eclampsia (PE) threaten the homeostatic differentiation of STB. Since, HIV-1 requires the expression of co-receptors on STB to undergo vertical transmission, the aim of this study was to determine the effect of PE and HIV infection on the different stages of STB maturation [mature (H2A+) versus differentiating (H2A-)] and to immuno-localize and quantify the expression of histone 2A (H2A) i.e., positive (H2A+) and H2A negative (H2A-) nuclei within placental conducting and exchange villi. We also compared the expression of H2A + and H2A- nuclei between normotensive versus PE groups, HIV status and across the study population.Study Design: Placental tissue was obtained from pregnant normotensive (n = 30) and pre-eclamptic (n = 30) women after informed written consent. The study groups were further categorized by their HIV status. Immunohistochemistry using the anti-histone 2A (H2A) antibody to identify fully differentiated functional (mature) STB was performed using conventional techniques. Morphometric image analysis was utilized to quantify placental histone H2A immuno-expression in placental exchange and conducting villi. Statistical analysis was performed using GraphPad Prism software.Results: H2A + and H2A- nuclei were immuno-localized within STB of the exchange and conducting villi with H2A- nuclei prominent on the periphery. In the exchange villi, the immuno-expression of H2A + and H2A- nuclei were lower in the PE group compared to the normotensive group (p = 0.0003 and p < 0.0001 respectively). A reduced immuno-expression of H2A+ and H2A- nuclei was lower in exchange villi of HIV+ compared to HIV- placentae (p = 0.0002 and p = 0.0276 respectively).Conclusions: PE and HIV reduces the percentage of H2A + and H2A- immuno-expression indicative of mature STB and actively differentiating STB respectively. We speculate that the different maturation states of STB and their orientation resultant of PE pathogenesis may be protective against the process of HIV-1 vertical transmission. [ABSTRACT FROM AUTHOR]

Introduction: Hypertensive disorder in pregnancy (HDP) represents the most common medical complication in pregnancy. It is the leading cause of maternal and perinatal mortality and morbidity. Vascular endothelial growth factor (VEGF) stimulates vascular endothelial cell growth, survival, and proliferation, and they are known to be expressed in human placenta. The aim of this study was to determine the VEGF expression in the placenta of hypertensive and normotensive patients. Materials and Methods: This is a retrospective, cross-sectional study from January 1, 2015 to December 31, 2015. A total of 30 placentae comprised of 15 hypertensive and 15 normotensive cases were assessed. VEGF expression in placenta was assessed by immunohistochemistry, and the number of syncytial knots was counted. Results: Our study showed an increased syncytial knot formation in the placenta of hypertensive mothers. VEGF expression was seen in syncytiotrophoblasts of 14 of the hypertensive cases (14/15, 93.3%), while only two of the normotensive cases were positive (2/15, 13.3%). There were no statistically significant differences in VEGF expression in other placenta cells, that is, cytotrophoblasts (P = 1.0), decidual cells (0.1394), maternal endothelial cells (0.5977), and fetal endothelial cells (P = 1.0). Conclusions: This study showed an increased number of syncytial knots is a consistent histological finding in the placenta of patient with HDP. VEGF expression was significantly increased in syncytiotrophoblasts in placenta of hypertensive group, and it could be used as a biomarker for hypertension.

The early-stage placental barrier is characterized by a lack of fetal circulation and by a thick trophoblastic barrier, whereas the later-stage placenta consists of vascularized chorionic villi encased in a thin, differentiated trophoblast layer, ideal for nutrient transport. In this work, predictive models of early- and late-stage placental transport are created using blastocyst-derived placental stem cells (PSCs) by modulating PSC differentiation and model vascularization. PSC differentiation results in a thinner, fused trophoblast layer, as well as an increase in human chorionic gonadotropin secretion, barrier permeability, and secretion of certain inflammatory cytokines, which are consistent with in vivo findings. Further, gene expression confirms this shift toward a differentiated trophoblast subtype. Vascularization results in a molecule type- and size-dependent change in dextran and insulin permeability. These results demonstrate that trophoblast differentiation and vascularization have critical effects on placental barrier permeability and that this model can be used as a predictive measure to assess fetal toxicity of xenobiotic substances at different stages of pregnancy., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

