Research

27 pages, 8367 KiB

Open AccessArticle

Pan-Genomic Regulation of Gene Expression in Normal and Pathological Human Placentas

by Clara Apicella, Camino S. M. Ruano, Basky Thilaganathan, Asma Khalil, Veronica Giorgione, Géraldine Gascoin, Louis Marcellin, Cassandra Gaspar, Sébastien Jacques, Colin E. Murdoch, Francisco Miralles, Céline Méhats and Daniel Vaiman

Cells 2023, 12(4), 578; https://doi.org/10.3390/cells12040578 - 10 Feb 2023

Cited by 5 | Viewed by 1921

Abstract

In this study, we attempted to find genetic variants affecting gene expression (eQTL = expression Quantitative Trait Loci) in the human placenta in normal and pathological situations. The analysis of gene expression in placental diseases (Pre-eclampsia and Intra-Uterine Growth Restriction) is hindered by [...] Read more.

In this study, we attempted to find genetic variants affecting gene expression (eQTL = expression Quantitative Trait Loci) in the human placenta in normal and pathological situations. The analysis of gene expression in placental diseases (Pre-eclampsia and Intra-Uterine Growth Restriction) is hindered by the fact that diseased placental tissue samples are generally taken at earlier gestations compared to control samples. The difference in gestational age is considered a major confounding factor in the transcriptome regulation of the placenta. To alleviate this significant problem, we propose here a novel approach to pinpoint disease-specific cis-eQTLs. By statistical correction for gestational age at sampling as well as other confounding/surrogate variables systematically searched and identified, we found 43 e-genes for which proximal SNPs influence expression level. Then, we performed the analysis again, removing the disease status from the covariates, and we identified 54 e-genes, 16 of which are identified de novo and, thus, possibly related to placental disease. We found a highly significant overlap with previous studies for the list of 43 e-genes, validating our methodology and findings. Among the 16 disease-specific e-genes, several are intrinsic to trophoblast biology and, therefore, constitute novel targets of interest to better characterize placental pathology and its varied clinical consequences. The approach that we used may also be applied to the study of other human diseases where confounding factors have hampered a better understanding of the pathology. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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14 pages, 5430 KiB

Open AccessArticle

The Autocrine Role of Placental Extracellular Vesicles from Missed Miscarriage in Causing Senescence: Possible Pathogenesis of Missed Miscarriage

by Yi Zhang, Yunhui Tang, Yang Liu, Jiayi Wang, Ye Shen, Xinyi Sun, Matthew Kang, Min Zhao and Qi Chen

Cells 2022, 11(23), 3873; https://doi.org/10.3390/cells11233873 - 01 Dec 2022

Cited by 1 | Viewed by 1450

Abstract

Placental dysfunction, including senescent changes, is associated with the pathogenesis of missed miscarriage, although the underlying mechanism is unclear. Increasing evidence indicates that placenta-specific miRNAs are packaged in extracellular vesicles (EVs) from placental syncytiotrophoblasts and are released into the maternal circulation. Aberrant cargos [...] Read more.

Placental dysfunction, including senescent changes, is associated with the pathogenesis of missed miscarriage, although the underlying mechanism is unclear. Increasing evidence indicates that placenta-specific miRNAs are packaged in extracellular vesicles (EVs) from placental syncytiotrophoblasts and are released into the maternal circulation. Aberrant cargos including miRNAs in placental EVs have been reported to be associated with the pathogenesis of complicated pregnancies. In this study, we compared the miRNA profiles in EVs derived from missed miscarriage and healthy placentae and investigated possible biological pathways which may be involved in senescence, one cause of missed miscarriage. The total concentration of RNA in placental EVs was not different between the two groups. However, there were 54 and 94 differentially expressed miRNAs in placental large and small EVs from missed miscarriage compared to EVs from healthy controls. The aberrantly expressed miRNAs seen in placental EVs were also observed in missed miscarriage placentae. Gene enrichment analysis showed that some of those differentially expressed miRNAs are involved in cellular senescence, endocytosis, cell cycle and endocrine resistance. Furthermore, transfection of trophoblasts by a single senescence-associated miRNA that was differentially expressed in placental EVs derived from missed miscarriage did not cause trophoblast dysfunction. In contrast, EVs derived from missed miscarriage placenta induced senescent changes in the healthy placenta. Our data suggested that a complex of placental EVs, rather than a few differentially expressed miRNAs in placental EVs derived from missed miscarriage placentae could contribute in an autocrine manner to placental senescence, one of the causes of missed miscarriage. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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12 pages, 1831 KiB

