Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Molecular Insights into Placental Pathology

Print Special Issue Flyer
Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Related Special Issue
Published Papers

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 (20 July 2026) | Viewed by 14503

Share This Special Issue

Editors

Dr. Mary Wallingford

E-Mail Website
Guest Editor

Mother Infant Research Institute, Tufts Medical Center, Boston, MA 02111, USA
Interests: vascular biology of pregnancy
Special Issues, Collections and Topics in MDPI journals

Dr. Ana Correia-Branco

E-Mail Website
Guest Editor

Mother Infant Research Institute, Tufts Medical Center, Boston, MA 02111, USA
Interests: pregnancy diagnostics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The placenta is a complex organ which develops de novo during pregnancy and serves a vital role in fetal protection. Specialized vasculature at the maternal–fetal interface (MFI) within the placenta mediates the transport of oxygen, nutrients, waste, and other compounds between the maternal and fetal circulatory systems. Molecular pathways that regulate the development of the placenta and the MFI have been discovered, but the molecular pathways that govern placental health and disease remain incompletely understood. Advancements in this field are critical for the development of early diagnostic indicators of placental dysfunction and placental diseases.

Supervised by Dr. Ana Correia-Branco and Dr. Mary Wallingford, we are pleased to announce this Special Issue of the International Journal of Molecular Sciences, titled “Molecular Insights into Placental Pathology”, which aims to collect papers that investigate molecular mechanisms underlying the development of disorders of the placenta. Studies delineating candidate diagnostic indicators, experimental in vitro and in vivo studies, animal models, nonanimal model systems, and clinical studies are welcome.

Topics of interest include but are not limited to the following:

The role of trophoblast cells and molecular pathways in implantation and placentation.
Multi-omic approaches to understanding the molecular basis of placental dysfunction, including pre-eclampsia and other obstetric complications.
Novel diagnostic tools and biomarkers for the early detection of placental disorders, with a focus on placental health and the maternal–fetal interface.

Dr. Mary Wallingford
Dr. Ana Correia-Branco
Guest Editors

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 250 words) can be sent to the Editorial Office for assessment.

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-anonymized 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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

placenta
trophoblast
implantation
obstetrics
pre-eclampsia
placentation
maternal–fetal interface
pregnancy health
placenta diagnostics

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
Reprint: MDPI Books provides the opportunity to republish successful Special Issues in book format, both online and in print.

Further information on MDPI's Special Issue policies can be found here.

Related Special Issue

Molecular Insights into Placental Pathology: 2nd Edition in International Journal of Molecular Sciences

Published Papers (9 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

28 pages, 13184 KB

Open AccessArticle

Transcriptomic Analysis of Plac1 Ablation Reveals Broad Alterations in Signaling Pathways Essential for Prenatal Development and Overlap with a Preeclampsia-Associated Signature

by Suzanne Jackman, Xiaoyuan Kong, Yulan Piao, Alexei Sharov, Elin Lehrmann, Andrew Varshine, Ramaiah Nagaraja, David Schlessinger and Michael E. Fant

Int. J. Mol. Sci. 2026, 27(15), 7046; https://doi.org/10.3390/ijms27157046 - 6 Aug 2026

Viewed by 405

Abstract

Plac1 is an X-linked gene essential for placental and embryonic development. A knockout (KO) mouse model was used to define placental gene expression changes associated with Plac1 loss at E16.5 and E18.5 using gene expression microarray. Genes exhibiting at least a 1.5-fold change and FDR < 0.05 were considered significant. At E16.5, 717 genes were downregulated and 796 upregulated in KO placentas relative to wild type (WT), whereas at E18.5, 1121 genes were downregulated and 1151 upregulated. Subsets of highly and uniquely dysregulated genes were examined by gene-level curation alongside systems-level analyses, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Ingenuity Pathway Analysis (IPA), applied to the full differentially expressed gene (DEG) datasets. Downregulated genes were enriched for Rho GTPase-mediated and actin cytoskeleton-based processes, as well as membrane-associated signaling pathways with established roles in placental and embryonic development, vascular function, and branching morphogenesis. Overlap with pathways and molecular features associated with preeclampsia was also observed. In contrast, upregulated genes reflected, in part, immune activation and oxidative stress responses. These findings represent an important exploratory, hypothesis-generating analysis and provide a biologically coherent framework for understanding how Plac1 loss may be associated with placental dysfunction and pregnancy-related disease. Full article