The human placenta is at the interface between maternal and fetal circulations, and is crucial for fetal development. The nanoparticles of cerium dioxide (CeO2 NPs) from air pollution are an unevaluated risk during pregnancy. Assessing the consequences of placenta exposure to CeO2 NPs could contribute to a better understanding of NPs’ effect on the development and functions of the placenta and pregnancy outcome. We used primary villous cytotrophoblasts purified from term human placenta, with a wide range of CeO2 NPs concentrations (0.1–101 μg/cm2) and exposure time (24–72 h), to assess trophoblast uptake, toxicity and impact on trophoblast differentiation and endocrine function. We have shown the capacity of both cytotrophoblasts and syncytiotrophoblasts to internalize CeO2 NPs. CeO2 NPs affected trophoblast metabolic activity in a dose and time dependency, induced caspase activation and a LDH release in the absence of oxidative stress. CeO2 NPs decreased the fusion capacity of cytotrophoblasts to form a syncytiotrophoblast and disturbed secretion of the pregnancy hormones hCG, hPL, PlGF, P4 and E2, in accordance with NPs concentration. This is the first study on the impact of CeO2 NPs using human primary trophoblasts that decrypts their toxicity and impact on placental formation and functions.

A 19‐year‐old man suffering from testicular choriocarcinoma presented to the dermatology department with a cutaneous metastasis on his head. This metastasis was the first sign of disease that led to medical consultation. Histopathology revealed cytotrophoblasts and syncytiotrophoblasts, the later expressing human chorionic gonadotropin antigen. Whole body computed tomography showed multiple metastases of the brain, lung, liver, bone, paraaortic lymph nodes and left uvea; the primary was found in the left testicle. Despite neurosurgical intervention and chemotherapy the patient died 9 days after the biopsy of the cutaneous metastasis. Cutaneous metastases of testicular choriocarcinoma are exceptionally rare, with fewer than a dozen cases reported in the English‐language literature. The present case highlights that testicular choriocarcinoma metastatic to the skin should be included in the differential of cutaneous scalp tumors. [ABSTRACT FROM AUTHOR]

The placenta is an organ that secretes prostaglandin (PG) E2 into the fetal-placental circulation to regulate both vascular tone and remodeling of the fetal ductus arteriosus. Placental PGE2 synthesis might be mediated by microsomal PGE synthase-1 (mPGES-1), in addition to cyclooxygenase (COX) isoforms. Thus, the purpose of this study is to clarify the temporal and spatial expression patterns of mPGES-1, together with COX-1 and COX-2, in murine placenta. We found that mPGES-1 and COX-1 protein levels continuously increased in the placental labyrinth from gestational day (GD) 13.5 to GD19.5, becoming higher than in the decidua or the junctional zone by GD17.5. The PGE2 level at GD17.5 was also highest in the labyrinth. Immunofluorescence stainings for mPGES-1 and COX-1 in the labyrinth at GD17.5 overlapped and were located on the fetal side of the signals for connexin 26, which forms gap junctions between maternal-facing (SynT-I) and fetal-facing (SynT-II) syncytiotrophoblast layers, and on the maternal side of the signals for glucose transporter 1 on the basal plasma membrane of SynT-II. On the other hand, the signals for COX-2 did not overlap with those for mPGES-1. These results indicate that COX-1 and mPGES-1 are co-localized in murine placental SynT-II, facing the fetal-placental circulation. Therefore, SynT-II could contribute to placental synthesis of PGE2 for release into the fetal-placental circulation. [ABSTRACT FROM AUTHOR]

Choriocarcinoma is a tumor with poor prognosis which usually develops in the uterus and ovaries in females and testes in males. Choriocarcinomas primarily located in the urinary bladder occur extremely rare. In the radiological examination of the 28 year old male patient presented with cough, difficulty in breathing, dysuria and hematuria; lung lesions compatible with metastasis and a mass which was extending inside of the lumen in the anterior wall of the urinary bladder were determined. During the cystoscopic investigation, an incomplete transurethral resection was applied to the tumor. In the histopathological evaluation of the tumor tissue, cells compatible with syncytiotrophoblasts were observed among the polyhedral large mononuclear cells. While positive staining with pancytokeratin, cytokeratin 7, high molecular weight cytokeratin, human plasental lactogen, and human corionic gonadotrophin was observed in the tumor tissue, there was not any staining with epithelial membrane antigen, carcinoembryonic antigen, CD30, p63, and cytokeratin 20. Present histopathological and immunohistochemical findings were evaluated as compatible with coriocarcinoma. Because of being seen rarely, having poor prognosis, causing death due to metastasis, the necessity of holding in mind in the differential diagnosis of high grade urothelial carcinomas, it is purposed to present the case accompanied by literature information. [ABSTRACT FROM AUTHOR]

