bims-placeb 2025-10-12 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–10–12
nineteen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Morphological and functional aspects of the canine placental barrier: Evidence supporting a deciduo-chorial model.
Real-life per- and polyfluoroalkyl substances mixture impairs placental function: insights from a trophoblast spheroid model.
Regulation of the brain-placental axis, and its relevance to the health and disease of the offspring.
Placental mTOR signalling links mitochondrial dysfunction, nutrient transport and neonatal beta cell perturbations in mice.
Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.
Multi-omic analysis identifies erythroid cells as the major population in mouse placentas expressing genes for antigen presentation in MHC class II, chemokines, and antibacterial immune response.
Placental endocrine function is controlled by maternal gut Bifidobacterium in germ-free mice.
Perfluorooctanesulfonic Acid Facilitates the Migration of Choriocarcinoma Cell Line BeWo: Integrins as Potential Target.
Reproductive organ on-a-chip technologies and assessments of the fetal-maternal interface.
Placenta-Derived Proteins in Preeclampsia: A Human In Vivo Study.
SARS-CoV-2 delta and omicron variants alter trophoblast cell fusion and syncytiotrophoblast dynamics: new insights into placental vulnerability.
Contrast-Invariant Self-supervised Segmentation for Quantitative Placental MRI.
Wnt signalling maintains self-renewal of human hepatoblasts without blocking their differentiation.
Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver Syndrome.
The Mediation Role of the Placental IGF1 Signaling Pathway on Associations between Prenatal PFAS Exposure and Adverse Birth Outcomes: Evidence from Serial Mediation Models.
Identification of GPX3 as a key biomarker of placental ferroptosis in gestational diabetes mellitus via bioinformatics and clinical analysis.
Placental slice techniques in physiology, pathophysiology, and toxicology: A systematic review with a focus on precision-cut slices.
Integrated proteomic and metabolomic analysis reveals lipid metabolic dysregulation and ferroptosis as potential drivers of placental dysfunction in intrahepatic cholestasis of pregnancy.
Sonographic characteristics associated with early pregnancy loss in pregnancies conceived via in vitro fertilization.

Reprod Fertil. 2025 Oct 03. pii: RAF-25-0051. [Epub ahead of print]

Morphological and functional aspects of the canine placental barrier: Evidence supporting a deciduo-chorial model.

Giuliano Mario Corte, Jessica Griebel, Karl Klisch, Mahesa Wiesendanger, Mariusz Paweł Kowalewski.

   Abstract: The canine placenta, characterized by its deciduate and endotheliochorial nature, represents an intermediate placental type between non-invasive and highly invasive placentas. Decidual cells are involved in the prepartum parturition cascade. As they are the only cells expressing the nuclear progesterone receptor (PGR), they play a crucial role in luteal progesterone (P4)-dependent embryo-maternal communication and are essential for maintaining pregnancy. This study focuses on the quantity, morphology, and spatial arrangement of decidual cells. Immunohistochemistry (IHC) was used to localize and quantify PGR-expressing cells. Consecutive tissue sections were evaluated utilizing anti-PGR, -vimentin, and -pan-cytokeratin antibodies, providing insights into decidual cell morphology. This was followed by transmission electron microscopy (TEM) and serial section scanning electron microscopy (SEM) generating high-resolution 2D and 3D images, leading to reconstructions of decidual cells and their morphological interactions with neighboring cellular compartments. A significant reduction in PGR-expressing cells was observed at prepartum luteolysis. Decidual cells were found to be polymorph with extensive cytoplasmic branches, varying individually in their morphology. Further, for the first time, the 3D reconstructions highlighted the complex network of decidual cells, which were shown to form part of the feto-maternal barrier, supporting the existence of a deciduo-chorial interface in the canine placenta. Therefore, we propose a role for decidual cells as a morphological and biochemically active barrier between the fetal and maternal compartments. The decreasing P4/PGR signaling towards prepartum luteolysis is possibly associated with a reduction in the number of decidual cells during the progression of pregnancy as a sign of placental maturation toward parturition.
Lay summary: The dog has a deciduate placenta, meaning that specific maternal cells (decidual cells) form part of the placenta. This placenta shows restricted invasive behavior of fetal cells (trophoblast) into maternal uterine structures. Decidual cells are involved in the hormonal processes leading up to birth. They are the only placental cells expressing the nuclear progesterone receptor (PGR), which allows them to respond to progesterone, needed for the maintenance of pregnancy. This study focuses on the number, shape, and arrangement of decidual cells. We also found a significant reduction in PGR-expressing cells shortly before birth, when progesterone levels decrease. Interestingly, the drop in progesterone signaling is associated with a reduction in the number of decidual cells, indicating maturation of the placenta in preparation for delivery. Using electron microscopy, decidual cells were found to be irregularly shaped with long, branching extensions. For the first time, 3D reconstructions highlighted the complex network of decidual cells, which were shown to form part of the contact zone between mother and fetus - supporting the existence of a new type of interface in the canine placental labyrinth.

Keywords:  Placenta; decidual cells; deciduo-chorial interface; dog

DOI:  https://doi.org/10.1530/RAF-25-0051
Environ Res. 2025 Oct 07. pii: S0013-9351(25)02290-X. [Epub ahead of print] 123037

Real-life per- and polyfluoroalkyl substances mixture impairs placental function: insights from a trophoblast spheroid model.