(This article belongs to the Special Issue Molecular Insights into Placental Pathology)

► Show Figures

Figure 1

10 pages, 2455 KB

Open AccessArticle

The Expression of Placental 17β-Hydroxysteroid Dehydrogenase Genes Is Associated with the Elevation of Active Androgens and Estrogens in Pregnant Women, but Does Not Affect 11-Oxygenated C19 Steroids

by Yuko Yokohama, Yugo Watanabe, Ke-ichi Nakajima, Akihiro Umezawa, Satoru Takahashi, Yasuhiro Mori, Yasuhito Kato, Jun-ichi Kawabe and Takashi Yazawa

Int. J. Mol. Sci. 2026, 27(10), 4290; https://doi.org/10.3390/ijms27104290 - 12 May 2026

Cited by 1 | Viewed by 585

Abstract

The placenta produces a variety of steroid hormones through the catalytic activity of steroidogenic enzymes, including cytochrome P450 (CYP) hydroxylases and hydroxysteroid dehydrogenases (HSD). Large amounts of progesterone produced by the placenta are essential for the maintenance of pregnancy. Although androgens and estrogens are also elevated in maternal circulation during gestation, there are conflicting reports on whether de novo synthesis of these steroids occurs in the human placenta. To address this issue, we performed a comprehensive analysis of steroidogenic gene expression in early and term placenta. While none of the genes examined showed binary expression changes, 17β-HSDs, including HSD17B1 and AKR1C3, were markedly upregulated in the term placenta. CYP19A1 and HSD11B2 genes were also markedly upregulated. In contrast, CYP17A1, CYP21A2, CYP11B1, CYP11B2, and HSD17B3 were almost undetectable. Consistent with these findings, the plasma ratios of active to precursor sex steroids (estradiol/estrone and testosterone/androstenedione) were higher in pregnant than in non-pregnant women, although concentrations of all steroids increased. In contrast, plasma levels and profiles of 11-oxygenated androgens were unchanged. These results indicate that the human placenta does not significantly contribute to circulating levels of either classical or novel classes of androgens. Therefore, this study provides new insights into the tissue of origin and the physiological significance of sex steroids during gestation. Full article

(This article belongs to the Special Issue Molecular Insights into Placental Pathology)

► Show Figures

Figure 1

23 pages, 5464 KB

Open AccessArticle

Placental Histiocyte Phenotypes in Chronic Histiocytic Intervillositis: A Comprehensive Immunophenotypic and Morphologic Atlas

by Elise Gradhand, Luisa Strahler, Julia Bein, Margarete Mijatovic, Hannah-Ida Hullmeine, Andreas Weigert, Stephan Spahn, Eva Herrmann, Franz Bahlmann and Ella Hullmeine

Int. J. Mol. Sci. 2026, 27(7), 3024; https://doi.org/10.3390/ijms27073024 - 26 Mar 2026

Cited by 1 | Viewed by 850

Abstract

Chronic histiocytic intervillositis (CHI) is a placental lesion characterized by an inflammatory response, significantly influencing maternal and fetal outcomes. This study aims to develop a comprehensive morphologic atlas detailing the localization of fetal and maternal macrophages within the context of CHI. We employed immunohistochemical and multiplexing techniques to analyze placental samples, identifying expression patterns and spatial distribution of key macrophage markers, including CD68, CD163, CD14, and HLA-DR. The results revealed a marked accumulation of activated macrophages in both the intervillous space and villous stroma, with distinct differences in morphology and immunophenotype of fetal Hofbauer cells versus maternal macrophages. Our findings contribute to a better understanding of the immune landscape in CHI and provide a valuable resource for further research into placental immune dynamics. By establishing this morphologic atlas, we aim to enhance diagnostic and therapeutic strategies for affected pregnancies, thereby improving the diagnostic approach and making it more straightforward to recognize CHI histologically. Full article

(This article belongs to the Special Issue Molecular Insights into Placental Pathology)

► Show Figures

Figure 1

15 pages, 6875 KB

Open AccessArticle

Activation of the S100A8/A9 Alarmin Amplifies Inflammatory Pathways in Equine Ascending Placentitis

by Kirsten E. Scoggin, Shimaa I. Rakha, Ahmed M. Abdellatif, Fatma Adlan, Yosra A. Helmy, Rebecca Ruby, Barry Ball, Yatta Boakari and Hossam El-Sheikh Ali

