bims-placeb 2026-01-04 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–01–04
eleven papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Trophoblast adaptation to hypoxia: balance and dysfunction.
Whole-Genome Amplification on Single Circulating Trophoblast Cell.
Single-cell mapping of maternal-fetal cross-talk in preeclampsia.
MCT1 supports syncytiotrophoblast function and placental development in early pregnancy.
Complement factor H-point mutation promotes the development of preeclampsia-like phenotype with multiparity in mice.
Distinct macronutrient ratios optimize offspring survival, growth, and maternal glucose tolerance across mouse reproduction.
Elucidating the role of ABC transporters in the placental efflux of (-)- Δ9-tetrahydrocannabinol (THC) using a cocktail of ABC transport inhibitors.
Villitis of unknown etiology is a placental pathology associated with pregnancy complication: a systematic review and meta-analysis.
Multivariate fetal growth trajectory modeling and its association with maternal fatty acids.
Considerations for Implementation of Serum Biomarker Testing for Suspected Hypertensive Disorders of Pregnancy.
Biology and therapeutic potential of extracellular vesicle targeting and uptake.

Cell Commun Signal. 2025 Dec 29. 23(1): 538

Trophoblast adaptation to hypoxia: balance and dysfunction.

Qian Li, Xiaowei Wei, Yunqing Zhang, Weihong Zeng, Yi Lin.

  During placenta development, trophoblasts dynamically adapt to hypoxic microenvironments to orchestrate physiological functions and morphogenesis. Early gestation establishes a transient hypoxic niche essential for trophoblast stem cell (TSC) proliferation and differentiation. This niche undergoes a transition to physiological reoxygenation following the remodeling of uterine spiral arteries during gestational weeks 10 to 12, establishing a spatiotemporal oxygen gradient critical for placental development. Disrupted hypoxia sensing-exemplified by deficient hypoxia-inducible factor (HIF) signaling-leads to placental maldevelopment, while sustained HIF activation drives preeclampsia-like pathology, underscoring the delicate equilibrium of oxygen-responsive mechanisms. Emerging evidence highlights hypoxia-centered signaling cascades, epigenetic reprogramming, and metabolic plasticity as pivotal regulators of trophoblast adaptation. Deciphering these molecular networks not only elucidates the pathogenesis of gestational complications but also holds potential for efficient therapies to restore placental homeostasis.

Keywords:  Hypoxia; Hypoxia-inducible factors; Metabolism; Preeclampsia; Trophoblast

DOI:  https://doi.org/10.1186/s12964-025-02531-2
Methods Mol Biol. 2026 ;3003 11-23

Whole-Genome Amplification on Single Circulating Trophoblast Cell.

Imen Chakchouk, Ignatia B Van den Veyver.

  Whole-genome amplification (WGA) is a technique designed to amplify the entire genome from trace amounts of original template DNA, such as that from a single cell. This amplification provides sufficient DNA for downstream comprehensive genetic analysis. In cell-based noninvasive prenatal testing (cb-NIPT), single circulating trophoblast cells are isolated from the maternal bloodstream. Among the required steps in single trophoblast isolation are light paraformaldehyde fixation, permeabilization, and immunostaining, which are not compatible with all WGA methods. Following single trophoblast isolation and WGA, the amplified DNA is subjected to detailed SNP genotyping and next-generation sequencing for genetic testing. This protocol is a step-by-step guideline for WGA on circulating single trophoblasts isolated from maternal blood during pregnancy.

Keywords:  Maternal blood; Single circulating trophoblast; Whole-genome amplification

DOI:  https://doi.org/10.1007/978-1-0716-5060-8_2
Res Sq. 2025 Dec 08. pii: rs.3.rs-8254581. [Epub ahead of print]

Single-cell mapping of maternal-fetal cross-talk in preeclampsia.

