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1.
J Cell Sci ; 135(5)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33414166

RESUMO

Ferroptosis is a regulated, non-apoptotic form of cell death, characterized by hydroxy-peroxidation of discrete phospholipid hydroperoxides, particularly hydroperoxyl (Hp) forms of arachidonoyl- and adrenoyl-phosphatidylethanolamine, with a downstream cascade of oxidative damage to membrane lipids, proteins and DNA, culminating in cell death. We recently showed that human trophoblasts are particularly sensitive to ferroptosis caused by depletion or inhibition of glutathione peroxidase 4 (GPX4) or the lipase PLA2G6. Here, we show that trophoblastic ferroptosis is accompanied by a dramatic change in the trophoblast plasma membrane, with macro-blebbing and vesiculation. Immunofluorescence revealed that ferroptotic cell-derived blebs stained positive for F-actin, but negative for cytoplasmic organelle markers. Transfer of conditioned medium that contained detached macrovesicles or co-culture of wild-type target cells with blebbing cells did not stimulate ferroptosis in target cells. Molecular modeling showed that the presence of Hp-phosphatidylethanolamine in the cell membrane promoted its cell ability to be stretched. Together, our data establish that membrane macro-blebbing is characteristic of trophoblast ferroptosis and can serve as a useful marker of this process. Whether or not these blebs are physiologically functional remains to be established.


Assuntos
Ferroptose , Feminino , Humanos , Peroxidação de Lipídeos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Placenta , Gravidez , Trofoblastos
2.
Biomater Sci ; 9(21): 7247-7256, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34608901

RESUMO

The placental syncytiotrophoblast is a multinucleated layer that regulates transport between the mother and fetus. Fusion of trophoblasts is essential to form this layer, but this process can be disrupted in pregnancy-related disorders such as preeclampsia. Disease progression is also associated with changes in the extracellular matrix (ECM), but whether disease-specific ECM compositions play any causal role in establishing syncytiotrophoblast disease phenotypes remains unknown. Here, we develop a decellularization-based platform to isolate and characterize the role of human placental ECM composition on cell function, while controlling for the confounding effects of matrix structure and mechanics that can arise in conventional tissue decellularization/recellularization experiments. Using this approach, we demonstrate that ECM compositional changes that occur in preeclampsia have a statistically significant effect on adhesion, spreading, and fusion of placental trophoblasts. Proteomic analysis of ECM content then allowed us to identify and recreate selected differences in matrix composition; indicating that replacement of normally present Type IV Collagen by Type I Collagen in preeclampsia significantly affects fusion efficiency. These results indicate that disease-specific matrix compositions can play an important role in trophoblast fusion, suggesting novel matrix-targeting therapeutic strategies for pregnancy-related disorders. More broadly, this work demonstrates the utility of a decellularization-based approach in understanding the functional contributions of matrix composition in driving cellular disease phenotypes.


Assuntos
Placenta , Trofoblastos , Colágeno Tipo I , Matriz Extracelular , Feminino , Humanos , Gravidez , Proteômica
3.
Diagn Pathol ; 16(1): 88, 2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34602071

RESUMO

INTRODUCTION: COVID-19, the disease caused by the novel coronavirus SARS-CoV-2, is a severe systemic thrombotic syndrome that emerged in 2019, with an ensuing pandemic. To evaluate the impact of this disease on placental tissue and perinatal outcome, histological, immunohistochemical and ultrastructural analyses of placental tissue were performed for five cases of pregnant women with COVID-19. CASE REPORTS: All five pregnant women in this series developed COVID-19 in late pregnancy. Two patients experienced respiratory distress, and computed tomography revealed signs of pneumonia, with bilateral involvement, multiple lobular and subsegmental areas of consolidation and ground-glass opacities. Histological studies of placental tissue revealed the presence of slight signs of maternal vascular underperfusion (MVUs) or foetal vascular underperfusion (FVUs) lesions and mild inflammatory lesions. CD15 immunoreactivity in the placental tissue was low in all cases, demonstrating that in these cases there was not severe foetal hypoxia/asphyxia risk for newborns or distal vascular immaturity. In all cases examined, ultrastructural analyses showed spherical-like coronavirus particles with an electron intermediate-density core as well as projections from the surface as spike-like structures in the syncytiotrophoblasts. At term, all of the women delivered newborns who were negative for SARS-CoV-2 by nasopharyngeal testing in their first day of life. All newborns were exclusively breastfed and were discharged on the 3rd day of life. CONCLUSIONS: In conclusion, placental patterns in pregnancy due to COVID-19 in the late stage of gestation indicate no evidence of vertical trans-placental SARS-CoV-2 transmission or a significant impact on the perinatal outcome of newborns, in both mild and more severe cases.


