bims-placeb 2025-07-20 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–07–20
thirteen papers selected by
Carlos M Guardia, National Institute of Health

A roadmap towards targeted differentiation of mouse trophoblast stem cells into cell types of the feto-maternal exchange surface.
Interactions between placental Hofbauer cells and L. monocytogenes change throughout gestation.
Consumption of clinically relevant cannabidiol doses during pregnancy alters postnatal behavior in offspring.
Heterochronic changes in gene expression underlie placental evolution in the fish family Poeciliidae.
Effect of vitamin D3 supplementation starting mid-pregnancy on placental angiogenic factors and terminal villi: a secondary analysis of a randomized controlled trial in Bangladesh.
Impact of endocrine disrupting chemicals on macrophages at the maternal-fetal interface.
Long-read transcriptome assembly reveals vast isoform diversity in the placenta associated with metabolic and endocrine function.
Sex Differences in Hypertension Risk: Insights from Placental Genomics and Pregnancy-Driven Vascular Programming.
Microplastics and the Placenta: A Call to Action for Perinatal Research.
Placenta segmentation redefined: review of deep learning integration of magnetic resonance imaging and ultrasound imaging.
Centromere regulation in the germline and early embryo.
Mesenchymal-epithelial transition serves to rapidly, yet transiently, restore the endometrial epithelium during postpartum murine uterine regeneration.
Mouse Model of Surgical Uterine Injury and Subsequent Pregnancy Outcomes.

Stem Cell Res Ther. 2025 Jul 15. 16(1): 371

A roadmap towards targeted differentiation of mouse trophoblast stem cells into cell types of the feto-maternal exchange surface.

Noura Ballasy, Bethany N Radford, Shuhiba Mohammad, Wendy Dean, Myriam Hemberger.

   BACKGROUND: The characteristic constituents of the mature placenta are made up of highly specialised trophoblast cell types. Trophoblast stem cells (TSCs) possess the developmental plasticity to differentiate into all these mature placental cell types. However, TSCs are typically a heterogenous population with individual cells exhibiting varying degrees of stem cell marker expression. Moreover, standard differentiation protocols of mouse TSCs are based on a release from the stem cell state and result in a mixed population of various trophoblast cell types. This mix of differentiating cells is a particular impediment for functional investigations into the roles of specific trophoblast subtypes of the mouse placental labyrinth, i.e. the portion of the placenta that establishes the feto-maternal exchange unit.
METHODS: Murine TSCs were used to establish culture protocols that enhance the stem cell state of mouse TSCs and that drive differentiation into specific labyrinth trophoblast cell types. TSCs were treated with a panel of 35 epigenetic inhibitors and with 12 selected small molecule compounds either alone or in combination, and across a wide range of doses. TSC stemness and differentiation was assessed by RT-qPCR to determine the relative expression of trophoblast cell type-specific marker genes, and by immunofluorescence staining to verify enrichment of the cell type(s) of interest.
RESULTS: TSC markers CDX2 and SOX2 were robustly enriched upon treatment of mouse TSCs with the KDM1A inhibitor GSK-LSD1, indicative of an enhanced stem cell state. Treatment of differentiating TSCs with the LIMK2 inhibitor BMS-3 in conjunction with either the PPARG agonist rosiglitazone (Rosi) or with Tunicamycin and GSK-LSD1 promoted differentiation of labyrinth trophoblast cell types in general, at the expense of junctional zone trophoblast. Rosi in combination with the KDM1A1 inhibitor GSK-LSD1 or BMS-3 enriched for syncytiotrophoblast layer I cells and sinusoidal trophoblast giant cells, while high doses of Rosi resulted specifically in sinusoidal trophoblast giant cell differentiation. Rosi in combination with the protein synthesis inhibitor Tunicamycin enriched for syncytiotrophoblast layer I cells only. Activin A and the WNT agonist Chiron99021 resulted in predominant syncytiotrophoblast layer II differentiation.
CONCLUSION: Collectively, we establish a roadmap of treatment regimens that promote the differentiation of mouse TSCs into specific trophoblast cell types of the feto-maternal exchange surface. These insights will enable refined biochemical and molecular assessment strategies on defined trophoblast cell types that govern reproductive outcome.

Keywords:  Cell type specification; Directed differentiation; Drug panel; Labyrinth; Syncytiotrophoblast; Trophoblast stem cells

DOI:  https://doi.org/10.1186/s13287-025-04487-z
Sci Immunol. 2025 Jul 18. 10(109): eadq3066

Interactions between placental Hofbauer cells and L. monocytogenes change throughout gestation.