Yu Xia, Qiuguo Fu, Hermann Voss, Stefan Fest, Susanne Arnold, Mario Bauer, Beate Fink, Ana Claudia Zenclussen, Violeta Stojanovska.

  Per- and polyfluoroalkyl substances (PFAS) are persistent endocrine-disrupting chemicals (EDCs) linked to adverse reproductive outcomes. While the placenta is a known target of PFAS toxicity, most in vitro studies use two-dimensional (2D) cell culture models, often focusing on late-pregnancy tissue or blood PFAS concentrations and examining single compound exposures. In this study, we measure placenta PFAS concentrations in early pregnancy and design a placenta-relevant PFAS mixture to assess its impact on trophoblast function using a three-dimensional (3D) trophoblast spheroid model. PFAS levels in first-trimester placental tissue were quantified using liquid chromatography/triple quadrupole mass spectrometry. Six PFAS: perfluorononanoic acid (PFNA), perfluorooctanesulfonic acid (PFOS), perfluorobutanoic acid (PFBA), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), and perfluorodecanoic acid (PFDA); were selected based on their placenta concentrations and relevance to pregnancy complications to design the placenta real-life PFAS mixture. Next, trophoblast spheroids were propagated from two different cell lines, JEG-3 and HTR-8/SVneo, to assess the effects of PFAS mixture on trophoblast viability, apoptosis, invasion, hormone production, and gene expression. While trophoblast spheroid viability remained largely unaffected, we observed changes in trophoblast function. PFAS exposure significantly increased invasiveness in JEG-3 spheroids at 48 hours, but markedly reduced it in HTR-8/SVneo spheroids at 96 hours across varying concentrations. Additionally, pregnancy-specific hormone e.g. β-hCG production declined after 48 hours of PFAS mixture exposure in JEG-3 spheroids. Gene expression analysis revealed altered apoptosis and proliferation pathways in both trophoblast spheroids. Overall, our study highlights that physiologically relevant 3D trophoblast models can contribute to the broader comprehension of PFAS-associated reproductive health risk assessments.

Keywords:  3D cell culture; PFAS mixture; endocrine disrupting chemicals (EDCs); placenta; trophoblast gene expression; β-hCG

DOI:  https://doi.org/10.1016/j.envres.2025.123037
Syst Biol Reprod Med. 2025 Dec;71(1): 504-523

Regulation of the brain-placental axis, and its relevance to the health and disease of the offspring.

Susanta K Behura.

  The placenta develops as a transient organ during pregnancy to nurture the growing fetus. It supplies nutrients and oxygen to the fetus, collects fetal waste, and safeguards the fetus from infections and adverse pregnancy conditions. Emerging evidence suggests that the placenta plays adaptive functions to protect the developing brain from injury in adverse maternal conditions. Inadequate placental support can impact the developmental process of the brain, which increases the risk of brain diseases among the offspring. There is a remarkable coordination in gene expression between the placenta and fetal brain of mice, suggesting a robust regulation of the brain-placental axis. The deregulation of the brain-placental axis can have adverse effects on the fetal programming of brain development. Defective neuronal development of the fetus due to the abnormal or non-optimal placental functions can lead to an increased risk of different neuropsychiatric diseases in the adult life of the offspring. Thus, there is a growing interest to understand placental influences on fetal brain development and its links to the risk of brain diseases. Research on the brain-placental axis, also referred to as neuroplacentology, is a rapidly emerging interdisciplinary field that integrates concepts and tools from diverse areas, including reproductive biology, neuroscience, epigenetics, systems biology, and data sciences, among others. Recently, large-scale multiomics data and systems biology approaches have been applied to investigate the functional links between the placenta and fetal brain, and to dissect the cellular and molecular mechanisms of the regulation of the brain-placental axis. The primary objective of this review is to outline the current status and the future avenues of this emerging research field that holds huge potential to advance our knowledge about the role of the placenta in the developmental origin of brain health and disease.

Keywords:  Placenta; brain development; fetal origin; fetal programming; psychiatric disorder

DOI:  https://doi.org/10.1080/19396368.2025.2567543
Diabetologia. 2025 Oct 09.

Placental mTOR signalling links mitochondrial dysfunction, nutrient transport and neonatal beta cell perturbations in mice.

Megan Beetch, Eunice Oribamise, Seokwon Jo, Briana Clifton, Sarah Larson, Alex Hausmann, Alicia Wong, Brian Akhaphong, Elizabeth Morgan, Emilyn U Alejandro.