Assuntos
COVID-19/diagnóstico por imagem , Transmissão Vertical de Doenças Infecciosas , Pandemias , Complicações Infecciosas na Gravidez , SARS-CoV-2/fisiologia , Adulto , COVID-19/epidemiologia , COVID-19/patologia , COVID-19/virologia , Feminino , Humanos , Recém-Nascido , Placenta/diagnóstico por imagem , Placenta/patologia , Placenta/virologia , Gravidez , Resultado da Gravidez , Tomografia Computadorizada por Raios X , Trofoblastos/patologia , Trofoblastos/virologia
4.
Int J Mol Sci ; 22(19)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34639070

RESUMO

Upon activation, maternal platelets provide a source of proinflammatory mediators in the intervillous space of the placenta. Therefore, platelet-derived factors may interfere with different trophoblast subtypes of the developing human placenta and might cause altered hormone secretion and placental dysfunction later on in pregnancy. Increased platelet activation, and the subsequent occurrence of placental fibrinoid deposition, are linked to placenta pathologies such as preeclampsia. The composition and release of platelet-derived factors change over gestation and provide a potential source of predicting biomarkers for the developing fetus and the mother. This review indicates possible mechanisms of platelet-trophoblast interactions and discusses the effect of increased platelet activation on placenta development.


Assuntos
Plaquetas/metabolismo , Comunicação Celular , Placenta/fisiologia , Trofoblastos/metabolismo , Animais , Biomarcadores , Suscetibilidade a Doenças , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Humanos , Troca Materno-Fetal/fisiologia , Ativação Plaquetária/fisiologia , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/metabolismo
5.
Int J Mol Sci ; 22(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34638542

RESUMO

Preeclampsia is a pregnancy disorder associated with shallow placentation, forcing placental cells to live in hypoxic conditions. This activates the transcription factor kappa B (NFκB) in maternal and placental cells. Although the role of NFκB in preeclampsia is well documented, its mechanism of activation in trophoblastic cells has been never studied. This study investigates the mechanism of NFκB activation in a first trimester trophoblastic cell line (HTR8/SVneo) stimulated by a medium containing serum from preeclamptic (PE) or normotensive (C) women in hypoxic (2% O2) or normoxic (8% O2) conditions. The results indicate that in HTR8/SVneo cells, the most widely studied NFκB pathways, i.e., canonical, non-canonical and atypical, are downregulated in environment PE 2% O2 in comparison to C 8% O2. Therefore, other pathways may be responsible for NFκB activation. One such pathway depends on the activation of NFκB by the p53/RSK1 complex through its phosphorylation at Serine 536 (pNFκB Ser536). The data generated by our study show that inhibition of the p53/RSK1 pathway by p53-targeted siRNA results in a depletion of pNFκB Ser536 in the nucleus, but only in cells incubated with PE serum at 2% O2. Thus, the p53/RSK1 complex might play a critical role in the activation of NFκB in trophoblastic cells and preeclamptic placentas.