Open AccessArticle

Siglec-6 Signaling Uses Src Kinase Tyrosine Phosphorylation and SHP-2 Recruitment

by Adrianne L. Stefanski, Michael D. Renecle, Anita Kramer, Shilpi Sehgal, Purnima Narasimhan, Kristen K. Rumer and Virginia D Winn

Cells 2022, 11(21), 3427; https://doi.org/10.3390/cells11213427 - 29 Oct 2022

Cited by 5 | Viewed by 2118

Abstract

Preeclampsia is a pregnancy-specific disorder involving placental abnormalities. Elevated placental Sialic acid immunoglobulin-like lectin (Siglec)-6 expression has been correlated with preeclampsia. Siglec-6 is a transmembrane receptor, expressed predominantly by the trophoblast cells in the human placenta. It interacts with sialyl glycans such as [...] Read more.

Preeclampsia is a pregnancy-specific disorder involving placental abnormalities. Elevated placental Sialic acid immunoglobulin-like lectin (Siglec)-6 expression has been correlated with preeclampsia. Siglec-6 is a transmembrane receptor, expressed predominantly by the trophoblast cells in the human placenta. It interacts with sialyl glycans such as sialyl-TN glycans as well as binds leptin. Siglec-6 overexpression has been shown to influence proliferation, apoptosis, and invasion in the trophoblast (BeWo) cell model. However, there is no direct evidence that Siglec-6 plays a role in preeclampsia pathogenesis and its signaling potential is still largely unexplored. Siglec-6 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an ITIM-like motif in its cytoplasmic tail suggesting a signaling function. Site-directed mutagenesis and transfection were employed to create a series of Siglec-6 expressing HTR-8/SVneo trophoblastic cell lines with mutations in specific functional residues to explore the signaling potential of Siglec-6. Co-immunoprecipitation and inhibitory assays were utilized to investigate the association of Src-kinases and SH-2 domain-containing phosphatases with Siglec-6. In this study, we show that Siglec-6 is phosphorylated at ITIM and ITIM-like domains by Src family kinases. Phosphorylation of both ITIM and ITIM-like motifs is essential for the recruitment of phosphatases like Src homology region 2 containing protein tyrosine phosphatase 2 (SHP-2), which has downstream signaling capabilities. These findings suggest Siglec-6 as a signaling molecule in human trophoblasts. Further investigation is warranted to determine which signaling pathways are activated downstream to SHP-2 recruitment and how overexpression of Siglec-6 in preeclamptic placentas impacts pathogenesis. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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14 pages, 1437 KiB

Open AccessArticle

Fetal Myocardial Expression of GLUT1: Roles of BPA Exposure and Cord Blood Exosomes in a Rat Model

by Leonardo Ermini, Maurizio Mandalà, Laura Cresti, Sofia Passaponti, Laura Patrussi, Luana Paulesu, Kent Thornburg and Francesca Ietta

Cells 2022, 11(20), 3195; https://doi.org/10.3390/cells11203195 - 11 Oct 2022

Cited by 1 | Viewed by 1692

Abstract

Dietary exposure to Bisphenol A (BPA), an industrial chemical present in food containers, affects nutrient metabolism in the myocardium of offspring during intrauterine life. Using a murine model, we observed that fetal hearts from mothers exposed to BPA (2.5 μg/kg/day) for 20 days [...] Read more.

