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Physiology and Pathophysiology of Placenta 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 July 2024) | Viewed by 6919

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Dr. Giovanni Tossetta

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Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Via Tronto, 10/a, 60126 Ancona, Italy
Interests: pregnancy complications; preeclampsia; preterm birth; ovarian cancer; early marker of pregnancy complications; oxidative stress; chemoresistance
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Dear Colleagues,

This is a continued series of the hot topic of Physiology and Pathophysiology of Placenta; our first Special Issue of this topic received interesting contributions and discussions.

The development and differentiation of placental villous tree are two key processes tightly regulated during pregnancy. In fact, several growth factors, their receptors, and other types of molecules can regulate placental cell proliferation, differentiation, migration, and invasion. Thus, an impairment of normal placental development can lead to a series of pregnancy pathologies, i.e., preeclampsia (PE), fetal growth restriction (FGR), gestational trophoblastic diseases (GTD), and gestational diabetes mellitus (GDM). Furthermore, external factors, such as microbial agents, chemicals, and natural compounds, can affect placental development and function, impairing pregnancy outcome.

These pregnancy complications result in increased maternal and fetal mortality and morbidity, leading to life-long health implications in both mother and child.

The aim of this Special Issue is to provide an overview of placental development and pathophysiology in order to better understand the molecular mechanisms involved in pregnancy. We are inviting submissions of original research articles, reviews, and communication on topics relevant to any aspect of placental physiology, pathophysiology, biochemistry, and molecular biology.

Dr. Giovanni Tossetta
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

trophoblast
proliferation
differentiation
invasion
placenta
preeclampsia
fetal growth restriction
gestational diabetes mellitus
infection
pregnancy complications

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Published Papers (7 papers)

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Editorial

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3 pages, 177 KiB

Open AccessEditorial

Special Issue “Physiology and Pathophysiology of Placenta 2.0”

by Giovanni Tossetta

Int. J. Mol. Sci. 2024, 25(9), 4586; https://doi.org/10.3390/ijms25094586 - 23 Apr 2024

Viewed by 658

Abstract

We are pleased to present this Special Issue of the International Journal of Molecular Sciences, entitled “Physiology and Pathophysiology of Placenta 2 [...] Full article

(This article belongs to the Special Issue Physiology and Pathophysiology of Placenta 2.0)

Research

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19 pages, 3299 KiB

Open AccessArticle

Comparison of Molecular Potential for Iron Transfer across the Placenta in Domestic Pigs with Varied Litter Sizes and Wild Boars

by Zuzanna Kopeć, Rafał Radosław Starzyński, Małgorzata Lenartowicz, Małgorzata Grzesiak, Jolanta Opiela, Zdzisław Smorąg, Barbara Gajda, Jakub Nicpoń, Magdalena Ogłuszka, Xiuying Wang, Rafał Mazgaj, Adrian Stankiewicz, Wiktoria Płonka, Natalia Pirga-Niemiec, Sylwia Herman and Paweł Lipiński

Int. J. Mol. Sci. 2024, 25(17), 9638; https://doi.org/10.3390/ijms25179638 - 5 Sep 2024

Cited by 1 | Viewed by 847

Abstract

Neonatal iron deficiency anemia is prevalent among domestic pigs but does not occur in the offspring of wild boar. The main causes of this disorder in piglets of modern pig breeds are paucity of hepatic iron stores, high birth weight, and rapid growth. Replenishment of fetal iron stores is a direct result of iron transfer efficiency across the placenta. In this study, we attempted to investigate the molecular potential of iron transfer across the placenta as a possible cause of differences between wild boar and Polish Large White (PLW) offspring. Furthermore, by analyzing placentas from PLW gilts that had litters of different sizes, we aimed to elucidate the impact of the number of fetuses on placental ability to transport iron. Using RNA sequencing, we examined the expression of iron-related genes in the placentas from wild boar and PLW gilts. We did not reveal significant differences in the expression of major iron transporters among all analyzed placentas. However, in wild boar placentas, we found higher expression of copper-dependent ferroxidases such as ceruloplasmin, zyklopen, and hephaestin, which facilitate iron export to the fetal circulation. We also determined a close co-localization of ceruloplasmin and zyklopen with ferroportin, the only iron exporter. Full article

(This article belongs to the Special Issue Physiology and Pathophysiology of Placenta 2.0)

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16 pages, 2204 KiB

Open AccessArticle

In Situ Analyses of Placental Inflammatory Response to SARS-CoV-2 Infection in Cases of Mother–Fetus Vertical Transmission

by Denise Morotti, Silvia Tabano, Gabriella Gaudioso, Tatjana Radaelli, Giorgio Alberto Croci, Nicola Bianchi, Giulia Ghirardi, Andrea Gianatti, Luisa Patanè, Valeria Poletti de Chaurand, David A. Schwartz, Mohamed A. A. A. Hagazi and Fabio Grizzi

Int. J. Mol. Sci. 2024, 25(16), 8825; https://doi.org/10.3390/ijms25168825 - 13 Aug 2024

Viewed by 1043

Abstract

It has been shown that vertical transmission of the SARS-CoV-2 strain is relatively rare, and there is still limited information on the specific impact of maternal SARS-CoV-2 infection on vertical transmission. The current study focuses on a transcriptomics analysis aimed at examining differences in gene expression between placentas from mother–newborn pairs affected by COVID-19 and those from unaffected controls. Additionally, it investigates the in situ expression of molecules involved in placental inflammation. The Papa Giovanni XXIII Hospital in Bergamo, Italy, has recorded three instances of intrauterine transmission of SARS-CoV-2. The first two cases occurred early in the pandemic and involved pregnant women in their third trimester who were diagnosed with SARS-CoV-2. The third case involved an asymptomatic woman in her second trimester with a twin pregnancy, who unfortunately delivered two stillborn fetuses due to the premature rupture of membranes. Transcriptomic analysis revealed significant differences in gene expression between the placentae of COVID-19-affected mother/newborn pairs and two matched controls. The infected and control placentae were matched for gestational age. According to the Benjamani–Hochberg method, 305 genes met the criterion of an adjusted p-value of less than 0.05, and 219 genes met the criterion of less than 0.01. Up-regulated genes involved in cell signaling (e.g., CCL20, C3, MARCO) and immune response (e.g., LILRA3, CXCL10, CD48, CD86, IL1RN, IL-18R1) suggest their potential role in the inflammatory response to SARS-CoV-2. RNAscope^® technology, coupled with image analysis, was utilized to quantify the surface area covered by SARS-CoV-2, ACE2, IL-1β, IL-6, IL-8, IL-10, and TNF-α on both the maternal and fetal sides of the placenta. A non-statistically significant gradient for SARS-CoV-2 was observed, with a higher surface coverage on the fetal side (2.42 ± 3.71%) compared to the maternal side (0.74 ± 1.19%) of the placenta. Although not statistically significant, the surface area covered by ACE2 mRNA was higher on the maternal side (0.02 ± 0.04%) compared to the fetal side (0.01 ± 0.01%) of the placenta. IL-6 and IL-8 were more prevalent on the fetal side (0.03 ± 0.04% and 0.06 ± 0.08%, respectively) compared to the maternal side (0.02 ± 0.01% and 0.02 ± 0.02%, respectively). The mean surface areas of IL-1β and IL-10 were found to be equal on both the fetal (0.04 ± 0.04% and 0.01 ± 0.01%, respectively) and maternal sides of the placenta (0.04 ± 0.05% and 0.01 ± 0.01%, respectively). The mean surface area of TNF-α was found to be equal on both the fetal and maternal sides of the placenta (0.02 ± 0.02% and 0.02 ± 0.02%, respectively). On the maternal side, ACE-2 and all examined interleukins, but not TNF-α, exhibited an inverse mRNA amount compared to SARS-CoV-2. On the fetal side, ACE-2, IL-6 and IL-8 were inversely correlated with SARS-CoV-2 (r = −0.3, r = −0.1 and r = −0.4, respectively), while IL-1β and IL-10 showed positive correlations (r = 0.9, p = 0.005 and r = 0.5, respectively). TNF-α exhibited a positive correlation with SARS-CoV-2 on both maternal (r = 0.4) and fetal sides (r = 0.9) of the placenta. Further research is needed to evaluate the correlation between cell signaling and immune response genes in the placenta and the vertical transmission of SARS-CoV-2. Nonetheless, the current study extends our comprehension of the molecular and immunological factors involved in SARS-CoV-2 placental infection underlying maternal–fetal transmission. Full article