During placentation, cytotrophoblasts differentiate and fuse to form multinucleated cells (syncytiotrophoblasts) in a process that involves autophagy. Appropriate syncytial differentiation is essential for establishing a healthy pregnancy. In this study, we evaluated the effect of two chloroquine compounds, hydroxychloroquine (HCQ) and chloroquine (CQ), on syncytial differentiation and autophagy in cultured primary human trophoblasts (PHTs). PHT cells were isolated from the human term placenta. Bafilomycin, a well-known autophagy inhibitor, was used as a positive control. Biochemical and morphological differentiation was assessed in syncytiotrophoblasts, and autophagy-related proteins and genes were evaluated. Affymetrix Human Gene 2.0 ST Array profiling was used to identify genes affected by HCQ during syncytial differentiation. Chloroquine compounds lowered the production of beta-human chorionic gonadotropin (β-hCG) and the fusion index in PHTs. Syncytial differentiation in PHT was associated with the increased expression of ATG4C mRNA (autophagy-related gene), and this expression was affected by CQ but not by HCQ. Microarray analysis revealed that HCQ or CQ affected several genes (MMP15, GPC3, CXCL10, TET-1, and S100A7) during syncytial differentiation, which were different from that of the syncytial differentiation suppression (Ham's/Waymouth media) or autophagy inhibition (bafilomycin treatment). Using Kyoto Encyclopedia of Genes and Genomes analysis we identified that HCQ might affect JAK2 signaling in the syncytial differentiation of PHT. In conclusion, chloroquine compounds could mitigate biochemical and morphological syncytial trophoblast differentiation in cultured PHT cells through the JAK signaling pathway rather than the inhibition of autophagic activity. [Display omitted] • Chloroquine compounds mitigate syncytial trophoblast differentiation. • Effect of hydroxychloroquine and chloroquine on syncytialization was modest compared to bafilomycin or Ham's/Waymouth media. • Hydroxychloroquine can affect JAK2 signaling in relation to syncytial differentiation of PHTs. [ABSTRACT FROM AUTHOR]

Autophagy is a degradation process that acts in response to environmental stressors. Recently, autophagy has been detected in normal term, preeclamptic and intrauterine growth-restricted placentas. The object of this work was to investigate the presence of autophagy in first trimester voluntary interruption of pregnancy placental villi by the expression of autophagy-related proteins, light chain 3 (LC3), and Beclin-1. In first trimester placental villi laser scanning confocal microscopy (LSCM) analysis revealed LC3 and Beclin-1 immunoreactivity prevalently located in villous cytotrophoblasts. Using LSCM, LC3, and Beclin-1 were localized to the cytoplasm of the trophoblast layer in human full-term placentas. Beclin-1 expression and LC3 activation were confirmed by western blotting. These data emphasize that autophagy activation is different among cytotrophoblasts and syncytiotrophoblasts depending on the gestational age and thus we speculate that autophagy might play a prosurvival role throughout human pregnancy. [ABSTRACT FROM AUTHOR]

Background. There is complicated pathogeny involved in spontaneous abortion. At present, the focus of study is on the interface between mother and fetus, the trophoblasts. Indoleamine 2,3-dioxygenase (IDO) is the first and regulatory enzyme in the major route of l-tryptophan catabolism, which induces immunosuppression of T lymphocytes. In the present study we investigated the effect of Kidney-replenishing herb on the expression and activity of IDO in human syncytiotrophoblasts cultured in vitro and the balance of helper T cell (Th) cytokines. Methods. Syncytiotrophoblasts were cultured in vitro for 24, 48 or 72 h, with either control serum or serum made from Kidney-replenishing herb, without or with different concentrations of the IDO inhibitor 1-methyltryptophan (1-MT). Reverse transcription-polymerase chain reaction was applied to analyze the IDO mRNA transcription of syncytiotrophoblasts and Western blotting was applied to determine the expression of IDO protein in syncytiotrophoblasts. The concentration of interleukin-10 and interferon-γ in co-culture medium of syncytiotrophoblasts and decidual T lymphocytes was determined by enzyme-linked immunosorbent assay. High-performance liquid chromatography was used to determine the concentration of kynurenine (Kyn) and tryptophan (Tyr) in the co-culture medium, and the ratio of Kyn/Try was used to assess IDO activity. Results. IDO mRNA and protein were detected in human syncytiotrophoblasts cultured in vitro. The IDO inhibitor 1-MT caused the balance of Th cytokines to depart from type 2; when IDO activity was inhibited, Kidney-replenishing herb improved the expression of IDO mRNA and protein, promoted IDO activity and caused the balance of Th cytokines depart from type 1. Conclusion. Kidney-replenishing herb improves the expression of IDO mRNA and protein, promotes IDO activity to an appropriate value, resumes the balance of Th cytokines and regulates maternofetal tolerance. [ABSTRACT FROM AUTHOR]