Nagisa Yoshida, Anna Appios, Qian Li, Joseph P Hutton, George Wood, Martin Potts, Julia Aleksandrowicz, Enrico R Barrozo, Freya Dover, Holly Anderson, Katie Stephens, Irving L M H Aye, Jake R Thomas, Hannah C M Schenk, Adam M Bourke, Catherine E Aiken, Ashley Moffett, Andrew Sharkey, Anna V Protasio, Kjersti M Aagaard, James R Edgar, Betty Y W Chung, Naomi McGovern.

Hofbauer cells (HBCs) are extraembryonic macrophages generated de novo within the human placenta. In this study, we explored how the properties of HBCs change throughout gestation. Our analysis revealed transcriptomic differences between first-trimester and term HBCs, with many of the altered genes linked to immune responses. As pregnancy progresses, HBCs exhibit a marked decrease in phagosome maturation and acidification. We show that the differences between first-trimester and term HBCs are important in the context of infection with Listeria monocytogenes, a pathogen that crosses the placenta and replicates within macrophages. Specifically, we observed reduced colony-forming units and diminished actin recruitment by L. monocytogenes in first-trimester HBCs compared with term HBCs. Our findings indicate that the ability of L. monocytogenes to escape from vacuoles is impaired within first-trimester HBCs. Thus, the changes in HBC biology across pregnancy are important in shaping their interactions with L. monocytogenes.

DOI: https://doi.org/10.1126/sciimmunol.adq3066
bioRxiv. 2025 May 06. pii: 2025.04.30.651495. [Epub ahead of print]

Consumption of clinically relevant cannabidiol doses during pregnancy alters postnatal behavior in offspring.

Luis E Gomez Wulschner, Victoria N Chang, Won Chan Oh, Emily Anne Bates.

Pregnant people use cannabidiol (CBD), a non-psychoactive cannabinoid of cannabis, due to its perceived safety and to treat side-effects such as nausea, insomnia, pain, and anxiety. However, CBD crosses the placenta and accumulates in the fetal brain, where it can activate or repress the function of several molecular targets that are important for brain development. While consumption of high doses of CBD during pregnancy have been shown to disrupt offspring neurodevelopment and postnatal behavior, lower, more clinically relevant doses have not been assessed. Here, we show that oral consumption of 10 mg/kg/day CBD during pregnancy increases thermal pain sensitivity in exposed male mouse offspring. Additionally, we find that the same dose impairs cognition and reduces excitability of the prefrontal cortex in exposed female mouse offspring. These data show that lower doses of CBD consumption during pregnancy can impair fetal brain development and postnatal behavior.

DOI: https://doi.org/10.1101/2025.04.30.651495
Proc Biol Sci. 2025 Jul;292(2051): 20250573

Heterochronic changes in gene expression underlie placental evolution in the fish family Poeciliidae.

Jing Li, Polly Campbell, Axel Meyer, David Reznick.

  Placentas evolved nine times in the fish family Poeciliidae. Each time, the egg follicle is the maternal contribution to the placenta. In non-placental species, the follicle fully provisions the egg before fertilization. In placental species, provisioning continues throughout development, and the follicle becomes a more elaborate, well-vascularized organ. We generated transcriptomes for follicles from yolking eggs and developing embryos from two pairs of closely related placental and non-placental species that represent independent origins of placentation plus one non-placental outgroup. We identified genes expressed in eggs but not embryos of non-placental species that continue to be expressed during embryonic development in placental species. Their functions include the maternal transfer of nutrients and immunity. We then reconstructed the ancestral state of the non-placental common ancestor of each species pair and identified genes that were either upregulated or downregulated in developing embryos of placental species relative to non-placental species. These include clusters associated with lipid metabolism, immune response and tissue structure. The two placental lineages were convergent in the function of these genes, but few genes were in common between them. Thus, diverse gene regulatory changes converge on shared essential functions in the independent origins of a complex trait.

Keywords:  Poeciliidae; convergent evolution; evolution of complexity; live-bearing fish; placenta; transcriptomics

DOI:  https://doi.org/10.1098/rspb.2025.0573
BMC Pregnancy Childbirth. 2025 Jul 11. 25(1): 752

Effect of vitamin D3 supplementation starting mid-pregnancy on placental angiogenic factors and terminal villi: a secondary analysis of a randomized controlled trial in Bangladesh.

Anita Subramanian, Casey M Carr, Eszter Papp, Kellie E Murphy, Abdullah Al Mahmud, Daniel E Roth, Alison D Gernand.

   BACKGROUND: Angiogenesis is essential for placental growth and development. Improper placental vascular development can reduce blood flow to the fetus and increase the risk of adverse pregnancy and birth outcomes. The objectives of this study were to examine the effect of prenatal vitamin D supplementation on placental angiogenic factors and terminal villi, and associations between angiogenic factors, terminal villi and birth outcomes.
METHODS: This is a secondary analysis using data and specimens from the Maternal Vitamin D for Infant Growth trial in Dhaka, Bangladesh (n = 1298). Participants were enrolled at 17-24 weeks gestation and randomized to receive (IU/week): placebo, 4200, 16,800 or 28,000 vitamin D3 supplement until birth. Newborns and placentas were measured at birth. We examined a subset of randomly selected placentas (n = 80). Tissue sections were evaluated for vascular endothelial growth factor (VEGF-A) and placental growth factor (PlGF) using immunofluorescence. We measured intensity and percent area of expression for angiogenic factors, and total number and surface area of terminal villi. Vitamin D treatment effect was estimated using ANOVA. Regression models were used to assess associations of markers of placental angiogenesis with birth outcomes. Interactions by infant sex were examined.
RESULTS: The overall mean (SD) percent area of expression was 17.0 (4.0) for VEGF-A and 15.0 (1.9) for PlGF. The mean (SD) number of terminal villi was 39 (15) per 12 in2, and surface area was 0.096 (0.040) in2. Vitamin D treatment groups were similar to placebo for all outcomes. No associations were observed between angiogenic factors or terminal villi placental and birth outcomes.
CONCLUSIONS: Vitamin D supplementation starting from mid-pregnancy until birth did not affect expression of two key angiogenic factors or terminal villi in the placenta. Placental angiogenic factors or terminal villi did not have an association with birth outcomes. These results do not support a role of maternal vitamin D starting mid-pregnancy in impacting placental development.

Keywords:  Angiogenic factors; Placenta; Placental angiogenesis; Pregnancy; Trophoblast; Vasculature; Villi; Vitamin D

DOI:  https://doi.org/10.1186/s12884-025-07566-4
Semin Immunopathol. 2025 Jul 16. 47(1): 29

Impact of endocrine disrupting chemicals on macrophages at the maternal-fetal interface.

Bin Zhao, Qinsheng Lu, Miaojuan Chen, Gendie E Lash.

  Pregnancy is a complex and dynamic process, immune homeostasis at the maternal-fetal interface is one of the keys to a successful pregnancy and essential for fetal nutrient exchange and the establishment of immune tolerance. Healthy pregnant women with normally functioning immune systems can successfully maintain a semi-allogeneic fetus to full term without immune-mediated rejection, many immune cells including macrophages, NK cells, T cells, B cells and dendritic cells are involved in this process. In particular, macrophages play a vital role in the establishment of immune tolerance, infection prevention, spiral artery remodeling, and overall maternal and fetal health, due to their plasticity and diversity. However, environmental toxins like endocrine-disrupting chemicals (EDCs) can impact macrophage function, leading to pregnancy-related conditions. This review explores the current knowledge of macrophages at the maternal-fetal interface, their roles in pregnancy, and how EDCs affect their polarization and function.

Keywords:  Endocrine disrupting chemicals; Immune cell; Macrophage; Maternal-fetal interface; Placenta; Pregnancy; Reproduction

DOI:  https://doi.org/10.1007/s00281-025-01055-8
bioRxiv. 2025 Jun 27. pii: 2025.06.26.661362. [Epub ahead of print]

Long-read transcriptome assembly reveals vast isoform diversity in the placenta associated with metabolic and endocrine function.

Sean T Bresnahan, Hannah Yong, 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 plays a critical role in fetal development and mediates maternal metabolic effects on offspring health outcomes. Despite its importance, the placenta remains understudied in large-scale genomic initiatives, with most analyses focusing on gene-level expression based on annotations from adult tissue references that obscure isoform diversity particularly vital to understanding function in developmental tissues. Here, we employed largest-in-class long-read RNA sequencing (N = 72) to generate a comprehensive placental transcript reference, yielding 37,661 high-confidence isoforms across 12,302 genes. Our assembly revealed 14,985 novel isoforms of known genes and 2,759 transcripts representing previously unannotated genes, with extensive diversity in genes involved in obesity, placental lactogen production, and growth control. We demonstrate this approach has two immediate practical advantages: First, the improved reference reduced inferential uncertainty in isoform quantification by approximately 37%, reduced the frequency of low-confidence annotations and increased the yield (read depth) of high-confidence annotations. Second, in analyses of gestational diabetes mellitus (GDM) with short-read RNA-seq datasets from two independent, multi-ancestry birth cohorts (N = 344) as an exemplar, we were able to identify novel isoforms of chorionic somatomammotropin hormone 1 ( CSH1 ) mediating the effect of maternal hyperglycemia on birth weight that was not apparent in conventional gene-level analyses. These findings demonstrate that isoform-level annotation of placental transcriptomics provides greater sensitivity and specificity than gene-level approaches. This enhanced precision may be essential for understanding placental function in developmental programming of metabolism and reveal ancestry- and context-specific variation in placental function and responses to environmental exposures.