   AIMS/HYPOTHESIS: Fetal programming of metabolic health is influenced by the in utero environment. The placental nutrient sensor mechanistic target of rapamycin (mTOR) is implicated in regulating fetal growth and programming of offspring metabolic health, but the mechanisms are unknown.
METHODS: Using a placental mTOR deficiency model to induce fetal growth restriction (FGR), we investigated mTOR-modulated placental mitochondrial function, nutrient transport and developmental programming of pancreatic beta cells, which are exquisitely sensitive to nutrient levels in utero.
RESULTS: We found defects in placental mitochondria function and morphology that were specific to placentas of mTOR knockout (mTORKO) mice. Despite smaller placentas and FGR in both sexes, nutrient transporter expression and leucine flux were paradoxically increased in female mTORKO placentas. Female fetuses exposed to placental mTOR deficiency (mTORKOpl) displayed significantly reduced circulating insulin without neonatal perturbations in insulin secretion. However, average beta cell size and proliferation were increased in mTORKOpl female fetuses, possibly driven by system A (SNAT) amino acids, suggesting an immature beta cell phenotype. Adult mTORKOpl female offspring exhibit increased susceptibility to diet-induced obesity, insulin resistance and inability to mount a beta cell mass response to a hypernutrient environment.
CONCLUSIONS/INTERPRETATION: Our novel in vivo model of direct placental mTOR-driven FGR provides strong evidence linking placental dysfunction and amino acid transport to proper programming of beta cells in early life.

Keywords:  Amino acid transport; Beta cells; Insulin secretion; Mitochondria; Placenta; mTOR signalling

DOI:  https://doi.org/10.1007/s00125-025-06542-z
Placenta. 2025 Oct 01. pii: S0143-4004(25)00704-0. [Epub ahead of print]171 140-149

Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.

Leena Kadam, Kaylee Chan, Ethan Tawater, Leslie Myatt.

   INTRODUCTION: The placenta is exposed to an altered metabolic environment in obesity and gestational diabetes (GDM) leading to disruption in placental function. Mitochondria are critical for energy production and cellular adaptation to stress. We previously reported reduced trophoblast mitochondrial respiration in GDM. Here we examine changes in mitochondrial structure dynamics, quality and protein homeostasis as well as clearance in male and female placentas of pregnancies complicated by obesity and GDM. As obesity significantly increases the risk for GDM, our goal is to determine the distinct effects of each on placental mitochondria.
METHODS: We collected placental villous tissue following elective cesarean section at term from lean (LN, pre-pregnancy BMI 18.5-24.9), obese (OB, BMI>30) or obese with type A2 GDM women. Expression of proteins involved in mitochondrial biogenesis, structure dynamics, quality control and clearance were assessed by Western blotting. Significant changes between groups were determined in fetal sex-dependent and independent manner.
RESULTS: Only placentas from obese women showed increase in proteins regulating mitochondrial biogenesis (PGC-1α and SIRT1). We report fetal sex-specific changes in mitochondrial fusion but an overall decline in fission in OB and GDM placentas. Both maternal obesity and GDM affected proteins involved in maintaining mitochondrial protein quality and genome stability. This was accompanied by a reduction in mitochondrial complexes, suggesting impaired mitochondrial function. Obesity led to partial activation of mitophagy pathways (e.g., increased PINK1 without PARKIN activation), but GDM placentas failed to mount this response.
DISCUSSION: Obesity and GDM affect placental mitochondria through distinct complex sex-specific mechanisms that may contribute to altered mitochondrial function.

Keywords:  Diabetes; Mitochondria; Obesity; Placenta; Pregnancy

DOI:  https://doi.org/10.1016/j.placenta.2025.09.019
Front Immunol. 2025 ;16 1644983

Multi-omic analysis identifies erythroid cells as the major population in mouse placentas expressing genes for antigen presentation in MHC class II, chemokines, and antibacterial immune response.

Olga Perik-Zavodskaia, Roman Perik-Zavodskii, Saleh Alrhmoun, Kirill Nazarov, Julia Shevchenko, Konstantin Zaitsev, Sergey Sennikov.

   Introduction: Pregnancy is a complex process that requires a tightly regulated immune environment to support fetal development and protect against infections. The main barrier between fetus and mother is a specialized organ, the placenta, where the role of specific immune cell populations remains incompletely understood.
Methods: In this work, we used spatial transcriptomics at E12.5 to characterize immune and non-immune cell heterogeneity and spatial organization in the mouse placenta. In addition, we performed murine placental mononuclear cell flow cytometry proteomics, murine placental erythroid cell NanoString bulk transcriptomics, and murine placental erythroid cell LegendPlex secretomics at E12.5 and E19.5 to further analyze the immune landscape in the mouse placenta. We also performed single-cell RNA sequencing of human cord blood erythroid cells for cross-species comparisons.
Results: Our results show that erythroid cells constitute the predominant immunoregulatory population in murine placentas, comprising on average 80% and 40% of the placental mononuclear cells at E12.5 and E19.5, respectively, expressing Ctss, Cd74, H2-Aa, and H2-Ab1 genes involved in antigen presentation via MHC-II, and a PD-L1 checkpoint inhibition molecule gene expression. They also have gene expression of such immunomodulatory molecules as Tgfb1 and Tgfb3 cytokines, Ccl2, Ccl3, Ccl4, Ccl9, Cxcl1, Cxcl12, and Mif chemokines, and antimicrobial protein calprotectin S100a8, S100a9 genes.
Discussion: These results indicate that erythroid cells may act as potent regulators of immunity in murine placentas due to their vast number and repertoire of immunoregulatory molecules, shaping the immune landscape through diverse immunoregulatory mechanisms.