Nardhy Gomez-Lopez, Seungbaek Lee, Roberto Romero, Adi Tarca, Jose Galaz, Yi Xu, Gaurav Bhatti, Sivani Ravindran, Dustyn Levenson, Eva Kareus, Marcelo Farias-Jofre, Bogdan Panaitescu, Eloise Eyestone, Sonia Hassan, Tinnakorn Chaiworapongsa, Nandor Than, Roger Pique-Regi.

Preeclampsia (PE) arises from placental dysfunction, yet the cellular events that distinguish early-onset PE (EOPE) from late-onset PE (LOPE) are poorly defined. We generated a comprehensive single-cell atlas of the placenta of women with and without PE (78 patients), integrating maternal-fetal genotyping, multi-dimensional clustering, and cell-cell communication analysis. PE reshaped the abundance and transcriptional states of major placental cell types. EOPE was defined by expanded T and NK cells with reduced extravillous trophoblasts, whereas LOPE involved increased monocytes/macrophages and activation of ANNEXIN-, NOTCH-, ANGPTL-, and EGF-associated pathways. These onset-specific disruptions reveal distinct modes of immune-trophoblast dysregulation. Extending these insights to maternal circulation, multiple EOPE- and LOPE-derived placental mRNA signatures distinguished EOPE from controls at or after diagnosis, and an EOPE-derived CTB-1 protein signature showed moderate predictive value for LOPE. This atlas defines the cellular architecture of PE subtypes and establishes a foundation for developing early, noninvasive biomarkers.

DOI: https://doi.org/10.21203/rs.3.rs-8254581/v1
J Reprod Immunol. 2025 Dec 29. pii: S0165-0378(25)00407-3. [Epub ahead of print]173 104829

MCT1 supports syncytiotrophoblast function and placental development in early pregnancy.

Ruizhi Chen, Jiahui Xiao, Guanying You, Linlin Wang, Gang Feng, Lianghui Diao, Yuye Li.

  Spontaneous miscarriage affects approximately 15 % of clinically recognized pregnancies, often due to impaired placental development. While syncytiotrophoblast (STB) is essential for nutrient exchange and hormonal support, the molecular pathways that maintains function remain incompletely defined. Here, we identify monocarboxylate transporter 1 (MCT1) as a novel metabolic regulator of placental development. We show that MCT1 expression is markedly reduced in the villi of patients with spontaneous miscarriage, correlating with abnormal lactate accumulation. Using a mouse model, we demonstrate that MCT1 inhibition leads to pregnancy failure and impaired formation of the placental labyrinth, the key site for maternal-fetal exchange. Functional and transcriptomic analyses reveal that MCT1 deficiency disrupts syncytiotrophoblast organization and downregulates transcriptional regulators critical for trophoblast function. These findings suggest that MCT1 supports early pregnancy through the trophoblast gene regulatory networks and identify it as a potential target in reproductive failure.

Keywords:  Labyrinth; Lactic acid; MCT1; Syncytiotrophoblast; Transcriptional regulation

DOI:  https://doi.org/10.1016/j.jri.2025.104829
Placenta. 2025 Dec 25. pii: S0143-4004(25)00770-2. [Epub ahead of print]174 153-165

Complement factor H-point mutation promotes the development of preeclampsia-like phenotype with multiparity in mice.

Fei-Fei Chen, Zheng Li, Ying Tan, Hui Wang, Shi Chen, Feng Yu, Ying-Dong He, Qian Chen, Hui-Xia Yang, Ming-Hui Zhao.