Abstract: Objective: : To analyse in situ the placental expression of tumor necrosis factor-α (TNF-α), its receptors TNFRp55 and TNFRp75, and apoptosis in normotensive and preeclamptic pregnancies. Design and methods: : We simultaneously analyzed the immunostaining of TNF-α, its receptors and apoptosis in term placentas of 15 patients with preeclampsia and 15 normotensive pregnant women as controls. Results: : In normotensive villi TNF-α and TNFRp75 were expressed more in syncytiotrophoblasts than cytotrophoblasts or stromal cells, and were almost absent in endothelial cells. TNFRp55 was expressed uniformly in all types of placental cells. Apoptosis was more marked in syncytiotrophoblasts than cytotrophoblasts. In preeclamptic trophoblasts apoptosis was exaggerated whereas expression of TNF-α and its receptors remained unchanged. Conclusions: : Placental expression of TNF-α and TNFRp75 appear inter-adaptative and follow the same pattern, whereas TNFRp55 and TNF-α appear independent. In addition, the exaggerated apoptosis of preeclamptic trophoblasts may be dependent on factors other than the TNF-α system alone. [Copyright &y& Elsevier]

Syncytiotrophoblasts (SCTs) are directly bathed by maternal blood and, as such, are in direct contact with proinflammatory stimuli present in the maternal circulation. The extent and nature of cytokine responses induced in SCTs play a central role in the maintenance of pregnancy. Thrombin is a critical mediator of tissue factor-initiated blood coagulation. Thrombin has been more recently demonstrated to induce cytokine expression and inflammation in several cell types. To dissect the patterns of regulation of cytokine production in the placental villus, we compared the effects of thrombin and lipopolysaccharide (LPS) treatments on cytokine expression in SCTs and endothelial cells. For studies, primary cultures of cytotrophoblasts from human term placentas were differentiated to SCTs. We observed that the presence of thrombin only modestly enhanced interleukin-8 (IL-8) levels in SCTs in a manner that was not dose-dependent. Conversely, SCTs were exquisitely sensitive to LPS, the presence of which induced approximately a 10-fold increase in IL-8 levels with an EC50 ∼ 1 ng/mL. Northern blotting and real-time PCR results indicated that LPS (but not thrombin) treatment induced a >4-fold increase in levels of IL-8 mRNA. The addition of the anti-inflammatory steroid, dexamethasone, significantly reduced the LPS-mediated increase in levels of IL-8 in SCTs. Conversely, in human umbilical vein endothelial cells, thrombin and LPS treatments induced 10- and 20-fold increases in IL-8 expression, respectively. These results indicate that LPS, but not thrombin, promotes proinflammatory processes in SCTs, with cell-type specificity. The inability of thrombin in the intervillous space to evoke inflammatory responses in SCTs may constitute an important aspect of fetal survival. Conversely, our results suggest that SCTs do play a key role in infection-associated changes in placental cytokine expression. [ABSTRACT FROM AUTHOR]

Cytochrome c oxidase is a marker enzyme of the mitochondrial inner membrane. A change in the structure and activity of cytochrome c oxidase may alter the electron transport in the inner membrane, leading to insufficient adenosine triphosphate (ATP) production. ATP is essential for maintaining the function of cells. The aim of this study was to compare the expression of cytochrome c oxidase subunit I mRNA in placentas from normal and preeclamptic pregnancies. By means of in situ hybridization, frozen sections of placentas from 23 women with preeclampsia and 29 women with uneventful pregnancies were examined. Digoxigenin (DIG)-labeled probes were used to detect the expression of cytochrome c oxidase subunit I mRNA in the placentas. The expression density was assessed by using an image disposal and analysis system. Positive expression of cytochrome c oxidase subunit I mRNA was found in the cytoplasm of villous syncytiotrophoblasts. The mean light density of cytochrome c oxidase subunit I mRNA in placental villi of normal pregnant women was 0.2638, and 0.1763 in women with preeclampsia, a statistically significant difference ( P < 0.05). The number density of cytochrome c oxidase subunit I mRNA in placental villi was also significantly reduced in preeclamptic women compared with the control group ( P < 0.05). Our study demonstrates a reduced amount of cytochrome c oxidase subunit I mRNA in preeclamptic placentas compared to control placentas. We hypothesize that a reduced expression may play a role in the pathophysiology of preeclampsia. [ABSTRACT FROM AUTHOR]