Int. J. Mol. Sci. 2026, 27(3), 1550; https://doi.org/10.3390/ijms27031550 - 4 Feb 2026

Viewed by 1053

Abstract

Ascending placentitis is a significant cause of equine pregnancy loss, yet the upstream inflammatory triggers are poorly defined. Recently, we identified S100A8/S100A9 (S100A8/A9) alarmins as potential upstream regulators in a chronic equine placentitis model. The current study aimed to determine whether this upregulation is sustained in the acute model and in clinical cases, and to elucidate the expression of their downstream inflammatory mediators. Using an experimental model, we quantified S100A8/A9 mRNA expression in acute (n = 5) and chronic (n = 6) placentitis induced by Streptococcus equi ssp. zooepidemicus. We found mRNA expression of S100A8 and S100A9 was significantly upregulated in chorioallantois during both acute (p < 0.001) and chronic (p < 0.0001) disease compared to controls (n = 5), demonstrating their role is not limited to chronic pathology. A strong positive correlation (r = 0.945) underscored their coordinated expression. Immunohistochemistry revealed minimal staining in controls but dense infiltrations of S100A8/A9-positive neutrophils and macrophages in placentitis tissues. To define the clinical relevance of the downstream pathway, we analyzed RNA sequencing data from clinical placentitis cases (placentitis, n = 4) compared to normal postpartum placenta (control, n = 4). This confirmed upregulation of S100A8/A9 and revealed a concurrent increase in their receptors (TLR4, RAGE) and a spectrum of NF-κB-driven effectors, including pro-inflammatory cytokines (IL1β, IL6, TNF), chemokines (CXCL8, CCL2, CXCL10), and the apoptotic mediator CASP3. Our findings establish that S100A8/A9 upregulation is a sustained feature of equine placentitis and delineates a coherent S100A8/A9-TLR4/RAGE-NF-κB signaling axis that drives inflammation and tissue damage in clinical disease. These findings highlight the diagnostic potential of S100A8/A9 and position this alarmin system as a promising therapeutic target for mitigating infection-induced pregnancy loss. Full article

(This article belongs to the Special Issue Molecular Insights into Placental Pathology)

► Show Figures

Figure 1

26 pages, 6105 KB

Open AccessArticle

Disruption of the Placenta–Brain Axis in Transgenic Mice Lacking Serotonin Transporter (SERT) in Trophoblast Cells

by David T. Ellenberger, Zhen Lyu, Rosalind T. B. Herrington, Jessica A. Kinkade, Gustavo W. Leone, Ji Ying Sze, Nathan J. Bivens, R. Frank Baker, R. Michael Roberts, Trupti Joshi and Cheryl S. Rosenfeld

Int. J. Mol. Sci. 2026, 27(1), 436; https://doi.org/10.3390/ijms27010436 - 31 Dec 2025

Cited by 3 | Viewed by 1960

Abstract

Serotonin reuptake inhibitors (SSRIs) are commonly prescribed to pregnant women experiencing depression. Such drugs, however, might adversely affect placenta and fetal brain development. Parietal trophoblast giant cells (pTGCs) in the mouse placenta are postulated to internalize maternal serotonin (5-HT) via transport through SERT, encoded by Slc6a4, and to provide the initial source of 5-HT to the emerging brain via the placental–brain axis. Genetic deletion of Slc6a4 in pTGCs has been hypothesized to impact placental and fetal brain development. A transgenic mouse line with high-affinity SERT, encoded by Slc6a4, was selectively deleted by pairing mice with Cre recombinase linked to Prl2c2, with LoxP sites flanking the Slc6a4 gene. PRL2C2 is solely expressed by pTGCs and other giant cells of the placenta. To compare placental and fetal brain development in selective Slc6a4 KO and WT mice, 5-HT content in the placenta and fetal brains of conceptuses was measured. No significant differences in 5-HT content were evident between knockout (KO) and wild-type (WT) placentas or fetal brains. However, there were significantly fewer pTGCs in KO placentas compared to WT (p ≤ 0.05). Sexually dimorphic differences in gene expression were evident in the placenta and fetal brain between KO and WT counterparts, with female conceptuses showing the most dramatic responses, including decrease in Prl7a2, Prl5a1, Prl3a1, Slc28a3, and Ceacam 15 in female placental samples. These findings suggest that ablation of Slc6a4 in pTGC disrupts the placenta–brain axis in a sex-dependent manner. The results might have important clinical ramifications for pregnant women being treated with SSRIs. Full article