   INTRODUCTION: Preeclampsia, a severe pregnancy disorder associated with the placenta, remains incompletely understood in terms of its pathogenesis. Studies have suggested a link between complement activation and preeclampsia. In normal pregnancy, there is a moderate balance between complement-activating factor and regulatory protein. Fourteen percent of patients with preeclampsia/hemolysis, elevated liver enzymes and low platelet syndrome (HELLP syndrome) have a genetic mutation in complement regulators, leading to impaired regulation of the alternative complement pathway. However, the direct association between this and the precise role of pregnancy in triggering preeclampsia via complement system activation remains elusive.
METHODS: Here, we evaluated the clinicopathological characteristics of preeclampsia in female mice harboring heterozygous mutations in complement factor H (CFH) (FHW/R). Blood pressure, 24-h urine protein, blood biochemistry, routine blood tests, circulating complement activation factors, placental pathology, local complement activation and vascular activation were detected in both groups of mice.
RESULTS: Along with complement activation, these mice manifested hallmark features of human preeclampsia, including hypertension, proteinuria, increased lactic dehydrogenase, reduced placental weight, restricted fetal growth, characteristic histological alterations in the placenta and kidney, disrupted placental angiogenesis and renal endothelial cell injury.
CONCLUSIONS: We induced the key features of human preeclampsia in mice with heterozygous mutations in complement factor H,which suggest that individuals with increased genetic susceptibility to complement system overactivation may constitute a population which may have an increased risk to develop preeclampsia like phenotype of hypertension.

Keywords:  Complement activation; Complement alternative pathway; Complement factor H-Point mutation mice; Multiparity; Preeclampsia

DOI:  https://doi.org/10.1016/j.placenta.2025.12.010
Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2513044123

Distinct macronutrient ratios optimize offspring survival, growth, and maternal glucose tolerance across mouse reproduction.

Fay Morland, Melany H Malcolm, Laura Wilkinson, Christine Neyt, David R Grattan, Amanda E Brandon, Stephen J Simpson, Alistair M Senior, Samantha M Solon-Biet, Tracy L Perry, Michael Garratt.

  Pregnancy and lactation are reproductive periods that require major energy and nutrient investment by the mother. Dietary perturbations over reproduction can impair offspring development and increase the risk of metabolic disease for the mother. However, how the intake of specific macronutrients, independent of total calorie intake, influence maternal reproductive investment and metabolic health remains poorly understood. To understand the role of protein, carbohydrate, and fat intake in influencing these parameters, we fed mice one of ten isocaloric diets that differed systematically in their macronutrient make-up. We allowed females to breed and observed striking effects of different macronutrients on fetal development, with protein intake having strong positive effects on offspring survival, accompanied by major shifts in the morphological structure of the placenta and placental lactogen production. However, maternal glucose tolerance was strongly impaired by high protein intake during pregnancy, with reproductive females more susceptible to the effects of these macronutrients than nonpregnant animals. Strikingly, metabolic effects were reversed after lactation, with mothers developing a resilience to the chronic effects of protein and fat intake on glucose tolerance observed in virgin animals. During lactation, we also observed that offspring development was optimized by a different ratio of macronutrients compared to during pregnancy. These results highlight the importance of optimizing macronutrient, particularly protein, intake to specific levels during pregnancy, ensuring a balance that maintains maternal glucose tolerance while providing sufficient nutrients to ensure healthy offspring growth and survival.

Keywords:  diet; lactation; metabolism; pregnancy; reproduction

DOI:  https://doi.org/10.1073/pnas.2513044123
Placenta. 2025 Dec 23. pii: S0143-4004(25)00772-6. [Epub ahead of print]174 174-177

Elucidating the role of ABC transporters in the placental efflux of (-)- Δ9-tetrahydrocannabinol (THC) using a cocktail of ABC transport inhibitors.

Ankit Balhara, Xin Chen, Aditya R Kumar, Morgan E Wasickanin, Joshua W Monson, Jennifer R Damicis, Hillary J Kinsman, Nicholas Ieronimakis, Jashvant D Unadkat.

  We previously showed that THC is effluxed in the perfused human placenta cotyledons, but surprisingly this efflux was not inhibited by valspodar, a P-gp and BCRP inhibitor. P-gp and BCRP have multiple binding sites, and therefore THC may be binding to a transport site not blocked by valspodar. To test this hypothesis, we perfused human placenta cotyledons with THC in the absence and presence of a cocktail of P-gp and BCRP inhibitors. The inhibitor cocktail significantly increased the unbound maternal-to-fetal THC clearance index, indicating that P-gp and/or BCRP are likely involved in determining fetal THC exposure.

