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21 pages, 24532 KiB

Open AccessArticle

Epigenetic Dysregulation of Trophoblastic Gene Expression in Gestational Trophoblastic Disease

by Zoltan Szabolcsi, Amanda Demeter, Peter Kiraly, Andrea Balogh, Melissa L. Wilson, Jennifer R. King, Szabolcs Hetey, Zsolt Gelencser, Koji Matsuo, Beata Hargitai, Paulette Mhawech-Fauceglia, Petronella Hupuczi, Andras Szilagyi, Zoltan Papp, Lynda D. Roman, Victoria K. Cortessis and Nandor Gabor Than

Biomedicines 2021, 9(12), 1935; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9121935 - 17 Dec 2021

Cited by 7 | Viewed by 3020

Abstract

Gestational trophoblastic diseases (GTDs) have not been investigated for their epigenetic marks and consequent transcriptomic changes. Here, we analyzed genome-wide DNA methylation and transcriptome data to reveal the epigenetic basis of disease pathways that may lead to benign or malignant GTDs. RNA-Seq, mRNA [...] Read more.

Gestational trophoblastic diseases (GTDs) have not been investigated for their epigenetic marks and consequent transcriptomic changes. Here, we analyzed genome-wide DNA methylation and transcriptome data to reveal the epigenetic basis of disease pathways that may lead to benign or malignant GTDs. RNA-Seq, mRNA microarray, and Human Methylation 450 BeadChip data from complete moles and choriocarcinoma cells were bioinformatically analyzed. Paraffin-embedded tissues from complete moles and control placentas were used for tissue microarray construction, DNMT3B immunostaining and immunoscoring. We found that DNA methylation increases with disease severity in GTDs. Differentially expressed genes are mainly upregulated in moles while predominantly downregulated in choriocarcinoma. DNA methylation principally influences the gene expression of villous trophoblast differentiation-related or predominantly placenta-expressed genes in moles and choriocarcinoma cells. Affected genes in these subsets shared focal adhesion and actin cytoskeleton pathways in moles and choriocarcinoma. In moles, cell cycle and differentiation regulatory pathways, essential for trophoblast/placental development, were enriched. In choriocarcinoma cells, hormone biosynthetic, extracellular matrix-related, hypoxic gene regulatory, and differentiation-related signaling pathways were enriched. In moles, we found slight upregulation of DNMT3B protein, a developmentally important de novo DNA methylase, which is strongly overexpressed in choriocarcinoma cells that may partly be responsible for the large DNA methylation differences. Our findings provide new insights into the shared and disparate molecular pathways of disease in GTDs and may help in designing new diagnostic and therapeutic tools. Full article

(This article belongs to the Special Issue Gynecological Tumor and Placenta Development)

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12 pages, 840 KiB

Open AccessArticle

Transcriptomic Characterization of Postmolar Gestational Choriocarcinoma

by Constance Collet, Jonathan Lopez, Christophe Battail, Fabienne Allias, Mojgan Devouassoux-Shisheboran, Sophie Patrier, Nicolas Lemaitre, Touria Hajri, Jérôme Massardier, Benoit You, François Mallet, François Golfier, Nadia Alfaidy and Pierre-Adrien Bolze

Biomedicines 2021, 9(10), 1474; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101474 - 14 Oct 2021

Cited by 5 | Viewed by 1969

Abstract

The human placenta shares properties with solid tumors, such as rapid growth, tissue invasion, cell migration, angiogenesis, and immune evasion. However, the mechanisms that drive the evolution from premalignant proliferative placental diseases—called hydatidiform moles—to their malignant counterparts, gestational choriocarcinoma, as well as the [...] Read more.

The human placenta shares properties with solid tumors, such as rapid growth, tissue invasion, cell migration, angiogenesis, and immune evasion. However, the mechanisms that drive the evolution from premalignant proliferative placental diseases—called hydatidiform moles—to their malignant counterparts, gestational choriocarcinoma, as well as the factors underlying the increased aggressiveness of choriocarcinoma arising after term delivery compared to those developing from hydatidiform moles, are unknown. Using a 730-gene panel covering 13 cancer-associated canonical pathways, we compared the transcriptomic profiles of complete moles to those of postmolar choriocarcinoma samples and those of postmolar to post-term delivery choriocarcinoma. We identified 33 genes differentially expressed between complete moles and postmolar choriocarcinoma, which revealed TGF-β pathway dysregulation. We found the strong expression of SALL4, an upstream regulator of TGF-β, in postmolar choriocarcinoma, compared to moles, in which its expression was almost null. Finally, there were no differentially expressed genes between postmolar and post-term delivery choriocarcinoma samples. To conclude, the TGF-β pathway appears to be a crucial step in the progression of placental malignancies. Further studies should investigate the value of TGF- β family members as biomarkers and new therapeutic targets. Full article

