bims-placeb 2026-03-01 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–03–01
ten papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Evaluating chemotherapy-driven placental alterations and their impact on fetal development.
A primary cell-based fluidic co-culture model to investigate drug transport across the human placenta.
Single-cell analysis reveals the metabolic characteristics of porcine trophoblast cells during early pregnancy.
Polarized secretion of extracellular vesicles from the placenta to maternal and fetal bloodstreams in rats.
Polystyrene Nanoparticles Disrupt Oxidative Phosphorylation and Impair Placental Development in Mice.
Epithelial-mesenchymal plasticity in trophoblast differentiation.
SARS-CoV-2 infects human primary cytotrophoblasts mainly through a non-canonical entry route.
Regulation of Phosphatidylinositol Synthesis in Human Primordial Placenta.
The Placenta as a Target Organ for Poly- and Perfluoroalkyl Substances (PFASs): Molecular Mechanisms of Toxicity.
Placental ferroptosis in preeclampsia: An integrative and comprehensive review.

Front Toxicol. 2025 ;7 1688641

Evaluating chemotherapy-driven placental alterations and their impact on fetal development.

Katrien De Clercq, Carolina Velazquez, Eleonora Persoons, Vera Wolters, Marieke Van de Ven, Frédéric Amant.

   Background: Chemotherapy during pregnancy presents a clinical challenge, balancing maternal treatment efficacy with fetal safety. While chemotherapy after the first trimester is generally considered safe, its impact on placental development remains underexplored. This study investigates the effects of commonly used chemotherapeutic agents (CAs), including anthracyclines, taxanes, and platinum-based compounds, on maternal, placental, and fetal outcomes using a mouse model.
Methods: To model the chemotherapy exposure during pregnancy, pregnant mice received a single CA dose at embryonic day 13.5 (E13.5), equivalent to the beginning of the second trimester in human gestation. Placental and fetal outcomes were assessed at E15.5 and E18.5 using contrast-enhanced microtomography (micro-CT) and histopathological analyses to investigate the alterations associated to the exposure to differen CAs.
Results: Platinum-based agents, particularly carboplatin, significantly reduced fetal and placental weights and altered placental morphology, with persistent effects observed at E18.5. Contrast-enhanced microtomography (micro-CT) and histopathological analyses revealed reduced placental volumes, in both the labyrinth and junctional zones, and increased signs of trophoblast degeneration. Despite these changes, embryonic viability and litter size remained unaffected, suggesting that fetal growth restriction may be driven by placental insufficiency rather than direct fetal toxicity.
Conclusion: These findings underscore the importance of placental assessment in evaluating chemotherapy safety during pregnancy and highlight the potential long-term implications of platinum-based treatments on fetal development.

Keywords:  chemotherapy; contrast-enhanced microtomography; fetal-toxicity; placenta; pregnancy

DOI:  https://doi.org/10.3389/ftox.2025.1688641
J Physiol. 2026 Feb 26.

A primary cell-based fluidic co-culture model to investigate drug transport across the human placenta.

Barbara Fuenzalida, Nadja Koechli, Edgar Ontsouka, Chennakesava Cuddapah, Martin Mueller, Bram Sengers, Frantisek Staud, Christiane Albrecht.