During pregnancy, the calcium (Ca2+) transport machinery of the placenta is solely responsible for the nutrient supply to the developing fetus, where active Ca2+ transport occurs from the mother to the fetus. As part of a larger study to determine the role of Ca2+ in placental transport in vivo, we questioned whether calbindin-D9k (CaBP9k), which is mainly expressed in duodenum, uterus, and placenta of several mammals, is present in cytotrophoblast cells and syncytiotrophoblasts of human term placenta. We were interested in this protein because of its potential importance in serving as an indicator of Ca2+ availability and utilization in the placenta. Here, we demonstrated that CaBP9k transcript is present in both cell types, with a lower expression in cytotrophoblast cells as compared to syncytiotrophoblasts. Moreover, we showed by immunochemistry that CaBP9k protein was present in cytotrophoblast and syncytiotrophoblast placental tissue sections as well as in cultured cells. The occurrence of CaBP9k protein in trophoblast cells was further confirmed by Western blot analysis. Thus, these results indicate for the first time that CaBP9k is unequivocally expressed by trophoblast cells from human term placenta. [ABSTRACT FROM AUTHOR]

During gestation, transport by the placenta is solely responsible for nutrient supply to the developing fetus. In this context, calcium (Ca) transport machinery of the placenta thus represents the primary tissue site for regulating fetal Ca homeostasis. In humans, the transplacental movements of Ca increase dramatically during the last trimester of gestation, when fetal skeletal mineralization is at its highest. However, little is known about the exact mechanism of transport. Evidence suggests that some developmentally expressed cytosolic Ca-binding proteins (CaBPs) have an important role in regulating or shuttling cytosolic Ca since they are endowed with a high affinity for Ca (∼10 M). CaBPs belong to a large family of eukaryotic proteins containing a specific helix-loop-helix structure, referred to as the EF-hand motif, which counts more than 200 members. Several of these CaBPs were identified in the placenta: CaBP9k, CaBP28k, CaBP57k, oncomodulin, S-100P, S-100α, and S-100β. This review discusses the current views in this field to guide future investigations into the localization and functions of CaBPs during Ca intracellular homeostasis in the placenta. [ABSTRACT FROM AUTHOR]

The human placenta is at the interface between maternal and fetal circulations, and is crucial for fetal development. The nanoparticles of cerium dioxide (CeO2 NPs) from air pollution are an unevaluated risk during pregnancy. Assessing the consequences of placenta exposure to CeO2 NPs could contribute to a better understanding of NPs' effect on the development and functions of the placenta and pregnancy outcome. We used primary villous cytotrophoblasts purified from term human placenta, with a wide range of CeO2 NPs concentrations (0.1–101 μg/cm2) and exposure time (24–72 h), to assess trophoblast uptake, toxicity and impact on trophoblast differentiation and endocrine function. We have shown the capacity of both cytotrophoblasts and syncytiotrophoblasts to internalize CeO2 NPs. CeO2 NPs affected trophoblast metabolic activity in a dose and time dependency, induced caspase activation and a LDH release in the absence of oxidative stress. CeO2 NPs decreased the fusion capacity of cytotrophoblasts to form a syncytiotrophoblast and disturbed secretion of the pregnancy hormones hCG, hPL, PlGF, P4 and E2, in accordance with NPs concentration. This is the first study on the impact of CeO2 NPs using human primary trophoblasts that decrypts their toxicity and impact on placental formation and functions. [ABSTRACT FROM AUTHOR]

The placenta is the interface between mother and fetus in all eutherian species. However, our understanding of this essential organ remains incomplete. A substantial challenge has been the syncytial cells of the placenta, which have made dissociation and independent evaluation of the different cell types of this organ difficult. Here, we address questions concerning the ontogeny, specification, and function of the cell types of a representative hemochorial placenta by performing single nuclei RNA sequencing (snRNA-seq) at multiple stages of mouse embryonic development focusing on the exchange interface, the labyrinth. Timepoints extended from progenitor-driven expansion through terminal differentiation. Analysis by snRNA-seq identified transcript profiles and inferred functions, cell trajectories, signaling interactions, and transcriptional drivers of all but the most highly polyploid cell types of the placenta. These data profile placental development at an unprecedented resolution, provide insights into differentiation and function across time, and provide a resource for future study., Competing Interests: BM, RB No competing interests declared, (© 2020, Marsh and Blelloch.)