(This article belongs to the Special Issue Gynecological Tumor and Placenta Development)

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20 pages, 6404 KiB

Open AccessArticle

Cortisol Dose-Dependently Impairs Migration and Tube-like Formation in a Trophoblast Cell Line and Modulates Inflammatory and Angiogenic Genes

by Talita Guerreiro Rodrigues Húngaro, Marcos F. Gregnani, Thaís Alves-Silva, Florian Herse, Natalia Alenina, Michael Bader and Ronaldo C. Araújo

Biomedicines 2021, 9(8), 980; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080980 - 09 Aug 2021

Cited by 4 | Viewed by 2365

Abstract

Several stimuli can change maternal hormone levels during pregnancy. These changes may affect trophoblastic cells and modulate the development of the embryo and the placental tissue itself. Changes in cortisol levels are associated with impaired trophoblast implantation and function, in addition to other [...] Read more.

Several stimuli can change maternal hormone levels during pregnancy. These changes may affect trophoblastic cells and modulate the development of the embryo and the placental tissue itself. Changes in cortisol levels are associated with impaired trophoblast implantation and function, in addition to other pregnancy complications. This study aims to analyze the effects of low and high doses of cortisol on an extravillous trophoblast cell line, and the effects of various exposures to this hormone. SGHPL-4 cells were treated with cortisol at five doses (0–1000 nM) and two exposures (continuous: 24 h/day; and intermittent: 2 h/day). In intermittent treatment, cortisol acted mainly as an anti-inflammatory hormone, repressing gene expression of kinin B1 receptors, interleukin-6, and interleukin-1β. Continuous treatment modulated inflammatory and angiogenic pathways, significantly repressing angiogenic factors and their receptors. Cortisol affected cell migration and tube-like structures formation. In conclusion, both continuous and intermittent exposure to cortisol repressed the expression of inflammatory genes, while only continuous exposure repressed the expression of angiogenic genes, suggesting that a sustained increase in the levels of this hormone is more harmful than a high short-term increase. Cortisol also impaired tube-like structures formation, and kinin receptors may be involved in this response. Full article

(This article belongs to the Special Issue Gynecological Tumor and Placenta Development)

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17 pages, 3814 KiB

Open AccessArticle

Variants in Maternal Effect Genes and Relaxed Imprinting Control in a Special Placental Mesenchymal Dysplasia Case with Mild Trophoblast Hyperplasia

by Tien-Chi Huang, Kung-Chao Chang, Jen-Yun Chang, Yi-Shan Tsai, Yao-Jong Yang, Wei-Chun Chang, Chu-Fan Mo, Pei-Hsiu Yu, Chun-Ting Chiang, Shau-Ping Lin and Pao-Lin Kuo

Biomedicines 2021, 9(5), 544; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050544 - 13 May 2021

Cited by 4 | Viewed by 2311

Abstract

Placental mesenchymal dysplasia (PMD) and partial hydatidiform mole (PHM) placentas share similar characteristics, such as placental overgrowth and grape-like placental tissues. Distinguishing PMD from PHM is critical because the former can result in normal birth, while the latter diagnosis will lead to artificial [...] Read more.

Placental mesenchymal dysplasia (PMD) and partial hydatidiform mole (PHM) placentas share similar characteristics, such as placental overgrowth and grape-like placental tissues. Distinguishing PMD from PHM is critical because the former can result in normal birth, while the latter diagnosis will lead to artificial abortion. Aneuploidy and altered dosage of imprinted gene expression are implicated in the pathogenesis of PHM and also some of the PMD cases. Diandric triploidy is the main cause of PHM, whereas mosaic diploid androgenetic cells in the placental tissue have been associated with the formation of PMD. Here, we report a very special PMD case also presenting with trophoblast hyperplasia phenotype, which is a hallmark of PHM. This PMD placenta has a normal biparental diploid karyotype and is functionally sufficient to support normal fetal growth. We took advantage of this unique case to further dissected the potential common etiology between these two diseases. We show that the differentially methylated region (DMR) at NESP55, a secondary DMR residing in the GNAS locus, is significantly hypermethylated in the PMD placenta. Furthermore, we found heterozygous mutations in NLRP2 and homozygous variants in NLRP7 in the mother’s genome. NLRP2 and NLRP7 are known maternal effect genes, and their mutation in pregnant females affects fetal development. The variants/mutations in both genes have been associated with imprinting defects in mole formation and potentially contributed to the mild abnormal imprinting observed in this case. Finally, we identified heterozygous mutations in the X-linked ATRX gene, a known maternal–zygotic imprinting regulator in the patient. Overall, our study demonstrates that PMD and PHM may share overlapping etiologies with the defective/relaxed dosage control of imprinted genes, representing two extreme ends of a spectrum. Full article