Dietary exposure to Bisphenol A (BPA), an industrial chemical present in food containers, affects nutrient metabolism in the myocardium of offspring during intrauterine life. Using a murine model, we observed that fetal hearts from mothers exposed to BPA (2.5 μg/kg/day) for 20 days before mating and for all of the gestation had decreased expression of glucose transporter-1 (GLUT1), the principal sugar transporter in the fetal heart, and increased expression of fatty acid cluster of differentiation 36 transporter (CD36), compared to control fetuses from vehicle-treated mothers. We confirmed the suppression of GLUT1 by exposing fetal heart organotypic cultures to BPA (1 nM) for 48 h but did not detect changes in CD36 compared to controls. During pregnancy, the placenta continuously releases extracellular vesicles such as exosomes into fetal circulation. These vesicles influence the growth and development of fetal organs. When fetal heart cultures were treated with cord blood-derived exosomes isolated from BPA-fed animals, GLUT1 expression was increased by approximately 40%. Based on our results, we speculate that exosomes from cord blood, in particular placenta-derived nanovesicles, could contribute to the stabilization of the fetal heart metabolism by ameliorating the harmful effects of BPA on GLUT1 expression. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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15 pages, 3542 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Three-Dimensional Trophoblast Spheroids: An Alternative Model to Study the Physiological Properties of the Placental Unit

by Violeta Stojanovska, Susanne Arnold, Mario Bauer, Hermann Voss, Stefan Fest and Ana Claudia Zenclussen

Cells 2022, 11(18), 2884; https://doi.org/10.3390/cells11182884 - 15 Sep 2022

Cited by 7 | Viewed by 2642

Abstract

It was postulated that 3D cell culture models more accurately reflect the complex tissue physiology and morphology in comparison to 2D cell monolayers. Currently, there is a shortage of well-characterized and easily maintainable high-throughput experimental models of the human placenta. Here, we characterized [...] Read more.

It was postulated that 3D cell culture models more accurately reflect the complex tissue physiology and morphology in comparison to 2D cell monolayers. Currently, there is a shortage of well-characterized and easily maintainable high-throughput experimental models of the human placenta. Here, we characterized three different 3D cultures (e.g., spheroids) derived from trophoblast cell lines and studied their functionality in comparison to primary fetal trophoblasts and placental tissue. The spheroid growth rates of JEG3, BeWo and HTR8/SVneo cell lines were similar among each other and were significantly larger in comparison to primary trophoblast spheroids. All spheroids exhibited migratory properties and shortest distances were registered for JEG3 spheroids. Even though all spheroids displayed invasive capabilities, only the invasive features of HTR8/SVneo spheroids resulted in specific branching. This was in agreement with the invasive properties of the spheroids obtained from primary trophoblasts. Human chorionic gonadotropin production was highest in JEG3 spheroids and only increased when stimulated with cAMP and forskolin in BeWo, but not HTR8/SVneo spheroids. The gene expression analysis confirmed that 3D trophoblast cell cultures and especially HTR8/SVneo spheroids showed considerable similarities with the gene expression profile of primary placental tissue. This study offers a broad characterization of 3D trophoblast spheroids that, in turn, can help in selecting the best model depending on the scientific question that needs to be answered. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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15 pages, 4184 KiB

Open AccessArticle

Exporting Proteins Associated with Senescence Repair via Extracellular Vesicles May Be Associated with Early Pregnancy Loss

by Yi Zhang, Yunhui Tang, Xinyi Sun, Matt Kang, Min Zhao, Jiayi Wan and Qi Chen

Cells 2022, 11(18), 2772; https://doi.org/10.3390/cells11182772 - 06 Sep 2022

Cited by 8 | Viewed by 1875

Abstract

Introduction: Dysfunction of placental development is involved in early pregnancy loss. Senescent changes have been seen in missed miscarriage, one type of pregnancy loss. Extracellular vesicles (EVs) have been widely implicated in the pathogenesis of diseases. In this study, we investigated the protein [...] Read more.