  Although women often need to take medication during pregnancy, reliable human-based models mimicking the maternal-fetal interface and allowing predictions on drug transport across the human placenta are scarce. In this study, we developed a novel microfluidic Transwell-based co-culture model consisting exclusively of primary cells (trophoblasts/endothelial cells) for assessing maternal-fetal drug transfer. We aimed to (1) investigate the effects of fluidic flow on drug transfer patterns, (2) evaluate barrier integrity and different transfer processes (diffusion, active transport) across the combined trophoblast/endothelial monolayers and (3) determine the expression and functional activity of main placental drug efflux transporters (ABCB1 and ABCG2). After applying different flow rates (50/150 µl/min), our system maintained cellular integrity and barrier function while enhancing syncytialization markers such as hCG. Our model effectively mimics key features of the placental microenvironment, including polarized expression and functional activity of both efflux transporters. Using fluorescent substrates and specific inhibitors (ABCB1: Rhodamine 123/Cyclosporin A; ABCG2: Bodipy-FL-Prazosin/Ko123), we confirmed that both transporters are not only expressed in the primary co-cultures, but also actively restrict the passage of compounds in the mother-to-fetus direction. Importantly, our system also captured passive diffusion dynamics of reference compounds (antipyrine/caffeine), with transport rates increasing under higher flow, mirroring in vivo behaviour. While our model does not yet replicate the full complexity of the placenta, our findings provide strong evidence that dynamic flow systems can recapitulate key placental transport phenomena and offer a valuable in vitro model to study human-based transplacental transport processes. KEY POINTS: Medication use during pregnancy is an essential aspect of obstetrical care, it remains a major concern due to potential risks to fetal and placental development. Current in vitro models for assessing maternal-fetal drug transfer mostly consist of immortalized cell lines and/or lack critical components of the placental microenvironment, such as stromal cells or dynamic fluid flow. We developed a dynamic Transwell-based co-culture model , composed exclusively of primary trophoblast and endothelial cells. The model effectively mimics key features of the placental barrier properties, including polarized expression and functional activity of major placental drug efflux transporters. The dynamic primary cell based flow systems offer a physiologically relevant human in vitro model to investigate and predict transplacental drug transfer.

Keywords:  ABCB1; ABCG2; drug transport; microfluidic system; placenta; shear stress

DOI:  https://doi.org/10.1113/JP289606
Theriogenology. 2026 Feb 17. pii: S0093-691X(26)00067-1. [Epub ahead of print]257 117877

Single-cell analysis reveals the metabolic characteristics of porcine trophoblast cells during early pregnancy.

Yuhao Qiu, Xupeng Zang, Junying Ai, Yue Ding, Yongzhong Wang, Ting Gu, Ruhai Xu, Gengyuan Cai, Lihe Dai, Linjun Hong.

  The placenta is a crucial temporary organ during pregnancy, and its normal development is essential for the establishment of pregnancy. The porcine placenta is a non-invasive epitheliochorial placenta, and the implantation period (days 12-30 of pregnancy) serves as a critical junction throughout pregnancy, determining the success of pregnancy. During this period, the placenta undergoes intense cell proliferation and migration, and these processes require substantial energy support. However, the metabolic features of the placenta during this stage remain largely unexplored. This study integrated single-cell data from porcine placentas on days 16, 20, 24, and 28 of pregnancy to elucidate the metabolic landscape of the porcine placenta during early pregnancy. Our results indicate that trophoblast cells are among the most metabolically active cell types in the placenta. Furthermore, trophoblast cells exhibited highly active amino acid metabolism and sphingolipid metabolism, and different trophoblast subclusters had distinct metabolic characteristics. Through Cellchat and MEBOCOST analyses, it was found that different trophoblast subclusters may regulate the normal functions of other trophoblast subclusters via distinct metabolic signals. Additionally, it was found that there is sphingosine-1-phosphate (S1P)-mediated communication between trophoblast cells and endothelial cells (ECs). Our analysis provides new insights into understanding the dynamic changes of trophoblast cell metabolism in early porcine pregnancy and helps us understand the metabolic mechanisms during the development of trophoblast cells at the molecular dynamic level.

Keywords:  Amino acid metabolism; Angiogenesis; Cell–cell communication; Pigs; Single-cell RNA-Seq; Sphingolipid metabolism; Trophoblast

DOI:  https://doi.org/10.1016/j.theriogenology.2026.117877
Drug Metab Pharmacokinet. 2026 Jan 06. pii: S1347-4367(26)00002-9. [Epub ahead of print]67 101516

Polarized secretion of extracellular vesicles from the placenta to maternal and fetal bloodstreams in rats.

Kazunari Sasaki, Mai Inagaki, Masanori Tachikawa.