Assuntos
NF-kappa B/metabolismo , Pré-Eclâmpsia/patologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Trofoblastos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Hipóxia Celular/fisiologia , Linhagem Celular , Ativação Enzimática/genética , Feminino , Humanos , Placenta/patologia , Gravidez , Interferência de RNA , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/genética
6.
Int J Mol Sci ; 22(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34639216

RESUMO

In the placenta the proliferative cytotrophoblast cells fuse into the terminally differentiated syncytiotrophoblast layer which undertakes several energy-intensive functions including nutrient uptake and transfer and hormone synthesis. We used Seahorse glycolytic and mitochondrial stress tests on trophoblast cells isolated at term from women of healthy weight to evaluate if cytotrophoblast (CT) and syncytiotrophoblast (ST) have different bioenergetic strategies, given their different functions. Whereas there are no differences in basal glycolysis, CT have significantly greater glycolytic capacity and reserve than ST. In contrast, ST have significantly higher basal, ATP-coupled and maximal mitochondrial respiration and spare capacity than CT. Consequently, under stress conditions CT can increase energy generation via its higher glycolytic capacity whereas ST can use its higher and more efficient mitochondrial respiration capacity. We have previously shown that with adverse in utero conditions of diabetes and obesity trophoblast respiration is sexually dimorphic. We found no differences in glycolytic parameters between sexes and no difference in mitochondrial respiration parameters other than increases seen upon syncytialization appear to be greater in females. There were differences in metabolic flexibility, i.e., the ability to use glucose, glutamine, or fatty acids, seen upon syncytialization between the sexes with increased flexibility in female trophoblast suggesting a better ability to adapt to changes in nutrient supply.


Assuntos
Feto/fisiologia , Glicólise , Mitocôndrias/fisiologia , Placenta/fisiologia , Caracteres Sexuais , Trofoblastos/fisiologia , Adulto , Respiração Celular , Feminino , Feto/citologia , Humanos , Técnicas In Vitro , Masculino , Placenta/citologia , Gravidez , Trofoblastos/citologia
7.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638599

RESUMO

Proper placental development relies on tightly regulated trophoblast differentiation and interaction with maternal cells. Human endogenous retroviruses (HERVs) play an integral role in modulating cell fusion events in the trophoblast cells of the developing placenta. Syncytin-1 (ERVW-1) and its receptor, solute-linked carrier family A member 5 (SLC1A5/ASCT2), promote fusion of cytotrophoblast (CTB) cells to generate the multi-nucleated syncytiotrophoblast (STB) layer which is in direct contact with maternal blood. Another HERV-derived protein known as Suppressyn (ERVH48-1/SUPYN) is implicated in anti-fusogenic events as it shares the common receptor with ERVW-1. Here, we explore primary tissue and publicly available datasets to determine the distribution of ERVW-1, ERVH48-1 and SLC1A5 expression at the maternal-fetal interface. While SLC1A5 is broadly expressed in placental and decidual cell types, ERVW-1 and ERVH48-1 are confined to trophoblast cell types. ERVH48-1 displays higher expression levels in CTB and extravillous trophoblast, than in STB, while ERVW-1 is generally highest in STB. We have demonstrated through gene targeting studies that suppressyn has the ability to prevent ERVW-1-induced fusion events in co-culture models of trophoblast cell/maternal endometrial cell interactions. These findings suggest that differential HERV expression is vital to control fusion and anti-fusogenic events in the placenta and consequently, any imbalance or dysregulation in HERV expression may contribute to adverse pregnancy outcomes.


Assuntos
Retrovirus Endógenos/metabolismo , Produtos do Gene env/metabolismo , Proteínas da Gravidez/metabolismo , Comunicação Celular/fisiologia , Diferenciação Celular/fisiologia , Fusão Celular/métodos , Linhagem Celular Tumoral , Decídua/metabolismo , Feminino , Humanos , Antígenos de Histocompatibilidade Menor/metabolismo , Placenta/metabolismo , Gravidez , Trofoblastos/metabolismo
8.
J Immunol ; 207(10): 2433-2444, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34663619