Introduction: Dysfunction of placental development is involved in early pregnancy loss. Senescent changes have been seen in missed miscarriage, one type of pregnancy loss. Extracellular vesicles (EVs) have been widely implicated in the pathogenesis of diseases. In this study, we investigated the protein profiles in placental EVs derived from missed miscarriage in comparison with healthy pregnancy. We also investigated whether cargos packed into EVs are involved in the dysfunctional development of the placenta seen in missed miscarriage. Methods: Proteomic analysis of placental EVs derived from healthy and missed-miscarriage placentae was performed. Three senescence-repair-associated proteins, replication protein A-70 (RPA-70), proteasome activator subunit-4 (PMSE-4), and protein activated kinase-2, (PAK-2) were examined in placental EVs and placentae, and in placental explants that had been treated with or without GW4869, by western blotting and immunohistochemistry. Results: The total number of proteins associated with placental EVs was not different between the two groups. However, there were 106 and 151 abundantly expressed proteins associated with placental micro- or nano-EVs from missed miscarriage in comparison with EVs from controls. Of these abundant proteins, 59 and 81 proteins in placental micro- or nano-EVs, respectively, are associated with DNA damage/repair and cell death/survival. We further found higher levels of three senescence-repair-associated proteins (RPA-70, PMSE-4, and PAK-2) associated with placental EVs, but lower levels of these proteins in missed-miscarriage placentae. Regarding inhibition of EV formation or release by GW4869, we found that the expression of these three proteins was higher in GW4869-treated placental explants from missed miscarriage. Discussion: Our data may suggest that “inadvertently” sorting of cargos and exporting proteins associated with senescence-repair by placental EVs may be associated with the dysfunction of placental development seen in missed miscarriage. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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Review

Jump to: Research, Other

18 pages, 1660 KiB

Open AccessReview

Molecular Mechanisms Underlying Twin-to-Twin Transfusion Syndrome

by Kazuhiro Kajiwara, Katsusuke Ozawa, Seiji Wada and Osamu Samura

Cells 2022, 11(20), 3268; https://doi.org/10.3390/cells11203268 - 17 Oct 2022

Cited by 5 | Viewed by 3611

Abstract

Twin-to-twin transfusion syndrome is a unique disease and a serious complication occurring in 10–15% of monochorionic multiple pregnancies with various placental complications, including hypoxia, anemia, increased oxidative stress, and ischemia-reperfusion injury. Fetoscopic laser photocoagulation, a minimally invasive surgical procedure, seals the placental vascular [...] Read more.

Twin-to-twin transfusion syndrome is a unique disease and a serious complication occurring in 10–15% of monochorionic multiple pregnancies with various placental complications, including hypoxia, anemia, increased oxidative stress, and ischemia-reperfusion injury. Fetoscopic laser photocoagulation, a minimally invasive surgical procedure, seals the placental vascular anastomoses between twins and dramatically improves the survival rates in twin-to-twin transfusion syndrome. However, fetal demise still occurs, suggesting the presence of causes other than placental vascular anastomoses. Placental insufficiency is considered as the main cause of fetal demise in such cases; however, little is known about its underlying molecular mechanisms. Indeed, the further association of the pathogenic mechanisms involved in twin-to-twin transfusion syndrome placenta with several molecules and pathways, such as vascular endothelial growth factor and the renin–angiotensin system, makes it difficult to understand the underlying pathological conditions. Currently, there are no effective strategies focusing on these mechanisms in clinical practice. Certain types of cell death due to oxidative stress might be occurring in the placenta, and elucidation of the molecular mechanism underlying this cell death can help manage and prevent it. This review reports on the molecular mechanisms underlying the development of twin-to-twin transfusion syndrome for effective management and prevention of fetal demise after fetoscopic laser photocoagulation. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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15 pages, 1440 KiB

Open AccessReview

Endogenous Retroviruses and Placental Evolution, Development, and Diversity

by Kazuhiko Imakawa, Kazuya Kusama, Tomoko Kaneko-Ishino, So Nakagawa, Koichi Kitao, Takayuki Miyazawa and Fumitoshi Ishino

Cells 2022, 11(15), 2458; https://doi.org/10.3390/cells11152458 - 08 Aug 2022

Cited by 11 | Viewed by 6598

Abstract

The main roles of placentas include physical protection, nutrient and oxygen import, export of gasses and fetal waste products, and endocrinological regulation. In addition to physical protection of the fetus, the placentas must provide immune protection throughout gestation. These basic functions are well-conserved; [...] Read more.