Keywords:  CD71+ erythroid cells; NanoString; erythroid cells; fetomaternal tolerance; placenta; pregnancy; scRNA-seq; spatial transcriptomics

DOI:  https://doi.org/10.3389/fimmu.2025.1644983
J Transl Med. 2025 Oct 07. 23(1): 1031

Placental endocrine function is controlled by maternal gut Bifidobacterium in germ-free mice.

Jorge Lopez-Tello, Raymond Kiu, Zoe Schofield, Matthew J Dalby, Douwe van Sinderen, Gwénaëlle Le Gall, Lindsay J Hall, Amanda N Sferruzzi-Perri.

   BACKGROUND: Recent studies have shown that the maternal gut microbiota can regulate placental growth, particularly the transport region, in association with fetal growth. However, the specific role of certain microorganisms in modulating the hormonal production of the placenta, which is critical for supporting fetal development and maintaining a healthy pregnancy, remains largely unexplored. In this context, the objective of this study is to determine whether the maternal colonisation with the early life gut bacterium Bifidobacterium breve UCC2003 regulates placental endocrine function.
METHODS: Pregnant germ-free mice were colonized with or without Bifidobacterium breve UCC2003 (BIF) during pregnancy. The endocrine region of the placenta (junctional zone, Jz) was collected to assess its metabolic profile using metabolomics, the expression of key nutrient uptake genes, hormones and synthetic genes by qPCR, and proteome using LC-MS/MS.
RESULTS: BIF colonised dams had increased lactate and taurine concentrations in the placental Jz. BIF presence was also associated with upregulated expression of nutrient carriers, particularly those involved in large neutral amino acid and monocarboxylate uptake (e.g., Slc7a8 and Slc16a4). Additionally, key hormones, such as prolactins and pregnancy-specific glycoproteins, were upregulated. The Jz proteome was changed in BIF colonised dams, with over 400 proteins dysregulated. Pathway analysis revealed more than 150 biological processes were altered, including transcriptional activity, protein synthesis, cell cycle progression, and metabolic regulation. Proteins regulated by BIF in the placental Jz were correlated with fetal growth and nutrient levels (namely glucose). Notably, maternal-associated BIF reduced the number of fetal resorptions (early fetal loss).
CONCLUSIONS: In germ-free mice, maternal-associated gut Bifidobacterium breve UCC2003 regulates placental endocrine capacity, by altering its metabolic profile and ability to produce endocrine factors. This study provides the first clear evidence that the maternal gut microbiota not only influences placental transport function, but also regulates its endocrine outputs.

Keywords:  Bifidobacterium; Endocrinology; Gut; Microbiota; Placenta; Pregnancy

DOI:  https://doi.org/10.1186/s12967-025-07198-4
Environ Pollut. 2025 Oct 03. pii: S0269-7491(25)01584-2. [Epub ahead of print] 127210

Perfluorooctanesulfonic Acid Facilitates the Migration of Choriocarcinoma Cell Line BeWo: Integrins as Potential Target.

Jing Li, Maoxing Pan, Qingyuan Dai, Yongfeng Deng, Shuqin Tang, Hongli Tan.

  The migration of placental trophoblasts is a crucial biological process essential for the maintenance of pregnancy. Perfluorooctanesulfonic acid (PFOS), a prototypical per- and polyfluoroalkyl substance, has been linked to a variety of adverse pregnancy outcomes. However, the regulatory effects and molecular mechanisms of PFOS on trophoblast migration, particularly at concentrations reflective of human internal exposure, remain inadequately explored. In this study, we utilized the BeWo choriocarcinoma cell model to evaluate PFOS effects on trophoblast migration at human internal exposure concentrations (0.02 μM, 0.2 μM, and 2.0 μM). Our findings reveal that PFOS significantly promotes trophoblast migration in a dose-dependent manner. Mechanistic profiling identified dysregulated activation of the extracellular matrix (ECM)-receptor interaction pathway and metabolic reprogramming, notably in amino acid metabolism, as potential drivers of this promoted migration. Further, integrin α5 (ITGA5), α3 (ITGA3), and α2 (ITGA2) were identified as putative molecular targets of PFOS. These findings, despite originating from BeWo choriocarcinoma cells model, provide novel mechanistic insights into the link between environmental PFOS exposure and placental dysfunction, thereby contributing to our understanding of the molecular basis underlying PFOS-associated pregnancy complications.

Keywords:  Cell migration; ECM-receptor interaction pathway; Integrins; PFOS; Placental trophoblast cells

DOI:  https://doi.org/10.1016/j.envpol.2025.127210
Front Lab Chip Technol. 2024 ;3

Reproductive organ on-a-chip technologies and assessments of the fetal-maternal interface.

Hannah A Richards, Alison J Eastman, Dusty R Miller, David E Cliffel.

  In this review, we discuss recent reproductive organ-on-a-chip (OoC) experiments that encompass multiple target areas of investigation, including model fabrication strategies, transport mechanisms, and immunology. We highlight fetal membrane and placental biology, OoC history and background, and the designs of reproductive OoC platforms. Reproductive OoC designs include fetal membrane models such as the Fetal Membrane-on-a-chip (FMOC) and others, placental models such as the placenta on-a-chip, and full reproductive tract models such as EVATAR. Diverse fabrication strategies and the integration of multiple model materials are explored. OoC samples can be analyzed with many analytical techniques, including mass spectrometry, fluorescence microscopy, ELISAs, impedance spectroscopy, and electrochemical techniques. The future of reproductive OoC models is a promising technology for advancing preterm birth (PTB) research, pharmacology studies, and fertility technologies.