  The placenta is a maternal organ that secretes various proteins that support maternal pregnancy and fetal growth. Placenta-derived extracellular vesicles (EVs) encapsulate these proteins and are secreted into the maternal or fetal bloodstream in a polarized manner. In this study, we aimed to elucidate the distinct protein expression profiles of EV-enriched fractions obtained from the uterine veins, umbilical veins, and umbilical arteries of pregnant rats. EV-rich fractions were prepared from the plasma of pregnant rats using the Mag-NET method. In total, 2839 protein groups in the EV fractions were identified using global proteomics. The protein expression profiles of the EVs derived from the uterine veins mostly differed from those derived from the umbilical veins/arteries. However, a very limited difference in protein abundance was observed between the umbilical veins and arteries. The abundances of fetuin-B and alpha-fetoprotein were considerably greater in EVs from the uterine veins and umbilical veins/arteries, respectively, which is consistent with previous results. Prolactin-like hormones were predominantly expressed in EV-rich fractions collected from the uterine vein. These results suggest that the placenta undergoes polarized secretion of EVs into the maternal and fetal bloodstreams.

Keywords:  Extracellular vesicles; Placenta; Polarized secretion; Transporter; Umbilical artery; Umbilical vein; Uterine vein

DOI:  https://doi.org/10.1016/j.dmpk.2026.101516
Toxics. 2026 Feb 08. pii: 158. [Epub ahead of print]14(2):

Polystyrene Nanoparticles Disrupt Oxidative Phosphorylation and Impair Placental Development in Mice.

Bingyi Wang, Xinyi Xie, Nairui Fan, Qiqi Deng, Nannan Shi, Denglu Long, Weipeng Huang, Siqi Zhu, Zhi Chen, Xin Cheng, Xuesong Yang, Guang Wang, Qihao Zhang.

   BACKGROUND: Microplastics and nanoplastics, as pervasive and persistent environmental pollutants, are raising growing concerns regarding their potential risks to reproductive health, particularly pregnancy outcomes. Although the reproductive toxicity of polystyrene nanoplastics (PS-NPs) has been reported, the specific mechanisms underlying their effects on placental development and offspring health following gestational exposure remain unclear.
METHOD: This study aimed to investigate the effects of gestational exposure to PS-NPs of different sizes (50 and 200 nm) and concentrations (1, 3, and 10 mg/mL) on placental function and embryonic development in ICR mice. An exposure model was established via tail vein injection, and samples were collected on embryonic Day 14.5 (E14.5).
RESULTS: the exposed groups tended towards increased embryo weight, embryo length, and embryo head circumference. Transcriptomic analysis revealed that PS-NP exposure significantly downregulated the expression of Ndufa5 (a subunit of mitochondrial respiratory chain complex I) and mt-CO1 (a core subunit of complex IV), but upregulated the expression of the genes Cldn1 (tight junction protein) and Erbb3 (receptor tyrosine kinase) in the placenta. Differentially expressed genes were enriched primarily in pathways related to oxidative phosphorylation, the tricarboxylic acid (TCA) cycle, and ErbB signalling.
CONCLUSIONS: These changes collectively led to decreased mitochondrial ATP production, increased oxidative stress in the placenta, and potentially altered placental barrier function and trophoblast cell proliferation signalling. This study reveals a novel mechanism by which PS-NPs disrupt placental development and embryonic growth through impairment of placental energy metabolic homeostasis and key signalling pathways, thus providing crucial experimental evidence for assessing the reproductive and developmental toxicity of nanoplastics.

Keywords:  Ndufa5; mitochondrial function; mt-CO1; oxidative phosphorylation; oxidative stress; placenta; polystyrene nanoplastics (PS-NPs)

DOI:  https://doi.org/10.3390/toxics14020158
Placenta. 2026 Feb 13. pii: S0143-4004(26)00056-1. [Epub ahead of print]

Epithelial-mesenchymal plasticity in trophoblast differentiation.

Nicholas P Illsley, Stacy Zamudio.

  The differentiation of cytotrophoblast (CTB) into extravillous trophoblast (EVT) is central to development of the human placenta. This review explores the process by which CTB differentiate into invasive EVT. At its core is a mechanism known as the epithelial-mesenchymal transition (EMT), whereby immobile epithelial cells are transformed into an invasive, mesenchymal phenotype. Analysis of EMT-associated genes in first trimester CTB and EVT shows clear evidence of an EMT, promoting transition from CTB to EVT. The same analysis of third trimester cells shows evidence of an MET (mesenchymal-epithelial transition); EVT regress from the invasive first trimester mesenchymal phenotype to one characterized as mesenchymal but non-motile and non-proliferative. Of the EMT-master regulators, only the expression of the ZEB2 transcription factor showed a major increase in expression in first trimester EVT, which then reversed in third trimester cells. Overexpression of ZEB2 in trophoblast cell lines led to a pro-EMT shift in molecular markers, a more mesenchymal morphology and increased invasiveness, confirming its probable role in stimulating first trimester EMT. To confirm and compare the EMT observed in EVT with the several known types of EMT, we conducted a deeper gene expression analysis, enabling development of a trophoblast-specific EMT signature. Analysis of DNA methylation revealed genome-wide hypomethylation of third trimester EVT but also a small geneset with gains of methylation. EMT-associated genes showing a gain of methylation and differential expression comprised both pro-EMT and pro-MET genes, suggesting a regulated balance, maintaining the third trimester phenotype. The existence of multiple phenotypes on the EMT spectrum supports the concept of trophoblast epithelial-mesenchymal plasticity (EMP), with EMT-mediated generation of invasive first trimester cells followed by MET-assisted regression to the third trimester phenotype.

Keywords:  Cytotrophoblast; Epithelial-mesenchymal transition; Extravillous trophoblast

DOI:  https://doi.org/10.1016/j.placenta.2026.02.009
Mol Hum Reprod. 2026 Feb 26. pii: gaag015. [Epub ahead of print]

SARS-CoV-2 infects human primary cytotrophoblasts mainly through a non-canonical entry route.

Hélène Pinatel, Marie-Eve Brien, Mathilde Broquière, Marie-Pier Scott-Boyer, Arnaud Droit, Sylvie Girard, Géraldine Delbès, Laurent Chatel-Chaix, Cathy Vaillancourt.

  Since the beginning of the COVID-19 pandemic, vulnerable populations such as pregnant persons have been at higher risk of severe symptoms and poor outcomes. Although reports of SARS-CoV-2 vertical transmission remain rare, several studies showed that maternal infection during pregnancy can induce histomorphological and inflammatory alterations in the placenta. However, the permissiveness of human trophoblasts to various variants of the virus remains poorly characterized. In this study, human primary villous cytotrophoblasts isolated from term placentas, along with trophoblastic cell lines BeWo, JEG-3, and HIPEC-65 were infected with the ancestral SARS-CoV-2 strain, which disseminated worldwide in early 2020. Permissiveness was assessed with quantitative RT-PCR, immunostaining of viral protein Nucleocapsid, and plaque assays. To investigate viral entry routes, cells were treated with Camostat mesylate (an inhibitor of the co-entry factor TMPRSS2) or chloroquine phosphate (an endosomal entry inhibitor) and viral fitness was assessed by plaque assays. Primary villous cytotrophoblasts and JEG-3 cells were also tested for infection with three pre-omicron SARS-CoV-2 variants of concern. Our results show that primary villous cytotrophoblasts are permissive to all tested SARS-CoV-2 strains in vitro. Infection with the ancestral SARS-CoV-2 strain relies mainly on a non-canonical endosomal entry pathway. Notably, JEG-3 cells represent an appropriate and convenient model for studying trophoblast infection by SARS-CoV-2, as they exhibit high permissiveness to the ancestral strain, and the SARS-CoV-2 entry pathway is similar to that in villous cytotrophoblasts. Overall, this study reveals that the cytotrophoblastic permissiveness to SARS-CoV-2 depends on the viral genetic nature and provides new insights into its entry route in human trophoblasts.

Keywords:  COVID-19; JEG-3 cells; SARS-CoV-2; cytotrophoblast; variants of concern; viral entry

DOI:  https://doi.org/10.1093/molehr/gaag015
Biomolecules. 2026 Feb 14. pii: 300. [Epub ahead of print]16(2):

Regulation of Phosphatidylinositol Synthesis in Human Primordial Placenta.

Bence Kovács, Zoltán Erdélyi, Gergely Asbóth, Gábor Gimes, Balázs Mészáros, Zsófia Erdélyi, Tamás Marton, Nándor Ács, Dorina Supák, Sándor Valent, Zoltán Kukor.

  Phosphatidylinositol and its derivatives are essential components of cell membranes and play pivotal roles in growth signaling pathways. In the human primordial placenta, phosphatidylinositol synthesis is catalyzed by phosphatidylinositol synthase (PIS) and the phosphatidylinositol-exchange enzyme (IE), both of which require divalent cations. We investigated whether GTP-binding proteins modulate this biosynthetic process. Incorporation of [3H]inositol into phosphatidylinositol was measured in trophoblast tissue and microsomes from 8 to 10-week placentas. Our results demonstrate that Mn2+ strongly enhances phosphatidylinositol synthesis, and stimulation with AlF4- further increases incorporation rates by up to 2.5-fold. In contrast, Mg2+ combined with the non-hydrolyzable GTP analog GIDP elevated synthesis by 58%, whereas Mn2+ plus GIDP reduced incorporation by 30%. Complementary in silico protein-protein interaction analyses suggest that G-proteins may directly associate with inositol-exchange enzymes, providing a potential mechanism for the observed regulatory effects. These findings indicate that phosphatidylinositol synthesis is modulated in a manner consistent with G-protein involvement, with distinct effects depending on the prevailing enzymatic pathway. We propose that rapid trophoblast proliferation may involve feedback mechanisms mediated by distinct G-protein subtypes acting on early steps of the phosphatidylinositol cycle.

Keywords:  G protein; human primordial placenta; phosphatidylinositol synthesis; signal transduction

DOI:  https://doi.org/10.3390/biom16020300
Int J Mol Sci. 2026 Feb 22. pii: 2036. [Epub ahead of print]27(4):

The Placenta as a Target Organ for Poly- and Perfluoroalkyl Substances (PFASs): Molecular Mechanisms of Toxicity.

Paola Inés Ingaramo, Maria Laura Zenclussen.

  Exposure to poly- and perfluoroalkyl substances (PFASs) has been a cause for concern for decades due to evidence linking exposure to these substances with adverse health effects. Its widespread use in industrial and consumer products combined with their persistence in the environment poses a toxicological and regulatory challenge. Due to its ubiquity, resistance to degradation, and accumulation in biological systems, humans are exposed to a mixture of multiple PFASs, which complicates the analysis of exposure effects. As PFASs pose a risk to human health, it is crucial to study their impact during vulnerable periods, such as pregnancy. In this regard, understanding the impact of PFASs on the placenta is essential, as they can affect both pregnancy and the well-being of the developing fetus. This article reviews the current evidence linking PFAS exposure with altered placental function, focusing on the affected molecular pathways. Furthermore, we examine current methodologies for analyzing the effects of exposure to complex mixtures and explore how these approaches could be employed to evaluate the potential impact of such mixtures on placental function in the context of real-life exposure to these chemicals.

Keywords:  NAMs; PFAS; oxidative stress; placenta

DOI:  https://doi.org/10.3390/ijms27042036
J Reprod Immunol. 2026 Feb 16. pii: S0165-0378(26)00032-X. [Epub ahead of print]174 104863

Placental ferroptosis in preeclampsia: An integrative and comprehensive review.

Tamir Edri, Sapir Lianski, Sarah M Cohen, Ofer Beharier.

  Ferroptosis, a regulated form of iron-dependent cell death driven by lipid peroxidation, has recently gained attention as a potential contributor to the pathophysiology of preeclampsia, a major cause of maternal and perinatal morbidity and mortality. This review synthesizes current evidence linking ferroptosis to placental dysfunction and explores its relevance to the pathogenesis of preeclampsia. We examine how disrupted iron metabolism, oxidative stress, and impaired antioxidant defenses create a permissive environment for ferroptotic damage in the syncytiotrophoblast. Key biochemical pathways, including redox phospholipid metabolism, glutathione-GPX4 activity, and mitochondrial function, are reviewed in detail. We also discuss emerging data connecting placental ferroptosis to systemic maternal manifestations via sFlt-1 release and extracellular vesicle-mediated endothelial injury. Finally, we highlight therapeutic implications, including pharmacological inhibition of ferroptosis and drug repurposing strategies. By integrating diverse mechanistic insights, ferroptosis emerges as a unifying paradigm that may reshape our understanding and treatment of preeclampsia.

Keywords:  Ferroptosis; Iron metabolism; Lipid peroxidation; Placental dysfunction; Preeclampsia; SFlt-1; Therapeutic targets

DOI:  https://doi.org/10.1016/j.jri.2026.104863