RESUMO

Throughout gestation, the maternal immune system is tightly modulated to allow growth of a semiallogeneic fetus. During the third trimester, the maternal immune system shifts to a proinflammatory phenotype in preparation for labor. What induces this shift remains unclear. Cell-free fetal DNA (cffDNA) is shed by the placenta and enters maternal circulation throughout pregnancy. Levels of cffDNA are increased as gestation progresses and peak before labor, coinciding with a shift to proinflammatory maternal immunity. Furthermore, cffDNA is abnormally elevated in plasma from women with complications of pregnancy, including preterm labor. Given the changes in maternal immunity at the end of pregnancy and the role of sterile inflammation in the pathophysiology of spontaneous preterm birth, we hypothesized that cffDNA can act as a damage-associated molecular pattern inducing an inflammatory cytokine response that promotes hallmarks of parturition. To test this hypothesis, we stimulated human maternal leukocytes with cffDNA from primary term cytotrophoblasts or maternal plasma and observed significant IL-1ß and CXCL10 secretion, which coincides with phosphorylation of IFN regulatory factor 3 and caspase-1 cleavage. We then show that human maternal monocytes are crucial for the immune response to cffDNA and can activate bystander T cells to secrete proinflammatory IFN-γ and granzyme B. Lastly, we find that the monocyte response to cffDNA leads to vascular endothelium activation, induction of myometrial contractility, and PGE2 release in vitro. Our results suggest that the immune response to cffDNA can promote key features of the parturition cascade, which has physiologic consequences relevant to the timing of labor.


Assuntos
Ácidos Nucleicos Livres/imunologia , Feto/imunologia , Monócitos/imunologia , Parto/imunologia , Trofoblastos/imunologia , Feminino , Humanos , Gravidez
9.
Phytomedicine ; 93: 153773, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34649213

RESUMO

BACKGROUND: Preeclampsia (PE) is a severe hypertension-related disorder occurring during pregnancy that leads to significant mortality and morbidity in both the foetus and mother. Atractylenolide (ATL), a traditional Chinese natural agent isolated from the herb Atractylodes macrocephala, exhibits a series of pharmacological activities, including anti-oxidative stress and anti-inflammatory effects. PURPOSE: The impacts of ATL on apoptosis and oxidative stress in HTR-8/SVneo cells during PE development was investigated. STUDY DESIGN: We identified ATL by an overlap analysis of the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database using the keyword 'gestational hypertension' and Traditional Chinese Medicine (Batman-TCM) database using the keyword 'Atractylodes macrocephala'. METHODS: Cell viability, proliferation, and migration were detected by CCK-8, EdU, and transwell assays. Flow cytometry and 2',7'-dichlorodihydrofluorescein diacetate were used to assess apoptosis and reactive oxygen species (ROS) levels. RESULTS: EdU and CCK-8 assays demonstrated that ATL significantly enhanced the viability of HTR-8/SVneo cells. Transwell assays showed that ATL remarkably induced the migration of HTR-8/SVneo cells. Moreover, ROS production in HTR-8/SVneo cells was induced by H2O2, whilst ATL alleviated this H2O2-induced ROS production and apoptosis in cells. CONCLUSION: ATL attenuated apoptosis and oxidative stress in HTR-8/SVneo cells in PE by activating the MAPK/ERK signalling pathway. ATL has potential to be utilized as a potential therapeutic candidate for PE.


Assuntos
Pré-Eclâmpsia , Apoptose , Movimento Celular , Feminino , Humanos , Peróxido de Hidrogênio/metabolismo , Estresse Oxidativo , Pré-Eclâmpsia/metabolismo , Gravidez , Trofoblastos/metabolismo
10.
Cell Mol Life Sci ; 78(21-22): 6995-7008, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34608506