Keywords:  female reproductive tract; fetal membrane on-a-chip; fetal membranes; microfluidic; organ-on-chip; placenta

DOI:  https://doi.org/10.3389/frlct.2024.1449303
Hypertension. 2025 Oct 09.

Placenta-Derived Proteins in Preeclampsia: A Human In Vivo Study.

Ane Cecilie Westerberg, Maren-Helene Langeland Degnes, Ina Jungersen Andresen, Hilde Sellevoll, Tove Lekva, Thor Ueland, Lina Bergman, Tore Henriksen, Marie Cecilie Paasche Roland, Manuela Zucknick, Trond Melbye Michelsen.

   BACKGROUND: Placental dysfunction, a key feature of preeclampsia, has been linked to altered placental release of proteins into the maternal circulation. However, the identity of placenta-derived proteins in preeclampsia is unclear due to the inaccessibility of the placenta during pregnancy. This study aimed to identify placenta-derived proteins in preeclampsia, characterize their associated biological processes, and assess their biomarker potential.
METHODS: We used the 4-vessel sampling method to collect blood from the ingoing and outgoing vessels of the placenta during cesarean section to identify proteins secreted from the placenta. Prospectively collected samples from a separate pregnancy cohort were also included. Proteins were quantified on the SomaLogic 5000-plex platform.
RESULTS: We identified 620 placenta-derived proteins, including 229 proteins released in both healthy pregnancies and in preeclampsia, 345 proteins released in preeclampsia only, and 46 proteins released in healthy controls only. Biological process gene ontologies linked to oxidative stress and cellular turnover were enriched among the placenta-derived proteins in preeclampsia, but not in healthy pregnancies. In the prospective cohort, 21 of the 620 placenta-derived proteins had altered levels in preeclampsia at least 3 weeks before, and on average >7 weeks before delivery. Among these, prediction performance for preeclampsia was promising for 11 biomarker candidates in single protein models (area under the curve >0.7) and 17 significantly improved prediction when combined with clinical variables as compared with a clinical model alone.
CONCLUSIONS: Using a unique in vivo sampling method, we identified placenta-derived proteins in preeclampsia, several of which showed promising biomarker potential.

Keywords:  biomarkers; gene ontology; placenta; preeclampsia; pregnancy

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.125.24886
Cell Death Dis. 2025 Oct 07. 16(1): 718

SARS-CoV-2 delta and omicron variants alter trophoblast cell fusion and syncytiotrophoblast dynamics: new insights into placental vulnerability.

Manel Essaidi-Laziosi, Catia Alvarez, Michal Yaron, Pascale Sattonnet-Roche, Kenneth Adea, Mélanie Cornut, Christine Wuillemin, Meriem Bekliz, Yoann Sarmiento, Chloe Gibson, Laurent Kaiser, Anne-Laure Rougemont, Isabella Eckerle, Marie Cohen.

Pregnancy is associated with an increased risk of severe COVID-19. In addition, SARS-CoV-2 infection during gestation has been linked to adverse obstetrical outcomes and placental abnormalities. Nevertheless, the susceptibility of early trophoblast cells to SARS-CoV-2 and the potential consequences of infection on trophoblast function remain unclear. In this study, we assessed the permissiveness of first trimester trophoblast cells to SARS-CoV-2 infection and its impact on trophoblast cells fusion. To address this, we isolated primary cytotrophoblast (CTB) cells from first trimester human placentas and allow their differentiation into STB in vitro. These cells were infected with SARS-CoV-2 variants of concern, including Delta and Omicron (BA.1, BA.2, BA.5). Viral replication was assessed by RT-qPCR and immunofluorescence, while host cell responses, including expression of viral entry receptors and innate immunity genes, were measured by RT-qPCR. Trophoblast fusion was evaluated by staining and calculating the fusion index. In parallel, placental tissues from SARS-CoV-2-infected pregnancies were analyzed by immunohistochemistry to quantify syncytial knots (SK) formation in vivo. Our results demonstrate that both first trimester CTB and STB are permissive to SARS-CoV-2 infection in a variant- and donor-dependent manners, with Delta exhibiting higher replication efficiency compared to Omicron variants. In STB, viral replication did not correlate with the induction of entry receptors or type III interferon responses. However, in CTB, viral replication was significantly associated with enhanced cell fusion. In parallel, an increased number of SK was observed in infected placental areas in vivo compared to non-infected regions from the same placenta and to gestational age-matched controls. Altogether, these in vitro and in vivo results suggest that SARS-CoV-2 infection in early pregnancy may alter STB turnover, potentially contributing to placental dysfunction and adverse pregnancy outcomes.

DOI: https://doi.org/10.1038/s41419-025-08016-x
Perinat Preterm Paediatr Image Anal (2025). 2026 ;16118 141-152

Contrast-Invariant Self-supervised Segmentation for Quantitative Placental MRI.