The main roles of placentas include physical protection, nutrient and oxygen import, export of gasses and fetal waste products, and endocrinological regulation. In addition to physical protection of the fetus, the placentas must provide immune protection throughout gestation. These basic functions are well-conserved; however, placentas are undoubtedly recent evolving organs with structural and cellular diversities. These differences have been explained for the last two decades through co-opting genes and gene control elements derived from transposable elements, including endogenous retroviruses (ERVs). However, the differences in placental structures have not been explained or characterized. This manuscript addresses the sorting of ERVs and their integration into the mammalian genomes and provides new ways to explain why placental structures have diverged. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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30 pages, 870 KiB

Open AccessReview

Non-Coding RNAs and Prediction of Preeclampsia in the First Trimester of Pregnancy

by Manabu Ogoyama, Hironori Takahashi, Hirotada Suzuki, Akihide Ohkuchi, Hiroyuki Fujiwara and Toshihiro Takizawa

Cells 2022, 11(15), 2428; https://doi.org/10.3390/cells11152428 - 05 Aug 2022

Cited by 10 | Viewed by 2775

Abstract

Preeclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality. The only fundamental treatment for PE is the termination of pregnancy. Therefore, not only severe maternal complications but also perinatal complications due to immaturity of the infant associated with early [...] Read more.

Preeclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality. The only fundamental treatment for PE is the termination of pregnancy. Therefore, not only severe maternal complications but also perinatal complications due to immaturity of the infant associated with early delivery are serious issues. The treatment and prevention of preterm onset preeclampsia (POPE) are challenging. In 2017, the ASPRE trial showed that a low oral dose of aspirin administered to POPE high-risk women in early pregnancy reduced POPE by 62%. A prediction algorithm at 11–13 weeks of gestation identifies POPE with 75% sensitivity when the false positive rate is set at 10%. New biomarkers to increase the accuracy of the prediction model for POPE high-risk women in early pregnancy are needed. In this review, we focused on non-coding RNAs (ncRNAs) as potential biomarkers for the prediction of POPE. Highly expressed ncRNAs in the placenta in early pregnancy may play crucial roles in placentation. Furthermore, placenta-specific ncRNAs have been detected in maternal blood. In this review, we summarized ncRNAs that were highly expressed in the primary human placenta in early pregnancy. We also presented highly expressed ncRNAs in the placenta that were associated with or predictive of the development of PE in an expression analysis of maternal blood during the first trimester of pregnancy. These previous studies showed that the chromosome 19 microRNA (miRNA) -derived miRNAs (e.g., miR-517-5p, miR-518b, and miR-520h), the hypoxia-inducible miRNA (miR-210), and long non-coding RNA H19, were not only highly expressed in the early placenta but were also significantly up-regulated in the blood at early gestation in pregnant women who later developed PE. These maternal circulating ncRNAs in early pregnancy are expected to be possible biomarkers for POPE. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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9 pages, 689 KiB

Open AccessReview

ANNEXIN A1: Roles in Placenta, Cell Survival, and Nucleus

by Stefanie Oliveira de Sousa, Mayk Ricardo dos Santos, Samuel Cota Teixeira, Eloisa Amália Vieira Ferro and Sonia Maria Oliani

Cells 2022, 11(13), 2057; https://doi.org/10.3390/cells11132057 - 29 Jun 2022

Cited by 6 | Viewed by 2678

Abstract

The unbiased approaches of the last decade have enabled the collection of new data on the biology of annexin A1 (ANXA1) in a variety of scientific aspects, creating opportunities for new biomarkers and/or therapeutic purposes. ANXA1 is found in the plasma membrane, cytoplasm, [...] Read more.

The unbiased approaches of the last decade have enabled the collection of new data on the biology of annexin A1 (ANXA1) in a variety of scientific aspects, creating opportunities for new biomarkers and/or therapeutic purposes. ANXA1 is found in the plasma membrane, cytoplasm, and nucleus, being described at low levels in the nuclear and cytoplasmic compartments of placental cells related to gestational diabetic diseases, and its translocation from the cytoplasm to the nucleus has been associated with a response to DNA damage. The approaches presented here open pathways for reflection upon, and intrinsic clarification of, the modulating action of this protein in the response to genetic material damage, as well as its level of expression and cellular localization. The objective of this study is to arouse interest, with an emphasis on the mechanisms of nuclear translocation of ANXA1, which remain underexplored and may be beneficial in new inflammatory therapies. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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Graphical abstract

33 pages, 979 KiB

Open AccessReview

Stem Cell-Based Trophoblast Models to Unravel the Genetic Causes of Human Miscarriages

by Tatiana V. Nikitina and Igor N. Lebedev

Cells 2022, 11(12), 1923; https://doi.org/10.3390/cells11121923 - 14 Jun 2022

Cited by 6 | Viewed by 3633

Abstract

Miscarriage affects approximately 15% of clinically recognized pregnancies, and 1–3% of couples experience pregnancy loss recurrently. Approximately 50–60% of miscarriages result from chromosomal abnormalities, whereas up to 60% of euploid recurrent abortions harbor variants in candidate genes. The growing number of detected genetic [...] Read more.

Miscarriage affects approximately 15% of clinically recognized pregnancies, and 1–3% of couples experience pregnancy loss recurrently. Approximately 50–60% of miscarriages result from chromosomal abnormalities, whereas up to 60% of euploid recurrent abortions harbor variants in candidate genes. The growing number of detected genetic variants requires an investigation into their role in adverse pregnancy outcomes. Since placental defects are the main cause of first-trimester miscarriages, the purpose of this review is to provide a survey of state-of-the-art human in vitro trophoblast models that can be used for the functional assessment of specific abnormalities/variants implicated in pregnancy loss. Since 2018, when primary human trophoblast stem cells were first derived, there has been rapid growth in models of trophoblast lineage. It has been found that a proper balance between self-renewal and differentiation in trophoblast progenitors is crucial for the maintenance of pregnancy. Different responses to aneuploidy have been shown in human embryonic and extra-embryonic lineages. Stem cell-based models provide a powerful tool to explore the effect of a specific aneuploidy/variant on the fetus through placental development, which is important, from a clinical point of view, for deciding on the suitability of embryos for transfer after preimplantation genetic testing for aneuploidy. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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Other

Jump to: Research, Review

24 pages, 1313 KiB

Open AccessSystematic Review

Placental Changes and Neuropsychological Development in Children—A Systematic Review

by Maria Lodefalk, Felix Chelslín, Johanna Patriksson Karlsson and Stefan R. Hansson

Cells 2023, 12(3), 435; https://doi.org/10.3390/cells12030435 - 28 Jan 2023

Viewed by 1819

Abstract

Placental dysfunction may increase the offspring’s later-life disease risk. The objective of this systematic review was to describe associations between pathological placental changes and neuropsychological outcomes in children after the neonatal period. The inclusion criteria were human studies; original research; direct placental variables; [...] Read more.

Placental dysfunction may increase the offspring’s later-life disease risk. The objective of this systematic review was to describe associations between pathological placental changes and neuropsychological outcomes in children after the neonatal period. The inclusion criteria were human studies; original research; direct placental variables; neuropsychological outcomes; and analysis between their associations. The exclusion criterion was the offspring’s age—0–28 days or >19 years. The MEDLINE and EMBASE databases were last searched in May 2022. We utilized the ROBINS-I for the risk of bias assessment and performed a narrative synthesis. In total, 3252 studies were identified, out of which 16 were included (i.e., a total of 15,862 participants). Half of the studies were performed on children with neonatal complications, and 75% of the studies reported an association between a placental change and an outcome; however, following the completion of the funnel plots, a risk of publication bias was indicated. The largest study described a small association between placental size and a risk of psychiatric symptoms in boys only. Inconsistency between the studies limited the evidence in this review. In general, no strong evidence was found for an association between pathological placental changes and childhood neuropsychological outcomes after the neonatal period. However, the association between placental size and mental health in boys indicates a placental sexual dimorphism, thereby suggesting an increased vulnerability for male fetuses. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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