RESUMO

Preeclampsia is a hypertensive disorder of pregnancy. Many studies have shown that epigenetic mechanisms may play a role in preeclampsia. Moreover, our previous study indicated that the differentially methylated genes in preeclampsia were enriched in the Wnt/ß-catenin signaling pathway. This study aimed to identify differentially methylated Wnt/ß-catenin signaling pathway genes in the preeclamptic placenta and to study the roles of these genes in trophoblast cells in vitro. Using an Illumina Infinium HumanMethylation 850 K BeadChip, we found that the Wnt signaling pathway was globally hypermethylated in the preeclamptic group compared with the term birth group, but hypomethylated in the preeclamptic group compared with the preterm birth group. Among all Wnt/ß-catenin signaling pathway factors, WNT3 was the most significantly differentially expressed gene and was hypomethylated in the preeclamptic group compared to the nonhypertensive groups, namely, the preterm birth group and term birth group. This result was confirmed by pyrosequencing. Through quantitative real-time PCR and western blot analysis, the WNT3 gene was found to be highly expressed in preeclamptic placental tissues, in contrast to other WNT factors, which were previously reported to be expressed at low levels in placental tissues. Additionally, in the HTR8/SVneo cell line, knockdown of WNT3 suppressed the Wnt/ß-catenin signaling pathway, consistent with the findings for other WNT factors. These results prompted us to speculate that the WNT3 gene counteracts the low activation state of the Wnt signaling pathway in the preeclamptic placenta through methylation modification.


Assuntos
Metilação de DNA/fisiologia , Placenta/fisiologia , Pré-Eclâmpsia/genética , Via de Sinalização Wnt/genética , Proteína Wnt3/genética , Adulto , Epigênese Genética/genética , Feminino , Humanos , Masculino , Gravidez , Nascimento Prematuro/genética , Nascimento a Termo/genética , Trofoblastos/fisiologia , beta Catenina/genética
11.
Int J Legal Med ; 135(6): 2357-2361, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34596774

RESUMO

Pulmonary embolism is a major cause of maternal morbidity during pregnancy. Beside the frequently encountered thromboembolism, trophoblastic cell embolism has also been reported in a few case reports. This phenomenon may be symptomless in physiological gestational process but is more pronounced in contexts of preeclampsia or gestational trophoblastic disease. It was exceptionally reported to be associated with death. Here, we report the case of a 15-year-old girl, who experienced dyspnea followed by cardiac arrests and disseminated intravascular coagulation. Echocardiography showed a massive proximal pulmonary embolism. Abdominal sonography revealed that she was 11 weeks pregnant. Autopsy confirmed the presence of multiple clot emboli in the proximal pulmonary arteries. Additionally, the histopathological examination showed a massive syncytiotrophoblastic embolism in the lung microcirculation. Microscopic examination of the uterus revealed an exaggerated placental site reaction. In conclusion, this exhaustive post-mortem study describes a previously unreported association between exaggerated placental site reaction and pulmonary trophoblastic embolism, with fatal issue. Forensic pathologists should be aware that a large sampling of the lungs and uterus and examination of both placenta and fetus are needed to achieve this diagnosis. This case study emphasizes the need for further work elucidating pathways of trophoblast deportation.


Assuntos
Placenta/fisiopatologia , Complicações Cardiovasculares na Gravidez , Artéria Pulmonar/patologia , Embolia Pulmonar/complicações , Tromboembolia/complicações , Trofoblastos/patologia , Adolescente , Autopsia , Evolução Fatal , Feminino , Humanos , Gravidez
12.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638993

RESUMO

Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality worldwide. Defects in trophoblast invasion, differentiation of extravillous trophoblasts and spiral artery remodeling are key factors in PE development. Currently there are no predictive biomarkers clinically available for PE. Recent technological advancements empowered transcriptome exploration and led to the discovery of numerous non-coding RNA species of which microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most investigated. They are implicated in the regulation of numerous cellular functions, and as such are being extensively explored as potential biomarkers for various diseases. Altered expression of numerous lncRNAs and miRNAs in placenta has been related to pathophysiological processes that occur in preeclampsia. In the following text we offer summary of the latest knowledge of the molecular mechanism by which lnRNAs and miRNAs (focusing on the chromosome 19 miRNA cluster (C19MC)) contribute to pathophysiology of PE development and their potential utility as biomarkers of PE, with special focus on sample selection and techniques for the quantification of lncRNAs and miRNAs in maternal circulation.


Assuntos
MicroRNA Circulante/sangue , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , RNA Longo não Codificante/sangue , Biomarcadores/sangue , Diferenciação Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 19/metabolismo , MicroRNA Circulante/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Gravidez , RNA Longo não Codificante/genética , Transcriptoma , Trofoblastos/metabolismo
13.
Biol Res ; 54(1): 30, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34517910

RESUMO

OBJECTIVE: This study aims to identify the effect of miR-146a-5p on trophoblast cell invasion as well as the mechanism in preeclampsia (PE). METHODS: Expression levels of miR-146a-5p and Wnt2 in preeclamptic and normal placentae were quantified. Trophoblast cells (HTR-8) were separately transfected with miR-146a-5p mimic, miR-146a-5p inhibitor, pcDNA3.1-Wnt2 or sh-Wnt2, and then the expression levels of miR-146a-5p, Wnt2, and epithelial-mesenchymal transition (EMT)-related proteins (Vimentin, N-cadherin and E-cadherin) were measured. Moreover, the proliferative, migratory and invasive capacities of trophoblast cells were detected, respectively. Dual luciferase reporter assay determined the binding of miR-146a-5p and Wnt2. RESULTS: Compared with normal placental tissues, the placentae from PE patients showed higher miR-146a-5p expression and lower Wnt2 expression. Transfection of miR-146a-5p inhibitor or pcDNA3.1-Wnt2 exerted pro-migratory and pro-invasive effects on HTR-8 cells and encouraged EMT in HTR-8 cells; transfection with miR-146a-5p mimic or sh-Wnt2 weakened the proliferative, migratory and invasive capacities as well as reduced EMT process of HTR-8 cells. Moreover, Wnt2 overexpression could partially counteract the suppressive effects of miR-146a-5p overexpression on the progression and EMT of HTR-8 cells. CONCLUSION: miR-146a-5p mediates trophoblast cell proliferation and invasion through regulating Wnt2 expression.


Assuntos
Transição Epitelial-Mesenquimal , MicroRNAs , Pré-Eclâmpsia , Trofoblastos/citologia , Movimento Celular , Proliferação de Células , Feminino , Humanos , MicroRNAs/genética , Placenta , Gravidez
14.
Int J Mol Sci ; 22(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34576036

RESUMO

Procoagulant extracellular vesicles (EV) and platelet activation have been associated with gestational vascular complications. EV-induced platelet-mediated placental inflammasome activation has been shown to cause preeclampsia-like symptoms in mice. However, the effect of EV-mediated placental thrombo-inflammation on trophoblast differentiation remains unknown. Here, we identify that the EV-induced thrombo-inflammatory pathway modulates trophoblast morphology and differentiation. EVs and platelets reduce syncytiotrophoblast differentiation while increasing giant trophoblast and spongiotrophoblast including the glycogen-rich cells. These effects are platelet-dependent and mediated by the NLRP3 inflammasome. In humans, inflammasome activation was negatively correlated with trophoblast differentiation marker GCM1 and positively correlated with blood pressure. These data identify a crucial role of EV-induced placental thrombo-inflammation on altering trophoblast differentiation and suggest platelet activation or inflammasome activation as a therapeutic target in order to achieve successful placentation.


Assuntos
Vesículas Extracelulares/genética , Inflamação/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Complicações Cardiovasculares na Gravidez/genética , Animais , Plaquetas/metabolismo , Plaquetas/patologia , Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Inflamassomos/genética , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Ativação Plaquetária/genética , Gravidez , Complicações Cardiovasculares na Gravidez/patologia , Fatores de Transcrição/genética , Trofoblastos/metabolismo , Trofoblastos/patologia
15.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502044