Xinliu Zhong, Ruiying Liu, Emily S Nichols, Xuzhe Zhang, Andrew F Laine, Emma G Duerden, Yun Wang.

  Accurate segmentation is critical for quantitative analysis of the placenta, yet remains challenging in T2*-weighted MRI due to echo-dependent contrast variation and limited manual annotations across echoes. We propose a contrast-augmented segmentation framework that exploits the inherent diversity of multi-echo T2*-weighted MRI to learn robust, contrast-invariant representations. Our method integrates: (i) masked autoencoding (MAE) for self-supervised pretraining on unlabeled multi-echo slices; (ii) masked pseudo-labeling (MPL) for semi-supervised domain adaptation across echo times; and (iii) global-local collaboration to align patch-level features with global anatomical context. We further introduce a semantic matching loss to encourage representation consistency across echoes of the same subject. Experiments on a clinical multi-echo placental MRI dataset demonstrate that our approach generalizes effectively across echo times and outperforms supervised baselines. To our knowledge, this is the first systematic framework tailored to multi-echo placental segmentation in T2*-weighted MRI.

Keywords:  MRI; Placenta; Segmentation; Self-Supervised Learning

DOI:  https://doi.org/10.1007/978-3-032-05997-0_13
Development. 2025 Oct 10. pii: dev.205026. [Epub ahead of print]

Wnt signalling maintains self-renewal of human hepatoblasts without blocking their differentiation.

Ekaterini D Zacharis, Carola M Morell, Rute A Tomaz, Arash Shahsavari, Charlotte Grey-Wilson, Maïa Pesic, Vasileios Galanakis, Eleanor C Williams, Irina Mohorianu, Irene Talon, Ludovic Vallier.

  Hepatoblasts play a key role in liver organogenesis by differentiating into hepatocytes and cholangiocytes, the main functional cell types of the liver. Mouse studies have shown the association of Wnt signalling with proliferation and differentiation of hepatoblasts. However, the exact function of this pathway in hepatic development is not fully uncovered, especially in human. Here, we use hepatoblast organoids (HBOs) derived from human foetal livers to investigate the importance of Wnt signalling in self-renewal and cell fate decisions during liver development. We first showed that Wnt plays a key role in hepatoblast self-renewal capacity in vitro by maintaining their proliferative state. However, Wnt was not sufficient to block differentiation of HBOs into hepatocytes or cholangiocytes, suggesting that other factors are necessary to maintain hepatoblast bipotency. Finally, single-cell transcriptomic analyses revealed that Wnt signalling activity correlates with hepatoblast proliferation in the human foetal liver, suggesting that the role for Wnt could be conserved in vivo. Taken together, our results support a model where Wnt signalling acts to preserve the proliferative capacity of hepatoblasts without being sufficient to maintain their bipotent state.

Keywords:  Cholangiocyte; Hepatoblast; Hepatocyte; Organoid; liver

DOI:  https://doi.org/10.1242/dev.205026
J Clin Invest. 2025 Oct 07. pii: e187532. [Epub ahead of print]

Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver Syndrome.

Alyssa F Solano, Kristina Preusse, Brittany Cain, Rebecca Hotz, Parthav Gavini, Zhenyu Yuan, Benjamin Bowen, Gabrielle Maco, Hope Neal, Ellen K Gagliani, Christopher Ahn, Hee-Woong Lim, Laura Southgate, Rhett A Kovall, Raphael Kopan, Brian Gebelein.

  Adams-Oliver Syndrome (AOS) is a rare congenital disorder characterized by scalp, limb, and cardiovascular defects. While variants in the NOTCH1 receptor, DLL4 ligand, and RBPJ transcription factor have been implicated in AOS, the driving tissue types and molecular mechanisms by which these variants cause pathogenesis are unknown. Here, we used quantitative binding assays to show that AOS-associated RBPJ missense variants compromise DNA binding but not cofactor binding. These findings suggest that AOS-associated RBPJ variants do not function as loss-of-function alleles but instead act as dominant-negative proteins that sequester cofactors from DNA. Consistent with this idea, mice carrying an AOS-associated Rbpj allele develop dominant phenotypes that include increased lethality and cardiovascular defects in a Notch1 heterozygous background, whereas Notch1 and Rbpj compound heterozygous null alleles are well-tolerated. To facilitate studies into the tissues driving AOS pathogenesis, we employed conditional genetics to isolate the contribution of the vascular endothelium to the development of AOS-like phenotypes. Importantly, our studies show that expression of the Rbpj AOS allele in endothelial cells is both necessary and sufficient to cause lethality and cardiovascular defects. These data establish that reduced Notch1 signaling in the vasculature is a key driver of pathogenesis in this AOS mouse model.

Keywords:  Development; Embryonic development; Genetic diseases; Mouse models; Vascular biology

DOI:  https://doi.org/10.1172/JCI187532
Environ Sci Technol. 2025 Oct 10.

The Mediation Role of the Placental IGF1 Signaling Pathway on Associations between Prenatal PFAS Exposure and Adverse Birth Outcomes: Evidence from Serial Mediation Models.