(This article belongs to the Special Issue Molecular Insights into Placental Pathology)

► Show Figures

Figure 1

23 pages, 3064 KB

Open AccessArticle

Immunohistochemical Analysis of Placental Tissue of Women Infected with SARS-CoV-2 During Pregnancy—A Prospective Clinical Study

by Marija Bicanin Ilic, Tamara Nikolic Turnic, Aleksandar Nikolov, Srdjan Mujkovic, Ivana Likic Ladjevic, Igor Ilic, Marija Spasojevic, Nikola Jovic, Jovana Joksimovic Jovic, Dejana Rakic, Begzudin Ahmetovic, Sara Rosic and Aleksandra Dimitrijevic

Int. J. Mol. Sci. 2025, 26(15), 7659; https://doi.org/10.3390/ijms26157659 - 7 Aug 2025

Cited by 2 | Viewed by 1913

Abstract

SARS-CoV-2 has an affinity for binding to the human Angiotensin-converting enzyme 2 (ACE2) receptor through cleavage and conformational changes at the S1–S2 boundary and the receptor binding domain of the spike protein, which is also the most variable part of SARS-CoV-2. This study aimed to investigate the expression of Angiotensin-converting enzyme 2 (ACE2), spike protein, and CD68+ markers in placental tissue to demonstrate a possible correlation with the level of systemic oxidative stress biomarkers in patients who were infected with SARS-CoV-2 during pregnancy. A prospective clinical cohort study was designed to investigate the presence of CD68+ macrophages, ACE2, and spike proteins in placental tissue using immunohistochemical methods and to compare these results with oxidative stress from our previous study. Spike and CD68+ macrophages’ immunoreactivity were more pronounced in the placental tissue of patients from the SARS-CoV-2 group. Placental tissue spike protein and CD68+ immunoreactivity correlate with maternal and fetal Thiobarbituric Acid Reactive (TBARS) levels. This study has confirmed that spike protein expression in placental tissue is associated with the newborn’s stay in intensive neonatal care. Therefore, immunoreactivity analysis for the Spike antigen is important in detecting newborns at risk of early neonatal complications. Full article

(This article belongs to the Special Issue Molecular Insights into Placental Pathology)

► Show Figures

Figure 1

23 pages, 1185 KB

Open AccessArticle

Potential Molecular Biomarkers of Preeclampsia—A Pilot Study

by Anna Romała, Eliza Matuszewska-Mach, Wiesław Markwitz, Maciej Brązert, Paulina Borysewicz, Dagmara Pietkiewicz, Jan Matysiak, Krzysztof Drews and Agata Szpera

Int. J. Mol. Sci. 2025, 26(13), 6149; https://doi.org/10.3390/ijms26136149 - 26 Jun 2025

Cited by 1 | Viewed by 2529

Abstract

Preeclampsia, one of the leading causes of maternal and fetal morbidity and mortality, affects approximately 3–5% of pregnancies worldwide. However, its etiology remains poorly understood. The aim of this study was to identify molecular markers of preeclampsia. Protein concentrations in blood and urine were determined using the Bio-Plex Kidney Toxicity 1 assay Bio-Rad, Hercules, CA, USA followed by magnetic separation and flow cytometry. This study included 51 patients with preeclampsia and 25 healthy pregnant women. The results revealed that five out of the six serum biomarkers of kidney injury were elevated in the preeclampsia group compared to the control group (calbindin 1, clusterin, glutathione transferase pi (GSTP1), monocyte chemotactic protein 1 (MCP-1), and kidney injury molecule type 1 (KIM-1)). Additionally, the serum concentrations of calbindin 1, clusterin, GSTP1, and KIM-1 were significantly higher in both early-onset and late-onset preeclampsia compared to the control group. The analysis of urinary proteins showed that only the KIM-1 concentration was elevated in late-onset preeclampsia compared to the control group. These findings suggest that the calbindin 1, clusterin, GSTP1, KIM-1, and MCP-1 concentrations in maternal plasma could serve as potential biomarkers for monitoring kidney injury in preeclamptic women. This study provides a foundation for future research to explore novel biomarkers of preeclampsia and renal injury in pregnant women. Full article

(This article belongs to the Special Issue Molecular Insights into Placental Pathology)