(This article belongs to the Special Issue Physiology and Pathophysiology of Placenta 2.0)

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13 pages, 6855 KiB

Open AccessArticle

Comprehensive Analysis of Placental DNA Methylation Changes and Fetal Birth Weight in Pigs

by Baohua Tan, Liyao Xiao, Yongzhong Wang, Chen Zhou, Huijun Huang, Zicong Li, Linjun Hong, Gengyuan Cai, Zhenfang Wu and Ting Gu

Int. J. Mol. Sci. 2024, 25(14), 7702; https://doi.org/10.3390/ijms25147702 - 13 Jul 2024

Cited by 1 | Viewed by 1008

Abstract

Birth weight is a complex multifactorial trait relevant to health states and disease risks in later life. The placenta is essential for proper fetal growth and facilitates gas, nutrient, and waste exchange between the mother and developing fetus. How changes in placental DNA methylation affect fetal birth weight remains to be fully elucidated. In this study, we used whole-genome bisulfite sequencing and RNA sequencing to reveal a global map of DNA methylation and gene expression changes between the placentas of highest birth weight and lowest birth weight piglets in the same litters. The transcriptome analysis identified 1682 differential expressed genes and revealed key transcriptional properties in distinct placentas. We also identified key transcription factors that may drive the differences in DNA methylome patterns between placentas. The decrease in DNA methylation level in the promoter was associated with the transcriptional activation of genes associated with angiogenesis, extracellular matrix remodeling, and transmembrane transport. Our results revealed the regulatory role of DNA methylation in gene transcription activity leading to the differences in placental morphological structures and birth weights of piglets. These results could provide novel clues to clarify the underlying regulatory mechanisms of placental development and fetal growth. Full article

(This article belongs to the Special Issue Physiology and Pathophysiology of Placenta 2.0)

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Review

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18 pages, 744 KiB

Open AccessReview

The Hidden Relationship between Intestinal Microbiota and Immunological Modifications in Preeclampsia Pathogenesis

by Enrica Zambella, Beatrice Peruffo, Alice Guarano, Annalisa Inversetti and Nicoletta Di Simone

Int. J. Mol. Sci. 2024, 25(18), 10099; https://doi.org/10.3390/ijms251810099 - 20 Sep 2024

Viewed by 601

Abstract

Preeclampsia is a multifactorial gestational syndrome characterized by increased blood pressure during pregnancy associated with multiorgan involvement. The impact of this disease on maternal and neonatal health is significant, as it can lead to various fetal comorbidities and contribute to the development of maternal comorbidities later in life. Consistent evidence has shown that the microbiota acts as a regulator of the immune system, and it may, therefore, influence the development of preeclampsia by modulating immune factors. This narrative review aims to investigate the role of the immune system in the pathogenesis of preeclampsia and to summarize the most recent literature on the possible link between preeclampsia and alterations in the intestinal microbiota. To this end, we conducted a literature search, aiming to perform a narrative review, on PubMed and Embase from January 1990 to March 2024, focusing on the latest studies that highlight the main differences in microbial composition between patients with and without preeclampsia, as well as the effects of microbial metabolites on the immune system. From the review of 28 studies assessing the intestinal microbiota in preeclamptic women, preeclampsia could be associated with a state of dysbiosis. Moreover, these patients showed higher plasmatic levels of endotoxin, pro-inflammatory cytokines, and T helper 17 cells; however, the findings on specific microbes and metabolites that could cause immune imbalances in preeclampsia are still preliminary. Full article

(This article belongs to the Special Issue Physiology and Pathophysiology of Placenta 2.0)

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13 pages, 1528 KiB

Open AccessReview

The Underlying Molecular Mechanisms of the Placenta Accreta Spectrum: A Narrative Review

by Erik Lizárraga-Verdugo, Saúl Armando Beltrán-Ontiveros, Erick Paul Gutiérrez-Grijalva, Marisol Montoya-Moreno, Perla Y. Gutiérrez-Arzapalo, Mariana Avendaño-Félix, Karla Paola Gutiérrez-Castro, Daniel E. Cuén-Lazcano, Paul González-Quintero and Carlos Ernesto Mora-Palazuelos

Int. J. Mol. Sci. 2024, 25(17), 9722; https://doi.org/10.3390/ijms25179722 - 8 Sep 2024

Viewed by 868

Abstract

Placenta accreta spectrum (PAS) disorders are characterized by abnormal trophoblastic invasion into the myometrium, leading to significant maternal health risks. PAS includes placenta accreta (invasion < 50% of the myometrium), increta (invasion > 50%), and percreta (invasion through the entire myometrium). The condition is most associated with previous cesarean deliveries and increases in chance with the number of prior cesarians. The increasing global cesarean rates heighten the importance of early PAS diagnosis and management. This review explores genetic expression and key regulatory processes, such as apoptosis, cell proliferation, invasion, and inflammation, focusing on signaling pathways, genetic expression, biomarkers, and non-coding RNAs involved in trophoblastic invasion. It compiles the recent scientific literature (2014–2024) from the Scopus, PubMed, Google Scholar, and Web of Science databases. Identifying new biomarkers like AFP, sFlt-1, β-hCG, PlGF, and PAPP-A aids in early detection and management. Understanding genetic expression and non-coding RNAs is crucial for unraveling PAS complexities. In addition, aberrant signaling pathways like Notch, PI3K/Akt, STAT3, and TGF-β offer potential therapeutic targets to modulate trophoblastic invasion. This review underscores the need for interdisciplinary care, early diagnosis, and ongoing research into PAS biomarkers and molecular mechanisms to improve prognosis and quality of life for affected women. Full article

(This article belongs to the Special Issue Physiology and Pathophysiology of Placenta 2.0)

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19 pages, 1328 KiB

Open AccessReview

Placental Origins of Preeclampsia: Insights from Multi-Omic Studies

by Chang Cao, Richa Saxena and Kathryn J. Gray

Int. J. Mol. Sci. 2024, 25(17), 9343; https://doi.org/10.3390/ijms25179343 - 28 Aug 2024

Viewed by 1140

Abstract

Preeclampsia (PE) is a major cause of maternal and neonatal morbidity and mortality worldwide, with the placenta playing a central role in disease pathophysiology. This review synthesizes recent advancements in understanding the molecular mechanisms underlying PE, focusing on placental genes, proteins, and genetic variants identified through multi-omic approaches. Transcriptomic studies in bulk placental tissue have identified many dysregulated genes in the PE placenta, including the PE signature gene, Fms-like tyrosine kinase 1 (FLT1). Emerging single-cell level transcriptomic data have revealed key cell types and molecular signatures implicated in placental dysfunction and PE. However, the considerable variability among studies underscores the need for standardized methodologies and larger sample sizes to enhance the reproducibility of results. Proteomic profiling of PE placentas has identified numerous PE-associated proteins, offering insights into potential biomarkers and pathways implicated in PE pathogenesis. Despite significant progress, challenges such as inconsistencies in study findings and lack of validation persist. Recent fetal genome-wide association studies have identified multiple genetic loci associated with PE, with ongoing efforts to elucidate their impact on placental gene expression and function. Future directions include the integration of multi-omic data, validation of findings in diverse PE populations and clinical subtypes, and the development of analytical approaches and experimental models to study the complex interplay of placental and maternal factors in PE etiology. These insights hold promise for improving risk prediction, diagnosis, and management of PE, ultimately reducing its burden on maternal and neonatal health. Full article

(This article belongs to the Special Issue Physiology and Pathophysiology of Placenta 2.0)

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