(This article belongs to the Special Issue Gynecological Tumor and Placenta Development)

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Review

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35 pages, 1942 KiB

Open AccessReview

by Jelena Krstic, Alexander Deutsch, Julia Fuchs, Martin Gauster, Tina Gorsek Sparovec, Ursula Hiden, Julian Christopher Krappinger, Gerit Moser, Katrin Pansy, Marta Szmyra, Daniela Gold, Julia Feichtinger and Berthold Huppertz

Biomedicines 2022, 10(5), 1065; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051065 - 04 May 2022

Cited by 13 | Viewed by 3386

Abstract

Placenta-specific trophoblast and tumor cells exhibit many common characteristics. Trophoblast cells invade maternal tissues while being tolerated by the maternal immune system. Similarly, tumor cells can invade surrounding tissues and escape the immune system. Importantly, both trophoblast and tumor cells are supported by [...] Read more.

Placenta-specific trophoblast and tumor cells exhibit many common characteristics. Trophoblast cells invade maternal tissues while being tolerated by the maternal immune system. Similarly, tumor cells can invade surrounding tissues and escape the immune system. Importantly, both trophoblast and tumor cells are supported by an abetting microenvironment, which influences invasion, angiogenesis, and immune tolerance/evasion, among others. However, in contrast to tumor cells, the metabolic, proliferative, migrative, and invasive states of trophoblast cells are under tight regulatory control. In this review, we provide an overview of similarities and dissimilarities in regulatory processes that drive trophoblast and tumor cell fate, particularly focusing on the role of the abetting microenvironments. Full article

(This article belongs to the Special Issue Gynecological Tumor and Placenta Development)

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29 pages, 2856 KiB

Open AccessReview

Placental Models for Evaluation of Nanocarriers as Drug Delivery Systems for Pregnancy Associated Disorders

by Louise Fliedel, Khair Alhareth, Nathalie Mignet, Thierry Fournier and Karine Andrieux

Biomedicines 2022, 10(5), 936; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10050936 - 19 Apr 2022

Cited by 8 | Viewed by 2585

Abstract

Pregnancy-associated disorders affect around 20% of pregnancies each year around the world. The risk associated with pregnancy therapeutic management categorizes pregnant women as “drug orphan” patients. In the last few decades, nanocarriers have demonstrated relevant properties for controlled drug delivery, which have been [...] Read more.

Pregnancy-associated disorders affect around 20% of pregnancies each year around the world. The risk associated with pregnancy therapeutic management categorizes pregnant women as “drug orphan” patients. In the last few decades, nanocarriers have demonstrated relevant properties for controlled drug delivery, which have been studied for pregnancy-associated disorders. To develop new drug dosage forms it is mandatory to have access to the right evaluation models to ensure their usage safety and efficacy. This review exposes the various placental-based models suitable for nanocarrier evaluation for pregnancy-associated therapies. We first review the current knowledge about nanocarriers as drug delivery systems and how placenta can be used as an evaluation model. Models are divided into three categories: in vivo, in vitro, and ex vivo placental models. We then examine the recent studies using those models to evaluate nanocarriers behavior towards the placental barrier and which information can be gathered from these results. Finally, we propose a flow chart on the usage and the combination of models regarding the nanocarriers and nanoparticles studied and the intended therapeutic strategy. Full article

(This article belongs to the Special Issue Gynecological Tumor and Placenta Development)

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20 pages, 1388 KiB

Open AccessReview

In Vitro Model of Human Trophoblast in Early Placentation

by Darina Bačenková, Marianna Trebuňová, Daša Čížková, Radovan Hudák, Erik Dosedla, Alena Findrik-Balogová and Jozef Živčák

Biomedicines 2022, 10(4), 904; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040904 - 15 Apr 2022

Cited by 10 | Viewed by 6020

Abstract

The complex process of placental implantation and development affects trophoblast progenitors and uterine cells through the regulation of transcription factors, cytokines, adhesion receptors and their ligands. Differentiation of trophoblast precursors in the trophectoderm of early ontogenesis, caused by the transcription factors, such as [...] Read more.

The complex process of placental implantation and development affects trophoblast progenitors and uterine cells through the regulation of transcription factors, cytokines, adhesion receptors and their ligands. Differentiation of trophoblast precursors in the trophectoderm of early ontogenesis, caused by the transcription factors, such as CDX2, TEAD4, Eomes and GATA3, leads to the formation of cytotrophoblast and syncytiotrophoblast populations. The molecular mechanisms involved in placental formation inside the human body along with the specification and differentiation of trophoblast cell lines are, mostly due to the lack of suitable cell models, not sufficiently elucidated. This review is an evaluation of current technologies, which are used to study the behavior of human trophoblasts and other placental cells, as well as their ability to represent physiological conditions both in vivo and in vitro. An in vitro 3D model with a characteristic phenotype is of great benefit for the study of placental physiology. At the same time, it provides great support for future modeling of placental disease. Full article

(This article belongs to the Special Issue Gynecological Tumor and Placenta Development)

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13 pages, 1739 KiB

Open AccessReview

Role of the Uteroplacental Renin–Angiotensin System in Placental Development and Function, and Its Implication in the Preeclampsia Pathogenesis

by Lucile Yart, Edith Roset Bahmanyar, Marie Cohen and Begoña Martinez de Tejada

Biomedicines 2021, 9(10), 1332; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101332 - 27 Sep 2021

Cited by 15 | Viewed by 2691

Abstract

Placental development and function implicate important morphological and physiological adaptations to thereby ensure efficient maternal–fetal exchanges, as well as pregnancy-specific hormone secretion and immune modulation. Incorrect placental development can lead to severe pregnancy disorders, such as preeclampsia (PE), which endangers both the mother [...] Read more.

Placental development and function implicate important morphological and physiological adaptations to thereby ensure efficient maternal–fetal exchanges, as well as pregnancy-specific hormone secretion and immune modulation. Incorrect placental development can lead to severe pregnancy disorders, such as preeclampsia (PE), which endangers both the mother and the infant. The implication of the systemic renin–angiotensin system (RAS) in the pregnancy-related physiological changes is now well established. However, despite the fact that the local uteroplacental RAS has been described for several decades, its role in placental development and function seems to have been underestimated. In this review, we provide an overview of the multiple roles of the uteroplacental RAS in several cellular processes of placental development, its implication in the regulation of placental function during pregnancy, and the consequences of its dysregulation in PE pathogenesis. Full article

(This article belongs to the Special Issue Gynecological Tumor and Placenta Development)

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17 pages, 1696 KiB

Open AccessReview

The Role and Clinical Interest of Extracellular Vesicles in Pregnancy and Ovarian Cancer

by Nazanin Yeganeh Kazemi, Benoìt Gendrot, Ekaterine Berishvili, Svetomir N. Markovic and Marie Cohen

Biomedicines 2021, 9(9), 1257; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9091257 - 18 Sep 2021

Cited by 11 | Viewed by 3327

Abstract

Ovarian cancer and pregnancy are two states in which the host immune system is exposed to novel antigens. Indeed, both the tumor and placenta must invade tissues, remodel vasculature to establish a robust blood supply, and evade detection by the immune system. Interestingly, [...] Read more.

Ovarian cancer and pregnancy are two states in which the host immune system is exposed to novel antigens. Indeed, both the tumor and placenta must invade tissues, remodel vasculature to establish a robust blood supply, and evade detection by the immune system. Interestingly, tumor and placenta tissue use similar mechanisms to induce these necessary changes. One mediator is emerging as a key player in invasion, vascular remodeling, and immune evasion: extracellular vesicles (EVs). Many studies have identified EVs as a key mediator of cell-to-cell communication. Specifically, the cargo carried by EVs, which includes proteins, nucleic acids, and lipids, can interact with cells to induce changes in the target cell ranging from gene expression to migration and metabolism. EVs can promote cell division and tissue invasion, immunosuppression, and angiogenesis which are essential for both cancer and pregnancy. In this review, we examine the role of EVs in ovarian cancer metastasis, chemoresistance, and immune modulation. We then focus on the role of EVs in pregnancy with special attention on the vascular remodeling and regulation of the maternal immune system. Lastly, we discuss the clinical utility of EVs as markers and therapeutics for ovarian cancer and pre-eclampsia. Full article

(This article belongs to the Special Issue Gynecological Tumor and Placenta Development)

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