Keywords:  Cocktail of ABC transporter inhibitors; Fetal exposure; Multiple binding sites; Perfused placenta; Placental transport; THC

DOI:  https://doi.org/10.1016/j.placenta.2025.12.012
Front Med (Lausanne). 2025 ;12 1656438

Villitis of unknown etiology is a placental pathology associated with pregnancy complication: a systematic review and meta-analysis.

Xiaoqian Zhang, Kang Yan, Xietong Wang.

   Background: Villitis of unknown etiology (VUE) is a chronic placental inflammatory lesion of high incidence, but its relationship with adverse pregnancy outcomes remains unclear. This meta-analysis quantifies its impact on five critical complications adverse pregnancy outcomes, including fetal growth restriction (IUGR), preeclampsia (PE), gestational hypertension, small gestation age (SGA), and stillbirth.
Methods: We used the search verb "villitis of unknown etiology" OR "VUE" OR "chronic villitis" OR "unknown etiology of villitis", from databases SCOUP, PubMed and Google Scholar, incorporating cohort studies, case-control studies. Heterogeneity was assessed via I 2 statistics.
Results: The incidence of VUE was higher in the IUGR, PE, gestational hypertension, SGA, and stillbirth groups than in the normal control group. VUE was significantly associated with an increased risk of stillbirth (OR = 3.64, 95% CI: 1.80-7.39) and pre-eclampsia (OR = 1.31, 95% CI: 1.03-1.65). A marginal association was observed between VUE and gestational hypertension (OR = 1.41, 95% CI: 0.892-2.23). In contrast, the associations of VUE with IUGR (OR = 1.56, 95% CI: 0.509-4.77) and SGA (OR = 1.01, 95% CI: 0.099-10.4) were not statistically significant and exhibited substantial heterogeneity.
Conclusion: VUE is strongly associated with stillbirth and PE, highlighting its role in the pathogenesis of placental-related diseases. While there are no significant associations were found with intrauterine growth restriction or small for gestational age infants based on current evidence, these findings solidify the link between VUE and specific obstetric syndromes.
Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=1077709, identifier PROSPERO (CRD4202121077709).

Keywords:  intrauterine growth restriction (IUGR); meta-analysis; preeclampsia (PE); stillbirth; villitis of unknown etiology (VUE)

DOI:  https://doi.org/10.3389/fmed.2025.1656438
Sci Rep. 2025 Dec 30.

Multivariate fetal growth trajectory modeling and its association with maternal fatty acids.

Shuai Huang, Jia-Jia Tang, He-Bin Chi, Han-Wen Zhang, Xiao-Yuan Fan, Feng Tang, Xian-Shu Lin, Bing-Rui Yang, Hong-Bo Qi, Yin-Yin Xia, Ting-Li Han, Hua Zhang.