► Show Figures

Figure 1

Review

Jump to: Research

23 pages, 6924 KB

Open AccessReview

The KISS1/KISS1R Axis in Human Placentation: Molecular Mechanisms and Implications for Foetal Growth Restriction and Pre-Eclampsia

by Elitsa Gyokova, Eleonora Hristova-Atanasova and Kamelia Dimitrova

Int. J. Mol. Sci. 2026, 27(9), 3748; https://doi.org/10.3390/ijms27093748 - 23 Apr 2026

Viewed by 578

Abstract

Pre-eclampsia and foetal growth restriction (FGR) are major pregnancy complications primarily driven by placental dysfunction, and remain leading causes of maternal and perinatal morbidity. Ultrasound imaging, Doppler studies, and angiogenic biomarkers like placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) constitute the main diagnostic modalities; however, these predominantly reflect established disease rather than early molecular disturbances underlying placentation. The identification of biomarkers directly associated with trophoblast signalling pathways has the potential to improve early risk stratification and enable mechanistic classifications. Kisspeptin signalling via its receptor (KISS1R) regulates trophoblast invasion, extracellular matrix remodelling, ERK1/2 activation, and angiogenic balance, thereby modulating spiral artery transformation. Kisspeptin-10 (KP-10), the minimal bioactive fragment of KISS1, is highly expressed in placental syncytiotrophoblasts and exerts its effects through the G-protein-coupled receptor KISS1R. Core features of early-onset FGR and pre-eclampsia (PE)—including defective placentation, maternal vascular malperfusion, and angiogenic imbalance—have been linked to dysregulation of this pathway. During normal gestation, maternal circulating kisspeptin concentrations rise exponentially. In contrast, pregnancies subsequently complicated by FGR or PE, particularly in the early gestation, are associated with reduced levels. However, the comparability of existing studies and their translational applicability are limited by a substantial methodological heterogeneity, including assay variability, gestational age dependence, and inadequate adjustment for maternal confounders. These limitations hinder robust conclusions regarding the role of kisspeptin in placental pathology. This review critically integrates molecular, pathophysiological, and clinical evidence relating to the role of KP-10 in placental dysfunction. The key question is whether KP-10 represents a mechanistic biomarker of trophoblast signalling dysfunction or merely a secondary marker of reduced placental mass; resolving this distinction is essential. Full article

(This article belongs to the Special Issue Molecular Insights into Placental Pathology)

► Show Figures

Figure 1

23 pages, 2424 KB

Open AccessReview

Molecular Insights into Human Placentation: From Villous Morphogenesis to Pathological Pathways and Translational Biomarkers

by Ioana Vornic, Radu Caprariu, Dorin Novacescu, Alina Cristina Barb, Victor Buciu, Adelina Băloi, Diana Szekely, Cristian Silviu Suciu, Catalin Dumitru, Raul Patrascu, Flavia Zara and Cristina Stefania Dumitru

Int. J. Mol. Sci. 2025, 26(19), 9483; https://doi.org/10.3390/ijms26199483 - 28 Sep 2025

Cited by 13 | Viewed by 3288

Abstract

Placental dysfunction underlies the major obstetric syndromes, including preeclampsia, fetal growth restriction, placenta accreta spectrum, pregnancy loss, and monochorionic twin complications. Recent molecular studies have revealed that dysregulated oxygen sensing, impaired angiogenic signaling, altered immune tolerance, and defective trophoblast fusion represent shared pathogenic pathways that converge across these disorders. Integrating morphological evidence with mechanistic data highlights how villous maldevelopment, shallow trophoblast invasion, and aberrant vascular remodeling translate into clinical disease. Advances in biomarker research have already transformed clinical care: the sFlt-1/PlGF ratio is now established in the prediction and management of preeclampsia, while placental proteins such as PAPP-A and PP13, nucleic acid signatures including cfDNA, cfRNA and miRNAs, and extracellular vesicle cargo show promising potential for early, non-invasive detection of placental pathology. Multi-omics approaches, particularly single-cell and spatial transcriptomics combined with proteomic and metabolomic profiling, are paving the way for composite diagnostic panels that capture the polygenic and multicellular nature of placental disease. This review synthesizes current knowledge of molecular mechanisms, histological correlates, and translational biomarkers, and outlines how precision obstetrics may emerge from bridging mechanistic discoveries with clinical applications. Full article

(This article belongs to the Special Issue Molecular Insights into Placental Pathology)

► Show Figures

Journal Menu

Journal Browser

Molecular Insights into Placental Pathology

Share This Special Issue

Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issue

Published Papers (9 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI