bims-placeb 2026-04-05 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–04–05
twenty-one papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Modeling Aspects of Human Placental Development with Trophoblast Stem Cells.
Environmentally Relevant Low-Dose Bisphenol A Enhances Invasion of Human Extravillous Trophoblasts with Associated Increases in MMP Activity.
Transporter-Mediated Uptake of Microcystin-LR in Human Trophoblasts: Regulation By Oxygen Concentration and Cell Fusion.
Maternal high-protein diet impairs fetal growth through placental dysfunction in mice.
Beyond traditional models: microfluidic technologies for engineering the human placenta in vitro.
Trophoblast Invasion Biology: From Normal Implantation to Accreta Spectrum and Choriocarcinoma.
TRIM28-mediated p53 ubiquitination inhibits trophoblast apoptosis to support normal placental development.
Comparative Analysis of Prenatal Stress Models: Placental and Neurodevelopmental Outcomes in Mice.
Benzene-Induced Growth Restriction and Compensatory Rebound in Mouse Fetuses and Placentas.
Platelets in pregnancy - protector or adversary?
Isolation and characterization of Hofbauer cells from human term placentas.
Sound of nurturing: Advanced photoacoustic and ultrasound imaging of placental hemodynamics.
Long-read assembly reveals vast transcriptional complexity in the placenta associated with metabolic and endocrine function.
Placental transcriptome profiling in congenital Chagas disease: gene networks associated with transmission.
Purification of HLA-G+ Extravillous Trophoblasts from Human Term Placental Tissues for Phenotyping and Functional Analysis.
Ultrastructural analysis of bovine trophoblast giant cells during their migration by serial block-face scanning electron microscopy (SBF-SEM).
Targeting the syncytiotrophoblast: A central player in the pathogenesis and therapy of preeclampsia.
Transfer of paracetamol across the placenta and fetal blood-brain barriers and its safety for use in pregnancy.
Non-serum PFAS biomarkers and human reproductive/perinatal outcomes: A systematic review.
Epigenetic remodeling induced by fatty acids: Chromatin modifications and cellular senescence during lipid overload.
Glucose Exposure After Fertilization Shifts Preimplantation Mouse Embryos Towards a More Autophagy-Dependent and Less Mitochondria-Dependent Development.

Methods Mol Biol. 2026 ;3027 41-59

Modeling Aspects of Human Placental Development with Trophoblast Stem Cells.

Ayelen Moreno-Irusta, Michael J Soares.

  Human trophoblast stem (TS) cells provide a powerful in vitro model to study trophoblast lineage specification, placental development, and pregnancy-related disorders. This chapter presents detailed methodologies for the maintenance, derivation, and differentiation of TS cells, with a focus on reproducibility. We describe optimized culture conditions that preserve stem cell identity, including culture medium composition, extracellular matrix requirements, and passaging techniques. Step-by-step protocols for inducing differentiation into extravillous trophoblast and syncytiotrophoblast are presented, along with morphological, molecular, and functional assays to assess lineage commitment. Additionally, we describe a procedure to generate organoids from TS cells. Practical guidance is provided for maintaining reproducibility across experiments. These protocols can be implemented to investigate the role of diverse proteins, including members of the ADAMTS family, in human placental development. By enabling reproducible and controlled TS cell expansion and trophoblast cell differentiation, this methodology supports both basic research and disease modeling.

Keywords:  Cytotrophoblast; Extravillous trophoblast cell; Placenta; Syncytiotrophoblast; Trophoblast stem cells

DOI:  https://doi.org/10.1007/978-1-0716-5218-3_4
Reprod Toxicol. 2026 Apr 01. pii: S0890-6238(26)00079-1. [Epub ahead of print] 109236

Environmentally Relevant Low-Dose Bisphenol A Enhances Invasion of Human Extravillous Trophoblasts with Associated Increases in MMP Activity.

Shoko Ogushi, Reina Abe, Takehiro Nakamura, Tsuyoshi Nakanishi, Tomoki Kimura.

  Bisphenol A (BPA), a widespread environmental endocrine-disrupting chemical, has been implicated in adverse effects on placental development and pregnancy outcomes. However, the impact of environmentally relevant low-dose BPA on human trophoblast function remains unclear. Here, we examined the effects of BPA on distinct trophoblast functions using multiple human trophoblast models. BeWo cells, a choriocarcinoma-derived model of syncytiotrophoblast (ST) differentiation, were used to assess the effects of BPA on ST formation, which was not significantly altered. In addition, the effects of BPA on trophoblast lineage differentiation toward either ST or extravillous trophoblast (EVT) were evaluated using a cytotrophoblast-derived in vitro differentiation model, with no significant impact observed. In contrast, HTR-8/SVneo cells, an immortalized first-trimester extravillous trophoblast (EVT) cell line commonly employed to study trophoblast migration and invasion, exhibited significantly enhanced motility upon exposure to 1nM BPA, as demonstrated by wound healing and transwell assays. Gelatin zymography revealed a slight increase of matrix metalloproteinases (MMP-2 and MMP-9) activity, suggesting a potential mechanism for increased invasiveness. These findings provide evidence that environmentally relevant low-dose BPA can promote EVT migration and invasion, accompanied by a modest increase in MMP activity, highlighting a potential pathway by which environmental BPA exposure may influence placental function and pregnancy outcomes.

Keywords:  Bisphenol A; Cell migration and invasion; Extravillous trophoblast; Placenta

DOI:  https://doi.org/10.1016/j.reprotox.2026.109236
bioRxiv. 2026 Mar 25. pii: 2026.03.22.713491. [Epub ahead of print]

Transporter-Mediated Uptake of Microcystin-LR in Human Trophoblasts: Regulation By Oxygen Concentration and Cell Fusion.

Michael Jeffrey Campbell, Mokshitkumar Patel, Chenghui Jiang, Xia Wen, Shuo Xiao, Lauren M Aleksunes.

Background: Rising global temperatures and eutrophication are increasing the intensity and frequency of cyanobacterial harmful algal blooms that release toxins including microcystin-LR (MC-LR). MC-LR inhibits protein phosphatases in the human liver and brain, but its accumulation in the placenta is unclear. Placental transporter expression varies across pregnancy and is influenced by physiological cues, such as low oxygen concentrations which activate HIF1A, and trophoblast cell fusion forming syncytiotrophoblasts that engage CREB-driven transcription. This study examined whether MC-LR accumulates in placental cells, which transporters mediate uptake, and how these transporters are regulated by HIF1A and CREB.
Methods: Intracellular accumulation of MC-LR (0.1-10 µM, 3 hour) was measured in human cytotrophoblasts (JAR, BeWo) and extravillous trophoblasts (HTR-8/SVneo) by western blotting for MC-LR-adducted proteins. Organic anion transporting polypeptide (OATP) involvement was tested using cyclosporin A (10 µM), an OATP inhibitor, before exposure to the OATP substrate or MC-LR. Cells were also cultured under 3%, 8%, or 20% O₂ to induce hypoxic responses or treated with forskolin (a potent intracellular cAMP inducer) to stimulate cell fusion before MC-LR exposure.
Results: MC-LR accumulated in all three placenta cell lines in a concentration-dependent manner. Cyclosporin A reduced MC-LR uptake by 57% in JAR cells, confirming OATP-mediated transport. Low O 2 increased OATP4A1 expression and function but reduced protein phosphatase expression, decreasing MC-LR-bound proteins by 52-72%. Forskolin increased OATP4A1 expression and enhanced MC-LR uptake >2.5-fold.
Conclusion: MC-LR enters placental trophoblasts via active OATP transport, likely OATP4A1, and uptake increases under hypoxia and trophoblast fusion.

DOI: https://doi.org/10.64898/2026.03.22.713491
Placenta. 2026 Mar 24. pii: S0143-4004(26)00101-3. [Epub ahead of print]178 30-38

Maternal high-protein diet impairs fetal growth through placental dysfunction in mice.

Ying Zhao, Long Cai, Liyuan He, Ge Gao, Martine Schroyen, Yu Pi, Wenjuan Sun, Dongxu Ming, Yanpin Li, Xilong Li.

   INTRODUCTION: Maternal dietary protein intake plays a vital role in pregnancy outcomes. However, the impact of popular high-protein diets, often accompanied by carbohydrate restriction, remains poorly understood. We investigated the effect of different levels of maternal protein during pregnancy on embryo implantation, placental development, and fetal growth in mice.
METHODS: Pregnant C57BL/6 mice were fed isocaloric purified diets containing 10% (low protein, LP), 20% (medium protein, MP), or 40% (high protein, HP) protein. Implantation was assessed on day 6.5, and gestational outcomes were analyzed on day 18.5.
RESULTS: Maternal protein did not affect implantation number or litter size. However, HP intake reduced fetal weight and placental efficiency. Morphologically, HP intake decreased the placental labyrinth zone/total area ratio compared to LP. It was further revealed that maternal HP intake reduced fetal serum glucose, increased fetal serum urea nitrogen, and activated hepatic gluconeogenic and amino acid catabolic pathways compared to MP. Mechanistically, HP intake induced placental oxidative stress, evidenced by enhanced malondialdehyde content, and decreased the activity of placental catalase, superoxide dismutase, and glutathione peroxidase. The expression of genes involved in antioxidant defense and amino acid transport was also suppressed in placenta. Moreover, maternal HP intake reduced ATP production, lowered mitochondrial DNA copy number, and downregulated gene expression of electron transport chain components.
DISCUSSION: Excessive maternal protein intake under isoenergetic conditions disrupts placental redox homeostasis and mitochondrial function, and impairs nutrient transfer. These alterations compromise placental efficiency and fetal growth, highlighting the potential risks associated with high-protein dietary patterns during pregnancy.

Keywords:  Amino acid transport; Fetal development; High-protein diet; Mitochondrial function; Oxidative stress; Placental function

DOI:  https://doi.org/10.1016/j.placenta.2026.03.016
Front Bioeng Biotechnol. 2026 ;14 1777568

Beyond traditional models: microfluidic technologies for engineering the human placenta in vitro.

Alice Masserdotti, Anna Cargnoni, Rashmi Ramakrishnan, Lisa Muiznieks, Justine Lereculey-Beaumanoir, Ivana Brenta, Michael Gasik, Paola Chiodelli, Antonietta Rosa Silini, Ornella Parolini.

  The human placenta is a highly specialized and dynamic organ that supports fetal development by regulating maternal-fetal exchange, endocrine activity, and immune tolerance throughout pregnancy. Despite its central role in maternal and fetal health, studying human placental physiology and pathology remains challenging due to ethical constraints, limited tissue accessibility, and the complexity of the maternal-fetal interface. Traditional in vitro models and animal systems have provided valuable insights but often fail to capture the dynamic, multicellular, and perfused nature of the human placenta. Microfluidic technologies have recently emerged as powerful tools for placental modeling in vitro. By integrating controlled fluid flow, three-dimensional architecture, and relevant placental cell types, placenta-on-chip platforms enable a more physiologically relevant reconstruction of the maternal and fetal compartments. These systems support the study of placental barrier function, nutrient and drug transport, endocrine signaling, immune interactions, and responses to pathological stimuli under defined and reproducible and tunable conditions. As the field rapidly expands, a comprehensive synthesis is needed to clarify how these systems complement or surpass existing models and to identify the remaining translational gaps. Reliable microphysiological systems that replicate placental "functionality-on-chip" are essential for global regulatory efforts. The need for clinical data to guide safe and effective use of medicines during pregnancy and breastfeeding has led to recommendations from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use to include pregnant and breastfeeding women in clinical trials. This creates an urgent push for early data collection on drug effects in pregnancy and breastfeeding using lab studies. This underscores the need to develop in vitro systems that reliably predict the effects of drugs and toxicants on the placenta. This review critically examines current placental models, from conventional two- and three-dimensional cultures and animal models to advanced microfluidic systems. We highlight how microfluidic placental models overcome key limitations of traditional approaches and discuss their applications in developmental biology, pharmacokinetics, toxicology, infection studies, and pregnancy-related disorders. Collectively, emerging evidence suggests that microfluidic placental models are central tools for mechanistic studies and preclinical testing, bridging the gap between reductionist systems and human physiology. Future progress will depend on improving model standardization, incorporating additional cellular complexity and immune components, and aligning microfluidic outputs with clinically relevant endpoints. Advancing these platforms toward greater physiological fidelity and interoperability with multi-organ systems will be critical for translating placental research into improved maternal-fetal health outcomes. Beyond summarizing recent technological advances, this review uniquely positions placenta-on-chip systems within the broader landscape of existing placental models and emerging regulatory needs, highlighting their translational potential for drug safety, developmental toxicology, infection biology, and pregnancy-related disorders.

Keywords:  microfluidics; modeling; placenta; placenta-on-chip; placental models

DOI:  https://doi.org/10.3389/fbioe.2026.1777568
Vasc Biol. 2026 Mar 23. pii: VB-25-0016. [Epub ahead of print]

Trophoblast Invasion Biology: From Normal Implantation to Accreta Spectrum and Choriocarcinoma.

Dr Mishu Mangla, Dr Rohini Motwani, Dr Seetu Palo, Dr Aparna Setty.

  Trophoblast invasion is a finely regulated physiological process that demonstrates controlled cellular migration and vascular remodeling during human pregnancy. During normal implantation, cytotrophoblasts differentiate into extravillous trophoblasts (EVTs), which enter the maternal decidua and remodel spiral arteries, converting them into low-resistance vessels required for fetal nutrition. This balance of invasion and restraint promotes appropriate vascular adaptation at the maternal-fetal interface. Aberrations in this mechanism result in a range of pathological states, from excessive but non-malignant invasion in placenta accreta spectrum (PAS) to uncontrolled, malignant invasion in choriocarcinoma. In PAS, trophoblasts can infiltrate the myometrium due to dysregulated production of matrix metalloproteinases (MMP-2, MMP-9), integrins, and angiogenic factors (VEGF, HIF-1α). In choriocarcinoma, trophoblastic cells activate PI3K/AKT, Wnt/β-catenin, and Notch signalling, leading to hyperproliferation, immune evasion through PD-L1, and metastatic potential. Despite differences in clinical behaviour, many disorders have molecular mediators that link trophoblast invasion to vascular remodelling, angiogenesis, and immunological regulation. Emerging models including trophoblast organoids, placental explants, and placenta-on-a-chip technologies offer enhanced platforms to study such pathways at the cellular and molecular levels. This review highlights trophoblast invasion as a model of controlled angiogenic remodeling, providing mechanistic insight into both obstetric pathology and cancer biology. It underscores how studying placental invasion can inform therapeutic strategies targeting abnormal vascular invasion across diseases.

Keywords:  Angiogenesis; Choriocarcinoma; Malignancy; Matrix metalloproteinases; Placenta accreta spectrum (PAS); Trophoblast invasion; Vascular remodeling

DOI:  https://doi.org/10.1530/VB-25-0016
Open Life Sci. 2026 Jan;21(1): 20251236

TRIM28-mediated p53 ubiquitination inhibits trophoblast apoptosis to support normal placental development.

Huixiang Qian, Ruping Quan, Juan Chen, Yanghong Liu, Jing Hu, Ruizhen Li, Chao Lv.

  Tripartite motif-containing 28 (TRIM28), a transcriptional regulatory factor, is involved in various biological processes. However, its role in early-onset preeclampsia (EOPE) remains unclear. An EOPE mouse model was established using Nω-Nitro-L-arginine methyl ester (L-NAME), while TRIM28 or tumor protein p53 (p53) expression was modulated through lentiviral infections. Maternal blood pressure and urinary protein levels were measured. Placental tissues were collected at embryonic day 17.5 for hematoxylin-eosin staining, immunohistochemistry, Western blot, and real-time quantitative polymerase chain reaction. In vitro, HTR-8/SVneo trophoblast cells were exposed to hydrogen peroxide (H2O2) to simulate oxidative stress. TRIM28 and p53 were overexpressed via lentiviral vectors, and cell apoptosis and molecular changes were assessed. TRIM28 expression was significantly downregulated in placentas from EOPE mice. Mechanistically, TRIM28 suppressed p53 level, downregulating pro-apoptotic proteins Bcl-2-associated X protein (Bax) and cleaved caspase-3, while upregulating the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2). In trophoblast cells, TRIM28 alleviated H2O2-induced apoptosis by promoting p53 ubiquitination and thereby reducing its pro-apoptotic activity. TRIM28 attenuates oxidative stress-induced trophoblast apoptosis and may help protect against the development of EOPE.

Keywords:  TRIM28; apoptosis; p53 ubiquitination; placental development; pregnancy

DOI:  https://doi.org/10.1515/biol-2025-1236
Yale J Biol Med. 2026 Mar;99(1): 127-141

Comparative Analysis of Prenatal Stress Models: Placental and Neurodevelopmental Outcomes in Mice.

Mia Dukle, Faith M Fairbairn, Sara V Maurer, Madelyn M Grueter, Ahmed I Baig, Rachel Telles, Hanna E Stevens.

  Prenatal stress affects offspring development. The placenta, an important maternal-fetal mediator, is susceptible to prenatal stress, and its biology affects fetal neurodevelopment, particularly ventral forebrain. Ventral forebrain developmental disruption is linked to neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Currently, multiple mouse models are used to study these links. However, each model may induce unique effects in both placental and neurodevelopmental outcomes, which are rarely studied. To explore this, pregnant mice were exposed 3 times daily to one of three stress models: repeated restraint stress (RS), chronic unpredictable stress (CUS), or repeated footshock stress (FS) beginning at embryonic day (E)12. At E14 or E18, placenta and embryonic brain were collected, and qPCR and brain stereological measurements were performed. Placental immune and ventral forebrain GABAergic gene expression was impacted more at E14, with many changes not apparent by E18, suggesting an acute dysregulated state. Different models had both unique and overlapping effects. E18 analyses suggested adaptation to stress over time, with overall suppression or lack of placental immune factor changes, fewer deviations in the brain, and correlations between placenta and brain, particularly in females. Chronic unpredictable stress showed the most changes at E18. These findings suggest that, while each model has unique effects, as stress exposure progresses, placental immune functioning may promote the normalization of brain GABAergic systems, particularly in females. Further understanding the placenta-brain axis may be valuable in delineating mechanisms that increase and decrease risk of neurodevelopmental disorders.

Keywords:  GABAergic; Prenatal stress; chronic unpredictable stress; fetal development; immune factors; neurodevelopment; placenta; sex differences; ventral forebrain

DOI:  https://doi.org/10.59249/MHFP3728
Reprod Toxicol. 2026 Apr 01. pii: S0890-6238(26)00074-2. [Epub ahead of print] 109231

Benzene-Induced Growth Restriction and Compensatory Rebound in Mouse Fetuses and Placentas.

Megan E Cull, Lauren T L Brown, Perri M Grant, Lihua Xue, Louise M Winn.

  Benzene is a ubiquitous environmental toxicant and carcinogen, yet its effects on early placental and fetal development remain poorly defined. In our previous work, repeated mid-gestation benzene exposure increased fetal and placental size at gestational day (GD) 19, indicating compensatory growth responses. Here, we investigated the immediate consequences of the same exposure paradigm to determine how these effects unfold over time. Pregnant CD-1 mice received intraperitoneal injections (200mg/kg) of either benzene or a vehicle control on GD8, 10, 12, and 14, and fetal and placental outcomes were assessed at 2, 6, and 24hours after the final exposure. Benzene exposure initially reduced fetal and placental weight, which then increased over time and surpassed control values by 24hours. These growth dynamics were influenced by both sex and uterine position: males exhibited early growth deficits, while females showed delayed compensatory responses; fetuses in the left uterine horn were disproportionately growth-restricted at 2hours, though this difference was not evident at later timepoints. Together with our GD19 findings, these results define a growth trajectory in which in utero benzene exposure first restricts fetal and placental development, followed by rebound growth that ultimately exceeds control levels. These findings demonstrate that susceptibility to benzene is modified by intra-litter variables, with sex- and horn-specific factors contributing to variability in outcome. This work underscores the importance of accounting for intra-litter variability when evaluating developmental toxicants and highlights the need for future studies into the mechanisms driving rebound growth responses.

Keywords:  Benzene; Compensatory growth; Developmental toxicology; Fetal growth restriction; In utero exposure; Placental development; Sex-specific effects; Uterine position

DOI:  https://doi.org/10.1016/j.reprotox.2026.109231
Thromb Res. 2026 Mar 24. pii: S0049-3848(26)00081-2. [Epub ahead of print]260 109662

Platelets in pregnancy - protector or adversary?

Gerard Gurumurthy, Offer Erez, Jecko Thachil.

  Pregnancy places increased demands on the maternal haemostatic system where it must maintain a balance between bleeding and thrombosis. Platelets are crucial to this process. Platelets support placental development and secrete bioactive mediators that influence trophoblast invasion, vascular remodelling and innate immune crosstalk (platelet-leukocyte and complement interactions). Normal pregnancy is characterised by a gradual decrease in platelet count with advancing gestation. This mild thrombocytopenia toward term is driven by haemodilution, placental sequestration and platelet activation. However, excessive platelet activation can trigger thrombo-inflammatory response linked to the development of pre-eclampsia and foetal growth restriction. Platelet dysfunction and inherited thrombocytopenia may increase the risk of postpartum haemorrhage without directly affecting the pregnancy. Platelets therefore play a dual role in pregnancy where controlled activation is protective but uncontrolled stimulation leads to obstetric complications. An appreciation of this informs preventive strategies such as low-dose aspirin in high-risk pregnancies and individualised management of thrombocytopenia in selected cases.

Keywords:  Foetal growth restriction; Obstetric haematology; Placenta; Platelets; Pre-eclampsia; Pregnancy; Trophoblast

DOI:  https://doi.org/10.1016/j.thromres.2026.109662
Front Immunol. 2026 ;17 1671127

Isolation and characterization of Hofbauer cells from human term placentas.

Dancan M Wakoli, Bartholomew N Ondigo.

  Hofbauer cells (HBCs) are macrophages of fetal origin present in the human placenta that play a key role in maintaining a healthy pregnancy. They are the most abundant immune cells (> 90%) in the placental villi. They have been implicated in various complications of pregnancy, though their role in these pathologies remains rudimentary. In addition, despite being discovered over a century ago, there is no consensus on the specific time window between delivery and placental sample processing for HBCs isolation, the site of biopsy sampling, and isolation protocol. In previous studies, mechanical disintegration, enzymatic digestions, density gradient separation, homogenization, adherence, rosetting, and immune selection techniques have been used to isolate HBCs for immunological studies. Here we review current knowledge on HBCs isolation methods, their role in healthy and pathologic pregnancy, and the impact of pregnancy complications on HBCs population and phenotype. A literature search was conducted on Scopus, PubMed, and Google Scholar databases using specific keywords, including "Isolation of Hofbauer cells, Hofbauer cells and infectious diseases, Hofbauer cells on immune function, and Hofbauer cells and maternal autoimmune pathology." No restrictions were placed on the year of publication or author affiliation during the selection process. Developing a standardized and harmonized HBCs isolation technique(s) will allow comparative studies across laboratories, research groups studying HBCs. These standardized approaches will provide the necessary impetus for studies on HBCs and their functionality in healthy and placental pathologies.

Keywords:  Hofbauer cells; infectious diseases; isolation; macrophages; maternal autoimmune pathology; placenta

DOI:  https://doi.org/10.3389/fimmu.2026.1671127
Placenta. 2026 Mar 30. pii: S0143-4004(26)00104-9. [Epub ahead of print]

Sound of nurturing: Advanced photoacoustic and ultrasound imaging of placental hemodynamics.

Van Tu Nguyen, Nanchao Wang, Liping Feng, Junjie Yao.

  The placenta is a transient yet vital organ that regulates maternal-fetal exchange and profoundly influences pregnancy outcomes. Placental hemodynamic dysfunction is central to many major obstetric complications, including preeclampsia and fetal growth restriction. Despite advances in obstetric imaging, existing modalities such as Doppler ultrasound, magnetic resonance imaging, and X-Ray computed tomography remain limited in their ability to resolve placental microvasculature or quantify hemodynamics in vivo. Recent developments in photoacoustic (PA) and advanced ultrasound imaging have enabled assessment of placental vasculature, blood perfusion, and oxygenation with improved spatial and temporal resolution. Photoacoustic microscopy (PAM) and photoacoustic computed tomography (PACT) provide optical contrast derived from endogenous hemoglobin, offering functional insight into oxygen transport and vascular remodeling at various scales, while power Doppler (PWD), and ultrasound localization microscopy (ULM) deliver complementary blood flow and microvascular information at clinically-relevant depths. Integrating photoacoustic and ultrasound imaging allows for quantitative, multiscale visualization of placental hemodynamics from the macroscopic to the microscopic level. This review summarizes current progress in photoacoustic and ultrasound-based placental imaging, discusses different system implementations, reports important preclinical and clinical findings, and identifies remaining challenges in technical improvement and broad translation. Together, emerging photoacoustic and ultrasound imaging platforms promise to transform placental research and reproductive healthcare by enabling comprehensive, functional evaluation of maternal-fetal exchange in health and disease.

Keywords:  Advanced ultrasound imaging; Hemodynamics; Human placenta; Mouse placenta; Photoacoustic imaging

DOI:  https://doi.org/10.1016/j.placenta.2026.03.019
Nat Commun. 2026 Apr 02.

Long-read assembly reveals vast transcriptional complexity in the placenta associated with metabolic and endocrine function.

Sean T Bresnahan, Hannah E J Yong, Aryun Nemani, William H Wu, Sierra Lopez, Jerry Kok Yen Chan, Frédérique White, Pierre-Étienne Jacques, Marie-France Hivert, Shiao-Yng Chan, Michael I Love, Jonathan Y Huang, Arjun Bhattacharya.

The placenta is critical for fetal development and mediates effects of pregnancy complications on offspring metabolic health yet remains poorly characterized in genomic studies. Existing transcriptomic analyses rely on adult tissue reference annotations, overlooking developmentally important splicing diversity. Using largest-in-class long-read RNA-seq (n = 72), we create a comprehensive placental transcriptome reference identifying 37,661 high-confidence isoforms (14,985 previously unannotated) across 12,302 genes (2,759 previously unannotated). Contrary to characterizations of the placenta as a transcriptomic void, we find transcriptional breadth and complexity comparable to adult tissues, with high splicing diversity of obesity- and growth-related gene transcripts, including 108 distinct CSH1 (placental lactogen) isoforms. Applying this reference to short-read RNA-seq from diverse populations (n = 352) reduced inferential uncertainty in isoform quantification by approximately 30%. We find placental transcription mediated 36% of gestational diabetes mellitus effects on birth weight, with ancestry-specific effects including previously unannotated CSH1 isoforms mediating larger effects in European (24.4%) than Asian (13.4%) populations. These findings illustrate the importance of tissue-matched, long-read annotations for isoform-resolved transcriptomics.

DOI: https://doi.org/10.1038/s41467-026-71303-4
Front Cell Infect Microbiol. 2026 ;16 1749307

Placental transcriptome profiling in congenital Chagas disease: gene networks associated with transmission.

Sofia Apodaca, Emiliano E Campos, Kevin D Calupiña, Carolina Davies, Raúl H Lucero, Silvia A Longhi, Laura Kamenetzky, Maria Paola Zago, Alejandro G Schijman.

  Chagas disease, caused by Trypanosoma cruzi, affects over seven million people worldwide. Vertical transmission during pregnancy contributes to the urban spread of the disease, including in non-endemic regions. Although the placenta constitutes a critical barrier against fetal infection, the molecular mechanisms underlying congenital transmission remain poorly understood. To identify placental factors associated with transmission, we performed a transcriptomic analysis of placental tissues from deliveries of congenitally infected (M+B+), exposed but uninfected (M+B-), and unexposed/uninfected (M-B-) newborns. Differential gene expression analysis comparing M+B+ and M-B- placentas revealed overexpression of CEMIP (cell migration-inducing hyaluronidase 1), involved in extracellular matrix (ECM) remodeling and intracellular transport, together with ENSG00000304767, a novel long non-coding RNA located intronically within CEMIP. In contrast, PRRX1 (paired related homeobox 1), CADM3 (cell adhesion molecule 3), and CDH11 (cadherin 11), genes associated with transcriptional regulation and cell-cell adhesion, were underexpressed. In the M+B- versus M-B- comparison, MIR4300HG, a long non-coding RNA hosting MIR4300, was overexpressed, whereas CGB5 (chorionic gonadotropin subunit beta 5), essential for pregnancy maintenance, was underexpressed. Direct comparison between M+B+ and M+B- placentas showed overexpression of the CEMIP-associated lncRNA and CGB5, accompanied by downregulation of CADM3, NEGR1, PDPN, and CDH11, implicating altered adhesion and structural pathways in transmission. Overall, these findings indicate that placental cell adhesion and ECM integrity are disrupted in transmitting placentas. Gene set enrichment analysis using the Gene Ontology library revealed alterations of immune-related pathways in both infected mother groups, while highlighting ECM-related processes-particularly collagen organization and metabolism-as key contributors to transmission events. Cell type enrichment analysis showed overrepresentation of extravillous trophoblasts in M+B+ placentas, with the opposite pattern observed in M+B- cases. Conversely, syncytiotrophoblasts and villous cytotrophoblasts were enriched in non-transmitting placentas relative to controls. Immune-associated placental cell types were consistently reduced in both infected groups. Co-expression network analysis further confirmed compromised placental signaling and structural integrity in transmitting cases, identifying ENPP1 and SLC16A10 as central hub genes. Together, these RNA-seq data define key placental transcriptional alterations associated with congenital T. cruzi transmission which, upon future experimental validation may provide insights into molecular mechanisms governing fetal protection or susceptibility.

Keywords:  RNA-Seq; co-expression network analysis; congenital Chagas disease; differential gene expression; gene set enrichment analysis; host-parasite interaction; placenta; transcriptomics

DOI:  https://doi.org/10.3389/fcimb.2026.1749307
J Vis Exp. 2026 03 13.

Purification of HLA-G+ Extravillous Trophoblasts from Human Term Placental Tissues for Phenotyping and Functional Analysis.

Sayaka Tsuda, Angel Dasenbrock, Shweta Mahajan, Tamara Tilburgs.

The human maternal-fetal interface represents a unique immunological environment where maternal immune cells and fetal extravilllous trophoblasts (EVT) engage in direct cellular contact to establish and maintain immune tolerance. EVT exhibit a distinct immunophenotype characterized by the expression of tolerogenic molecules, including HLA-G, PD-L1, and PD-L2, which play pivotal roles in modulating maternal immune responses. In addition, human EVT express HLA-C that can be directly recognized by maternal NK and T cells and promotes their activation. Importantly, no orthologues of HLA-C or HLA-G are present in animal models used for research, and murine trophoblast lack MHC expression. Thus, investigating the phenotypic and functional properties of human EVT from placental tissues, under both physiological and pathological conditions, is essential for elucidating the mechanisms underlying pregnancy maintenance and pathophysiology of placental inflammation associated with preeclampsia, preterm birth, fetal growth restriction, and placenta accreta. This protocol outlines a comprehensive methodology for the isolation and characterization of primary human EVT from healthy term placental tissue as well as after preterm birth and preeclampsia. It includes: (1) dissection of placental and chorionic membrane tissues; (2) enzymatic digestion and the preparation of single cell suspensions; (3) EVT purification by FACS sort; (4) Phenotypic characterization by high-dimensional flow cytometry; and (5) short-term in vitro culture and co-culture with maternal immune cells for up to 96 h. Emphasis is placed on obtaining highly pure and viable EVT suitable for downstream applications such as immunological functional assays, protein and gene expression analysis. The implementation of this protocol enables a robust and reproducible platform for advancing understanding of EVT and maternal immune cell interactions and its implications in both healthy and complicated pregnancies.

DOI: https://doi.org/10.3791/69545
Placenta. 2026 Mar 18. pii: S0143-4004(26)00090-1. [Epub ahead of print]

Ultrastructural analysis of bovine trophoblast giant cells during their migration by serial block-face scanning electron microscopy (SBF-SEM).

Louiza Tiedje, Sophia Pankoke, Julia Hollenbach, Rüdiger Koch, Christoph Wrede, Christiane Pfarrer.

  Bovine trophoblast giant cells (TGC) are continuously formed and migrate towards the uterine epithelium (ME) to fuse with ME cells. To date it is not clear whether TGC differentiate from any uninucleate trophoblast cell and how exactly the migration works, because most data is based on two-dimensional images, generated by conventional transmission electron microscopy (TEM) with little opportunity for serial sections. Since the serial block face scanning electron microscopy (SBF-SEM) technique allows complete reconstruction of specifically selected tissue regions, we aimed to study TGC morphology and life cycle in relation to the feto-maternal interface in a three-dimensional setting. Placentome samples from six cows at different gestational stages were visualized by SBF-SEM (Zeiss Merlin VP Compact SEM with Gatan 3view2XP). The software Microscopy Image Browser was used for image processing, manual segmentation and analysis, while the software package IMOD was used for visualization. Here, TGC were divided morphologically into young, maturing and mature cells. A surprisingly high number of TGC still possessed contact with the fetal basement membrane (FBM). Young TGC had extensive contact to the FBM, while in maturing and mature TGC the contact occupied only small areas. In mid gestation, many TGC held simultaneous contact to the FBM and the ME (41-93%), which declined to 10% near term. To conclude, by adding a third dimension, SBF-SEM technology has questioned previous assumptions about TGC and hybrid cells and provides valuable new information about cell contacts and characteristics of bovine trophoblast cells.

Keywords:  Bovine; Placentome; Pseudopodium; Serial block-face scanning electron microscopy; Trophoblast giant cell; Ultrastructure

DOI:  https://doi.org/10.1016/j.placenta.2026.03.012
Pathol Res Pract. 2026 Mar 28. pii: S0344-0338(26)00113-5. [Epub ahead of print]282 156461

Targeting the syncytiotrophoblast: A central player in the pathogenesis and therapy of preeclampsia.

Xinyue Tong, Feng Huang, Baocheng Zhou, Mei Wang.

  Preeclampsia (PE) is a severe pregnancy-specific disorder and a leading cause of maternal and perinatal morbidity and mortality. Its complex pathogenesis and the lack of effective therapies beyond delivery represent a major unmet clinical need. The syncytiotrophoblast (STB), the multinucleated cell layer at the outermost layer of the placental villous structure formed by the fusion of villous cytotrophoblasts (VCTs), serve as a critical functional barrier and regulatory hub at the maternal-fetal interface. Recent research highlights the central role of STB in the development of PE. This review delineates the multifaceted dysfunction of STB in PE, including impairments in differentiation, secretion, metabolism, cell survival and cellular heterogeneity. We further evaluate the utility of current experimental models for investigating STB pathobiology and highlight cutting-edge strategies for PE prediction and therapy that target STB. By integrating these insights, this review underscores that a deep understanding of STB biology is pivotal for developing novel diagnostic, predictive and therapeutic solutions to combat PE.

Keywords:  Clinical implications; Experimental models; Pathogenesis; Preeclampsia; Syncytiotrophoblast

DOI:  https://doi.org/10.1016/j.prp.2026.156461
J Physiol. 2026 Apr 03.

Transfer of paracetamol across the placenta and fetal blood-brain barriers and its safety for use in pregnancy.

Yifan Huang, Liam Koehn.

  Paracetamol (acetaminophen) is the most widely used analgesic and antipyretic during pregnancy and has long been considered safe at recommended doses by national health authorities. However, recent preclinical and epidemiological studies have prompted renewed scrutiny of its pharmacology and safety profile in the context of fetal development. This review summarizes current evidence on the pharmacokinetics of paracetamol in pregnancy, placental transfer and permeability across the fetal brain barriers. We also examine findings from both experimental and population-based studies investigating short- and long-term prenatal exposure on offspring outcomes. Despite a great deal of research, evidence linking prenatal paracetamol exposure to adverse neurodevelopmental effects remains inconsistent and no conclusive causality has been established. Uncertainty and public confusion over the safety of paracetamol use in pregnancy is exacerbated by the heterogeneity of study designs, exposure assessment and confounding factors. Nonetheless, data from preclinical models suggest potential pathways that prenatal exposure may influence neurodevelopment, such as oxidative stress and endocrine modulation. However, alternative drug treatments or reasons for use, such as fever, if left untreated have stronger associations with detrimental physical and neurodevelopmental outcomes. Therefore, use of paracetamol when clinically indicated and at the lowest dose for the shortest duration necessary may be safest for maternal and fetal health. Nonetheless, ongoing research integrating mechanistic and epidemiological approaches is still essential to clarify the developmental consequences of fetal paracetamol exposure and to inform evidence-based recommendations for safe dosing regimens for maternal analgesic and antipyretic use.

Keywords:  acetaminophen; blood–brain barrier; paracetamol; placenta; pregnancy

DOI:  https://doi.org/10.1113/JP289609
Reprod Toxicol. 2026 Mar 30. pii: S0890-6238(26)00075-4. [Epub ahead of print] 109232

Non-serum PFAS biomarkers and human reproductive/perinatal outcomes: A systematic review.

Zeynep Arsalan, Sonia Sanajou.

  Most epidemiologic evidence linking per- and polyfluoroalkyl substances (PFAS) to reproductive outcomes relies on serum biomarkers, which may not accurately reflect exposure in target reproductive compartments. We systematically reviewed literature (1 Jan 2020 - 31 Dec 2025) investigating PFAS in non-serum matrices (follicular fluid, placenta, semen, human milk, urine, and hair). Following PRISMA 2020 guidelines, we identified 58 eligible studies (19 primary associations; 39 biomonitoring/mechanistic). Study quality was assessed via the Newcastle-Ottawa Scale, with most association studies rated as 'Good.' While findings were heterogeneous across matrix-outcome domains, consistent signals emerged for follicular-fluid PFAS and impaired embryo quality, and placental PFAS and sex-dimorphic fetal growth restriction. Toxicokinetic data revealed high transfer efficiencies for PFOA into follicular fluid (0.72-0.94) but significant retention of PFOS in placental tissue. These findings suggest that non-serum biomarkers provide a time-resolved, compartment-specific perspective that offers greater etiological resolution than systemic serum measurements. Future research should adopt this "matrix-aware" framework to better characterize localized reproductive risks and improve environmental risk assessments.

Keywords:  PFAS; follicular fluid; human biomonitoring; human milk; non-serum matrices; placenta; reproductive and perinatal outcomes

DOI:  https://doi.org/10.1016/j.reprotox.2026.109232
Ageing Res Rev. 2026 Mar 27. pii: S1568-1637(26)00107-8. [Epub ahead of print]118 103115

Epigenetic remodeling induced by fatty acids: Chromatin modifications and cellular senescence during lipid overload.

Karla Estephanía Ávila-Galicia, Adriana Alarcón-Aguilar, Ernesto Soto-Reyes, Mina Königsberg.

  Cellular senescence is a stable cell state sustained by specific gene expression programs that are established and maintained through dynamic changes in chromatin organization. Importantly, these programs are highly dependent on the nature of the senescence-inducing stimulus. In recent years, lipid overload has emerged as a relevant metabolic stress capable of inducing senescence across multiple cell types and tissues, particularly in the context of obesity and high-fat diets. Accumulating evidence indicates that this process is tightly linked to metabolic rewiring, which directly impacts chromatin-modifying enzymes and chromatin remodelers through fluctuations in key metabolites such as acetyl-CoA, NAD⁺, and α-ketoglutarate. In this review, we integrate current evidence on how fatty acid-driven metabolic alterations reshape chromatin dynamics to promote and stabilize cellular senescence.

Keywords:  Aging; Cellular senescence; Chromatin; Diet; Epigenomics; Fatty acids; High-fat; Obesity

DOI:  https://doi.org/10.1016/j.arr.2026.103115
Front Biosci (Landmark Ed). 2026 Mar 23. 31(3): 49320

Glucose Exposure After Fertilization Shifts Preimplantation Mouse Embryos Towards a More Autophagy-Dependent and Less Mitochondria-Dependent Development.

Kaname Sato, Ryoma Fujita, Yuu Akaike, Saya Kanie, Sotaro Yoshino, Shinji Nishikawa, Yoshiki Nakamura, Kodai Miyagi, Satoshi Kishigami.

   BACKGROUND: Optimizing culture conditions is essential for enhancing embryonic developmental potential. During the early developmental stages of preimplantation embryos, pyruvate is preferentially consumed in the lower-glucose environment of the fallopian tube, whereas glucose becomes the primary energy substrate in the higher-glucose uterine environment following compaction. However, the specific effects of glucose exposure on autophagy during early development of preimplantation mouse embryos remained unclear. This study used chloroquine (CQ), an autophagy inhibitor in preimplantation embryos. Furthermore, the effects of glucose exposure on the early embryo were investigated, with a focus on changes in autophagy and mitochondrial dependency during the process of embryo development.
METHODS: We examined the sensitivity of in vivo-fertilized embryos (1-cell and 2-cell flushed embryos; 1-CF and 2-CF, respectively) and in vitro-fertilized (IVF) embryos to CQ, and to rotenone, a mitochondrial respiration inhibitor, from the 2-cell stage. Furthermore, using glucose-free CZB medium and glucose-containing modified CZB (mCZB), comparisons were made of development rates, autophagy activity measured with DAPGreen, and mitochondrial activity measured with MitoTracker. Additionally, we examined the effects of O-GlcNAc transferase (OGT) inhibition using the OGT inhibitor OSMI-1.
RESULTS: Under CQ treatment, the blastocyst formation rate decreased significantly in IVF embryos and 1-CF embryos cultured in mCZB compared to 2-CF embryos, starting at 2.0 μM CQ treatment and this was accompanied by reduced cell numbers. Interestingly, autophagy activity detected by DAPGreen was significantly higher at the morula stage in IVF embryos compared with in 2-CF embryos. Oppositely, under rotenone treatment, the blastocyst formation rate increased significantly in IVF embryos and 1-CF embryos compared to 2-CF embryos, starting at 1.0 μM rotenone treatment. Next, glucose-deprived IVF embryos, which cultured in CZB for 24 hours starting at 2 hours after insemination, exhibited increased sensitivity to rotenone during development and elevated mitochondrial activity at the 2-cell stage, followed by decreased autophagy activity at the 4/8-cell stage. Finally, OSMI-1 treatment in mCZB for 24 hours starting at 2 hours after insemination showed an increased mitochondrial activity at the 2-cell stage but, unexpectedly, these embryos showed a tendency toward increased CQ sensitivity.
CONCLUSIONS: Our data indicate that, regardless of fertilization conditions, glucose exposure immediately after fertilization begins to shift preimplantation mouse embryos towards a more autophagy-dependent and less mitochondria-dependent mode of development. This shift is accompanied by increased autophagy activity and reduced mitochondrial activity, potentially mediated in part by O-GlcNAc modification.

Keywords:  animals; autophagy; fertilization in vitro; glucose; mice; mitochondria

DOI:  https://doi.org/10.31083/FBL49320