  Maternal circulating fatty acids are closely linked to fetal development. However, few studies have investigated the relationship between the maternal fatty acid levels at 11-14 weeks of gestation and fetal growth trajectories phenotype. A total of 655 pregnant women were selected from the Complex Lipids in Mothers and Babies cohort. Twenty fatty acids in maternal serum at 11-14 weeks of gestation were quantified by GC-MS. The trajectories of fetal head circumference (HC), biparietal diameter (BPD), abdominal circumference (AC), and femur length (FL) z-score at 11-14, 22-28, and 32-34 weeks of gestation were determined by group-based multi-trajectory modeling (GBMTM). Multinomial logistic regression and quantile-based g-computation (Qgcomp) were used to investigate the relationship between individual and mixed fatty acid exposures and the fetal growth trajectories. GBMTM identified four trajectory groups of fetal ultrasound measurements: stable falling, stable increasing, high stable increasing, and dramatically falling. The incidence of premature rupture of membranes, placental implantation, large-for-gestational-age (LGA) and macrosomia differed significantly between the four trajectory groups (p-values of 0.044, 0.008, < 0.001, and < 0.001, respectively). Higher maternal serum linoleic acid (LA, C18:2 n-6) and α-linolenic acid (ALA, C18:3 n-3) were associated with increased odds in the stable falling (OR = 1.004; 95% CI: 1.001, 1.008) and dramatically falling trajectory groups (OR = 1.042; 95% CI: 1.001, 1.085). Meanwhile, eicosadienoic acid (EDA, C20:2 n-6) was associated with decreased odds in the stable falling trajectory group (OR = 0.845;95% CI: 0.716, 0.998). Fetal growth trajectory classification based on GBMTM reveals associations between different trajectory groups and adverse pregnancy outcomes. In addition, serum fatty acids LA, ALA and EDA at 11-14 weeks of gestation were associated with the fetal growth trajectories phenotype.

Keywords:  Based multi; Computation; Fatty acids; Fetal growth; Group; Mixture analysis; Quantile g; Trajectory modeling

DOI:  https://doi.org/10.1038/s41598-025-30334-5
Clin Chem. 2025 Dec 30. 72(1): 152-162

Considerations for Implementation of Serum Biomarker Testing for Suspected Hypertensive Disorders of Pregnancy.

Ashten B Waks, Christina Frasik, Megan C Oakes.

BACKGROUND: Hypertensive disorders of pregnancy (HDPs) complicate 8% to 9% of all pregnancies. They are a leading cause of maternal and neonatal morbidity and mortality and contribute to over $2.2 billion of health care expenditures annually. In 2023, the FDA first approved a soluble fms-like tyrosine kinase 1 to placental growth factor ratio system for HDP risk stratification; however, little is known about the implementation of such biomarker testing outside of research contexts.
CONTENT: HDP severity drives clinical management and adverse perinatal outcomes. Placental biomarker testing aims to determine which patients are at risk for developing or progressing to the most severe HDPs. Widespread implementation of biomarker testing may increase access though it may not be cost-efficient or practice-changing for individual institutions. Accordingly, further attention must be paid to restrictive testing situations (e.g., low-resource settings) or even off-label uses (e.g., multiple gestations) that may solidify the role of biomarker testing in routine practice.
SUMMARY: This review aims to outline clinical and institutional considerations for placental biomarker utilization in the context of their FDA-approved uses and to highlight the potential advantages and disadvantages of various testing strategies.

DOI: https://doi.org/10.1093/clinchem/hvaf115
Nat Rev Mol Cell Biol. 2026 Jan 02.

Biology and therapeutic potential of extracellular vesicle targeting and uptake.

Léa Ripoll, Antje M Zickler, Pieter Vader, Samir El Andaloussi, Frederik J Verweij, Guillaume van Niel.

Extracellular vesicles (EVs) have gained significant attention owing to their role in pathophysiological processes and potential as therapeutic tools. EVs are small vesicles (30 nm-5 µm) containing specific cargo (proteins, nucleic acids and lipids) and are released from most cell types. Their capacity to target and induce phenotypical changes in recipient cells has established them as key mediators of intercellular communication. Although EV biogenesis is well studied, their uptake and fate in recipient cells are still poorly understood. In this Review, we focus on the cell biology underlying EV interactions with recipient cells and their intracellular fate. We discuss the mechanisms EVs use to achieve cell-specific targeting, cell signalling and functional cargo delivery and list the key challenges currently limiting our ability to harness these EVs into efficient therapeutic nanovehicles. We explore how our understanding of the molecular mechanisms supporting interactions of EVs with recipient cells and their functions herein can provide new strategies to use them for therapeutic approaches.

DOI: https://doi.org/10.1038/s41580-025-00922-4