RESUMO

Implantation consists of a complex process based on coordinated crosstalk between the endometrium and trophoblast. Furthermore, it is known that the microenvironment of this fetal-maternal interface plays an important role in the development of extravillous trophoblast cells. This is mainly due to the fact that tissues mediate embryonic signaling biologicals, among other molecules, prostaglandins. Prostaglandins influence tissue through several cell processes including differentiation, proliferation, and promotion of maternal immune tolerance. The aim of this study is to investigate the potential pathological mechanism of the prostaglandin E2 receptor 4 (EP4) in modulating extravillous trophoblast cells (EVTs) in unexplained recurrent marriage (uRM). Our results indicated that the expression of EP4 in EVTs was decreased in women experiencing uRM. Furthermore, silencing of EP4 showed an inhibition of the proliferation and induced apoptosis in vitro. In addition, our results demonstrated reductions in ß- human chorionic gonadotropin (hCG), progesterone, and interleukin (IL)-6, which is likely a result from the activation of the cyclic adenosine monophosphate (cAMP)- cAMP-dependent protein kinase A (PKA)-phosphorylating CREB (pCREB) pathway. Our data might provide insight into the mechanisms of EP4 linked to trophoblast function. These findings help build a more comprehensive understanding of the effects of EP4 on the trophoblast at the fetal-maternal interface in the first trimester of pregnancy.


Assuntos
Aborto Habitual/metabolismo , AMP Cíclico/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Transdução de Sinais , Trofoblastos/metabolismo , Aborto Habitual/patologia , Adulto , Apoptose , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Gonadotropinas/metabolismo , Humanos , Interleucina-6/metabolismo , Pessoa de Meia-Idade , Gravidez , Progesterona/metabolismo
16.
Cells ; 10(9)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34571867

RESUMO

Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (ß-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Trofoblastos/metabolismo , Adulto , Gonadotropina Coriônica/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Feminino , Expressão Gênica/fisiologia , Humanos , Placentação/fisiologia , Gravidez , Primeiro Trimestre da Gravidez/metabolismo
17.
Int J Mol Sci ; 22(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34575844

RESUMO

Oxygen levels in the placental microenvironment throughout gestation are not constant, with severe hypoxic conditions present during the first trimester. This hypoxic phase overlaps with the most critical stages of placental development, i.e., blastocyst implantation, cytotrophoblast invasion, and spiral artery remodeling initiation. Dysregulation of any of these steps in early gestation can result in pregnancy loss and/or adverse pregnancy outcomes. Hypoxia has been shown to regulate not only the self-renewal, proliferation, and differentiation of trophoblast stem cells and progenitor cells, but also the recruitment, phenotype, and function of maternal immune cells. In this review, we will summarize how oxygen levels in early placental development determine the survival, fate, and function of several important cell types, e.g., trophoblast stem cells, extravillous trophoblasts, syncytiotrophoblasts, uterine natural killer cells, Hofbauer cells, and decidual macrophages. We will also discuss the cellular mechanisms used to cope with low oxygen tensions, such as the induction of hypoxia-inducible factor (HIF) or mammalian target of rapamycin (mTOR) signals, regulation of the metabolic pathway, and adaptation to autophagy. Understanding the beneficial roles of hypoxia in early placental development will provide insights into the root cause(s) of some pregnancy disorders, such as spontaneous abortion, preeclampsia, and intrauterine growth restriction.


Assuntos
Hipóxia/metabolismo , Placenta/metabolismo , Placentação , Animais , Biomarcadores , Diferenciação Celular , Metabolismo Energético , Feminino , Regulação da Expressão Gênica , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Placenta/citologia , Gravidez , Primeiro Trimestre da Gravidez , Trofoblastos/citologia , Trofoblastos/metabolismo
18.
Cell Prolif ; 54(11): e13125, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34546587

RESUMO

OBJECTIVES: Successful pregnancy involves the homeostasis between maternal decidua and fetoplacental units, whose disruption contributes to compromised pregnancy outcomes, including recurrent spontaneous abortion (RSA). The role of cell heterogeneity of maternal decidua in RSA is yet to be illustrated. MATERIALS AND METHODS: A total of 66,078 single cells from decidua samples isolated from patients with RSA and healthy controls were analysed by unbiased single-cell RNA sequencing (scRNA-seq). RESULTS: Our scRNA-seq results revealed that stromal cells are the most abundant cell type in decidua during early pregnancy. RSA samples are accompanied by aberrant decidualization and obviously obstructed communication between stromal cells and other cell types, such as abnormal activation of macrophages and NK cells. In addition, the over-activated TNF superfamily member 12 (TNFSF12, TWEAK) and FASLG in RSA are closely related to stromal cell demise and pregnancy failure. CONCLUSIONS: Our research reveals that the cell composition and communications in normal and RSA decidua at early pregnancy and provides insightful information for the pathology of RSA and will pave the way for pregnancy loss prevention.