Congenital human cytomegalovirus (HCMV) infection is a major viral cause of birth defects, including microcephaly, neurological deficits, loss of hearing and vision, and intrauterine growth restriction. Despite its public health significance, there is no approved treatment for congenital infection during pregnancy; existing antivirals have unacceptable toxicities. The mechanisms of HCMV-induced placental injury, reduced capacity for compensatory development and transmission to the fetus are poorly understood, limiting the development of alternative strategies for clinical management of the disease. Recently, self-renewing, multipotent trophoblast progenitor cells (TBPCs) were reported to reside in the chorion of the human placenta and differentiate into the mature trophoblast subtypes - transport syncytiotrophoblasts and invasive cytotrophoblasts - forming chorionic villi, the functional units of the placenta. HCMV infects TBPCs, reducing the population of progenitor cells and their functional capacity to self-renew, migrate and differentiate. Human TBPCs and chorionic villus explants from first trimester represent relevant models for evaluating efficacies of new antiviral agents in protecting and restoring growth of the developing placenta in response to adverse conditions. Correlating pathology from complications of congenital HCMV infection with impaired development in the tissue environment of anchoring villus explants and defects in TBPC differentiation may enable identification of molecular pathways that could serve as targets for intervention. Here we summarize studies that could open up novel avenues of research on potential therapeutics to sustain placental development, promote differentiation and improve function and pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Fluorouracil is used for treatment of breast cancer even in pregnant women, except during fetal organogenesis. The purpose of this study was to clarify the transport mechanism of fluorouracil at the rat placental barrier. Maternal-to-fetal transfer of [ 3 H]fluorouracil in rats at gestational day 19.5 was saturable and much higher than that of [ 14 C]sucrose. The uptake of [ 3 H]fluorouracil was also saturable in rat placental trophoblast TR-TBT 18d-1 cells, which express both equilibrative nucleoside transporter (ENT) 1 and ENT2. Nitrobenzylthioinosine (NBMPR) at 0.1 μM had no effect on [ 3 H]fluorouracil uptake by TR-TBT 18d-1 cells, but 100 μM NBMPR almost completely inhibited the saturable component, suggesting involvement of ENT2, rather than ENT1 in the transport. Rat ENT2 cRNA-injected oocytes showed significantly increased [ 3 H]fluorouracil uptake compared with water-injected oocytes, while rat ENT1 cRNA-injected oocytes did not show an increase of [ 3 H]fluorouracil uptake. The Michaelis-Menten constant for rat ENT2-mediated uptake of [ 3 H]fluorouracil was 4.21 mM. The expression profile of ENT2 mRNA in rat placenta during pregnancy was almost constant from 13.5 to 21.5 days of gestation. In conclusion, ENT2 appears to be the mediator of fluorouracil transport in rat placental trophoblast cells., (Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Objective: Antibody-mediated disruption of the annexin A5 anticoagulant shield has been posited to be a thrombogenic mechanism in the antiphospholipid syndrome. We recently showed that the antimalarial drug, hydroxychloroquine, dissociates antiphospholipid immune complexes and restores annexin A5 binding to planar phospholipid bilayer. Using quantitative immunoassays, we demonstrated similar effects on BeWo trophoblasts. We therefore, investigated the effects of the drug on localization of annexin A5 in primary cultures of human placental syncytiotrophoblasts. Study Design: Laser confocal microscopy with computer-based morphometric analysis was used to localize annexin A5 and antiphospholipid antibodies on syncytiotrophoblasts exposed to polyclonal and monoclonal antiphospholipid and control immunoglobulin-Gs. Results: Hydroxychloroquine reversed the effects of the antiphospholipid antibodies on the syncytiotrophoblasts by markedly reducing immunoglobulin-G binding and restoring annexin A5 expression. Conclusion: These results provide the first morphologic evidence for this effect of hydroxychloroquine on human placental syncytiotrophoblasts and support the possibility of novel treatments that target antiphospholipid antibody binding. [ABSTRACT FROM AUTHOR]