Qiong Zhang, Yi Zhang, Jian Chen, Shaoya Huang, Jun Chen, Xiaohua Huang, Hao-Chen Lin, Fei-Fei Qu, Guang-Hui Dong, Jinbo Huang, Dan Cai, Xiao-Wen Zeng.

  Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) is associated with adverse birth outcomes, yet mechanistic pathways remain unclear. We measured 32 maternal serum PFAS (including their alternatives and isomers) and quantified placental mRNA levels of insulin-like growth factor 1 (IGF1), the IGF1 receptor (IGF1R), and the insulin receptor (INSR), alongside serum IGF1 and insulin levels, in 285 mother-infant pairs from the Maoming birth cohort. We applied simple, serial, and moderated mediation models to investigate placental IGF1 signaling as a mediator of PFAS-related preterm birth (PTB), low birth weight (LBW), and small-for-gestational-age (SGA). Simple mediation showed placental IGF1R mediated 15.08%-41.18% of associations between perfluorooctanesulfonate (PFOS) isomers and PTB (odds ratios [ORs-total effect]: 1.06-1.10), LBW (ORs: 1.05-1.10), or SGA (ORs: 1.05-1.10). Serial mediation identified a sequential pathway: PFOS exposure correlated with altered IGF1 expression, followed by IGF1R changes, and subsequent associations with PTB (ORs: 1.01-1.02), LBW (ORs: 1.01-1.02), and SGA (ORs: 1.01-1.02). Moderated mediation highlighted serum IGF1 and insulin as modifiers of these relationships. Molecular docking demonstrated preferential binding of branched PFOS to IGF1R's ligand-binding domains. This study integrates advanced mediation frameworks and molecular evidence to demonstrate that placental IGF1 signaling mediates PFAS-related adverse birth outcomes, elucidating mechanisms of developmental toxicity.

Keywords:  adverse birth outcomes; moderated mediation model; per- and polyfluoroalkyl substances; placental IGF1 signaling; prenatal exposure; serial mediation model

DOI:  https://doi.org/10.1021/acs.est.5c03825
Mol Divers. 2025 Oct 10.

Identification of GPX3 as a key biomarker of placental ferroptosis in gestational diabetes mellitus via bioinformatics and clinical analysis.

Padmanaban M Abirami, K L Milan, M Anuradha, Kunka Mohanram Ramkumar.

  Gestational diabetes mellitus (GDM) is characterized by glucose intolerance during pregnancy, and emerging evidence implicates dysregulated iron metabolism as a critical modulator of its pathogenesis. Ferroptosis, an iron-mediated cell death, has recently been studied in GDM, with research beginning to unravel the connection between iron-induced oxidative stress and placental dysfunction. In this study, we employed datasets from the Gene Expression Omnibus database to identify markers of ferroptosis that are associated with GDM. A total of 57 differentially expressed genes related to ferroptosis were identified. Feature selection was performed using machine learning approaches, including Boruta, Random Forest, and LASSO regression, to pinpoint the most critical genes. Among them, GPX3 emerged as the central biomarker linked to ferroptosis in GDM. We further validated GPX3 expression across various placental cell types using single cell RNA sequencing data. Further CIBERSORT analysis determined a significant association between GPX3 and several immune cell populations, including macrophages, B cells, monocytes, and T cells. Finally, mRNA expression of GPX3 was experimentally validated in placental samples from GDM patients, where it was found to correlate with a reduced sTFR/ferritin ratio, suggesting disrupted iron homeostasis. In conclusion, GPX3 is identified as a crucial immuno-ferroptotic biomarker in GDM, with potential diagnostic value. Integrating bioinformatics, machine learning, and clinical validation, this study highlights the role of GPX3 at the intersection of immune infiltration and iron metabolism, offering new insights for future diagnostic and therapeutic strategies in GDM.

Keywords:  Bioinformatics; Ferroptosis; Gestational diabetes mellitus; Machine learning; Placenta

DOI:  https://doi.org/10.1007/s11030-025-11373-6
Placenta. 2025 Oct 01. pii: S0143-4004(25)00708-8. [Epub ahead of print]171 150-177

Placental slice techniques in physiology, pathophysiology, and toxicology: A systematic review with a focus on precision-cut slices.

H Wang, F A Elzinga, A Nagelkerke, D J Touw, F Rozendaal, L A Hillawie, D Haan, B Brook, S J Gordijn, J R Prins, P Olinga, P Mian.

  Placental precision-cut tissue slices offer an advanced in vitro model that preserves tissue architecture and microenvironment, improving physiological relevance over traditional methods such as animal models and cell lines. This systematic review summarizes the methods and applications of placental slices in research. A PRISMA-guided systematic review was conducted in PubMed and Embase to identify studies involving slicing techniques in placenta-related research published up to June 6, 2025. Primary articles using human or animal placental slices for culture were included. Key study variables, including study aims, placenta characteristics, slice techniques, culture conditions, viability assessments, and main findings were extracted and analyzed. A total of 52 studies were included. Of these studies, 30 used human placenta (90.0 % from term pregnancies) and 24 used animal placentas (87.6 % late-term). Slicing methods were described in 33 studies, with 14 of those were manually prepared. The most commonly used culture condition was Krebs-Ringer bicarbonate buffer (36.5 %), combined with 95 % O2 and 5 % CO2 (79.5 %). Only eight studies conducted viability assessments, with histological morphology being the most frequently used approach. Based on research focus, the studies were categorized into physiological (69.2 %), pathophysiological (17.3 %), and toxicological (13.4 %) studies. In conclusion, this review summarizes current applications of placental slicing techniques and highlights the methodological diversity across studies. The variability in approaches underscore the need for standardized protocols, while the collective evidence supports the use of placental slices as a promising model for investigating placental physiology, pathophysiology, and toxicology.