Assuntos
Aborto Habitual/metabolismo , Perfilação da Expressão Gênica , Análise de Célula Única , Trofoblastos/fisiologia , Aborto Habitual/genética , Aborto Habitual/patologia , Adulto , Decídua/metabolismo , Decídua/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Células Matadoras Naturais/metabolismo , Gravidez , Análise de Célula Única/métodos , Trofoblastos/metabolismo , Adulto Jovem
19.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(3): 335-344, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34402258

RESUMO

Aberrant maternal inflammation and oxidative stress are the two main mechanisms of pathological pregnancy. The silence information regulator (sirtuin) family is a highly conserved family of nicotinamide adenine dinucleotide (NAD)-dependent deacylases. By regulating the post-translational modification of proteins, sirtuin is involved in various biological processes including oxidative stress and inflammation. Nowadays, emerging evidence indicates that sirtuin may be closely related to the occurrence and development of pathological pregnancy. The down-regulation of sirtuin can cause spontaneous preterm delivery by promoting uterine contraction and rupture of fetal membranes, cause gestational diabetes mellitus through promoting oxidative stress and affecting the activity of key enzymes in glucose metabolism, cause preeclampsia by reducing the proliferation and invasion ability of trophoblasts, cause intrahepatic cholestasis of pregnancy by promoting the production of bile acids and T helper 1 cell (Th1) cytokines, and cause intrauterine growth restriction through inducing mitochondrial dysfunction. Moreover, the expression and activation of sirtuin can be modulated through dietary interventions, thus sirtuin is expected to become a new target for the prevention and treatment of pregnancy complications. This article reviews the role of the sirtuin family in the occurrence and development of pathological pregnancy and its influence on the development of the offspring.


Assuntos
Diabetes Gestacional , Nascimento Prematuro , Feminino , Humanos , Gravidez , Trofoblastos
20.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360573

RESUMO

Serotonin (5-HT) plays an extensive role during pregnancy in regulating both the placental physiology and embryonic/fetal development. The uptake of 5-HT into cells is central to the control of local concentrations of 5-HT near its molecular targets. Here, we investigated the mechanisms of 5-HT uptake into human primary placental cells and cord blood platelets, all isolated immediately after birth. Trophoblasts and cord blood platelets showed 5-HT uptake with similar Michaelis constant (Km) values (~0.6 µM), typical of the high-affinity serotonin transporter (SERT). The uptake of 5-HT into trophoblasts was efficiently inhibited by various SERT-targeting drugs. In contrast, the uptake of 5-HT into feto-placental endothelial cells was not inhibited by a SERT blocker and showed a Km value (~782 µM) in the low-affinity range. Consistent with this, SERT mRNAs were abundant in term trophoblasts but sparse in feto-placental endothelial cells, whereas the opposite was found for the low-affinity plasma membrane monoamine transporter (PMAT) mRNAs. Organic cation transporter (OCT) 1, 2, and 3 mRNAs were absent or sparse in both cell types. In summary, the results demonstrate, for the first time, the presence of functional 5-HT uptake systems in feto-placental endothelial cells and fetal platelets, cells that are in direct contact with fetal blood plasma. The data also highlight the sensitivity to various psychotropic drugs of 5-HT transport into trophoblasts facing the maternal blood. The multiple, high-, and low-affinity systems present for the cellular uptake of 5-HT underscore the importance of 5-HT homeostasis at the maternal-fetal interface.


Assuntos
Feto/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Troca Materno-Fetal , Placenta/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/agonistas , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/farmacologia , Feminino , Feto/efeitos dos fármacos , Humanos , Placenta/efeitos dos fármacos , Gravidez , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismo
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