Keywords:  In vitro models; Placental precision-cut slices; Slicing techniques

DOI:  https://doi.org/10.1016/j.placenta.2025.09.022
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Oct 03. pii: S1388-1981(25)00100-3. [Epub ahead of print]1871(1): 159692

Integrated proteomic and metabolomic analysis reveals lipid metabolic dysregulation and ferroptosis as potential drivers of placental dysfunction in intrahepatic cholestasis of pregnancy.

Ruirui Dong, Gaoying Wang, Yingxian Shi, Jianyi Gao, Wen Hu, Ting Zhang.

  Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse fetal outcomes, while current biomarkers such as total bile acid remain suboptimal. This study aimed to identify novel biomarkers and clarify metabolic pathways underlying ICP through integrated metabolomic and proteomic analyses. Placental profiles were obtained from ICP model rats and healthy controls, with differential metabolites and proteins validated in human placental and serum samples. Multiomics integration revealed prominent dysregulation of lipid metabolism, particularly fatty acid degradation and biosynthesis, highlighting lipids as central players in ICP. Palmitic acid and acyl-CoA synthetase long chain family member 1 (ACSL1) were central to these pathways, markedly elevated in ICP, and showed high diagnostic value (area under the curve 0.794 and 0.825), with combined detection reaching 0.894. Both markers also stratified patients by disease severity, suggesting their potential use for disease monitoring and risk classification. Moreover, ferroptosis was implicated in ICP pathophysiology, supported by validations in both patient placental tissues and taurocholic acid (TCA)-treated trophoblast cells, showing reduced glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) together with increased six-transmembrane epithelial antigen of prostate 3 (STEAP3), transferrin receptor protein 1 (CD71), and acyl-CoA synthetase long-chain family member 4 (ACSL4). In summary, palmitic acid and ACSL1 represent promising biomarkers for ICP diagnosis and classification, while ferroptosis contributes to ICP-related placental dysfunction. These findings provide comprehensive evidence linking altered lipid metabolism and ferroptosis to ICP, offering new insights for clinical diagnosis and potential therapeutic strategies.

Keywords:  Biomarker; Ferroptosis; Intrahepatic cholestasis of pregnancy (ICP); Metabolomics; Multi-omics; Proteomics

DOI:  https://doi.org/10.1016/j.bbalip.2025.159692
Eur J Obstet Gynecol Reprod Biol. 2025 Oct 06. pii: S0301-2115(25)01035-8. [Epub ahead of print]315 114759

Sonographic characteristics associated with early pregnancy loss in pregnancies conceived via in vitro fertilization.

Nguyen Thao Thi Nguyen, Lester Watch, Carmen Rauh Garrido, Alexandra Bickett, Shakthi Unnithan, Tracy Truong, Alaattin Erkanli, Shelby Neal.

   RESEARCH QUESTION: Can gestational age-based sonographic criteria with near 100% positive predictive value (PPV) for early pregnancy loss (EPL) be established in pregnancies conceived via in vitro fertilization (IVF)?
DESIGN: A retrospective cohort study was conducted at a single academic IVF clinic, including all patients with a positive pregnancy test following embryo transfer between 2014 and 2021. Logistic regression assessed associations between gestational age and presence of sonographic markers (gestational sac, embryo, cardiac activity) with EPL. Youden's Index identified optimal gestational age cut-points for each marker.
RESULTS: The study included 913 patients (mean age 35.5 ± 4.8 years; mean BMI 27.6 ± 6.5 kg/m2). Most underwent frozen single embryo transfer at the blastocyst stage; 15.1 % had preimplantation genetic testing for aneuploidy (PGT-A). Outcomes included 727 live births (79.6 %), 176 EPLs (19.3 %), 3 stillbirths, and 7 terminations. Absence of a gestational sac or embryo by 44 days, or cardiac activity by 46 days, yielded PPVs for EPL of 100 %, 100 %, and 97 %, respectively. Logistic regression confirmed increased odds of EPL with absent markers at the specified gestational age cut-points: absence of a gestational sac at 44 days (OR 5.52, 95 % CI [3.40-8.94]), absence of an embryo at 44 days (OR 5.88, CI [3.64-9.49]), and absence of cardiac activity at 46 days (OR 2.86, CI [1.99-4.12]).
CONCLUSIONS: In IVF pregnancies, known gestational age may allow for earlier diagnosis of EPL, as compared to traditional criteria, which are based upon sonographic markers alone. Larger studies are needed to validate these proposed criteria and compare them to traditional criteria for diagnosis of EPL.

Keywords:  Early pregnancy loss; Gestational age; IVF; Miscarriage; Sonographic markers

DOI:  https://doi.org/10.1016/j.ejogrb.2025.114759