DOI: https://doi.org/10.1101/2025.06.26.661362
Int J Mol Sci. 2025 Jun 24. pii: 6034. [Epub ahead of print]26(13):

Sex Differences in Hypertension Risk: Insights from Placental Genomics and Pregnancy-Driven Vascular Programming.

Efthalia Moustakli, Anastasios Potiris, Athanasios Zikopoulos, Despoina Mavrogianni, Nikolaos Kathopoulis, Eirini Drakaki, Ismini Anagnostaki, Ioannis Tsakiridis, Themistoklis Dagklis, Charikleia Skentou, Peter Drakakis, Panagiotis Christopoulos, Sofoklis Stavros.

  The prevalence, pathogenesis, and long-term consequences of hypertension differ significantly across the sexes, and pregnancy is a special physiological stress test that can reveal a woman's underlying cardiovascular sensitivity. In addition to being direct risks to the health of the mother and fetus, hypertensive disorders of pregnancy (HDPs), especially preeclampsia, are also reliable indicators of future hypertension and cardiovascular disease in those who are afflicted. Fetal sex has a substantial impact on maternal vascular adaptation, according to new data from placental transcriptomics and epigenetics. This may be due to variations in the expression of angiogenic, immunomodulatory, and vasoactive genes. Sex-specific patterns of placental function, inflammation, and endothelium control are specifically influenced by X-linked gene dosage, escape from X-inactivation, and sex chromosomal composition. These biological variations highlight the placenta's potential function as a mediator and indicator of maternal cardiovascular risk, and they may help to explain why the incidence and severity of hypertensive pregnancy challenges vary depending on the fetal sex. The purpose of this review is to summarize the state of the art regarding how placental genetics and fetal sex influence maternal hypertensive risk both during and after pregnancy. Additionally, it will investigate how these findings may influence sex-specific cardiovascular screening, prediction, and prevention methods.

Keywords:  X-linked genes; epigenetics; hypertensive disorders of pregnancy; placental genomics; sex differences

DOI:  https://doi.org/10.3390/ijms26136034
Am J Perinatol. 2025 Jul 17.

Microplastics and the Placenta: A Call to Action for Perinatal Research.

Jamie Kim, Marcia Chen, Robert S White.

Microplastics have been detected in human placental and neural tissues, raising urgent concerns about their potential effects on maternal and fetal health. Emerging evidence links microplastics to systemic inflammation, neurotoxicity, and endocrine disruption, yet their impact on pregnancy outcomes and fetal development remains poorly understood. Given the placenta's central role in early-life health, perinatal researchers are uniquely positioned to lead investigations into this environmental threat. We call for collaborative, multidisciplinary research to better understand and mitigate the effects of microplastic exposure during pregnancy.

DOI: https://doi.org/10.1055/a-2657-6249
Vis Comput Ind Biomed Art. 2025 Jul 15. 8(1): 17

Placenta segmentation redefined: review of deep learning integration of magnetic resonance imaging and ultrasound imaging.

Asmaa Jittou, Khalid El Fazazy, Jamal Riffi.

  Placental segmentation is critical for the quantitative analysis of prenatal imaging applications. However, segmenting the placenta using magnetic resonance imaging (MRI) and ultrasound is challenging because of variations in fetal position, dynamic placental development, and image quality. Most segmentation methods define regions of interest with different shapes and intensities, encompassing the entire placenta or specific structures. Recently, deep learning has emerged as a key approach that offer high segmentation performance across diverse datasets. This review focuses on the recent advances in deep learning techniques for placental segmentation in medical imaging, specifically MRI and ultrasound modalities, and cover studies from 2019 to 2024. This review synthesizes recent research, expand knowledge in this innovative area, and highlight the potential of deep learning approaches to significantly enhance prenatal diagnostics. These findings emphasize the importance of selecting appropriate imaging modalities and model architectures tailored to specific clinical scenarios. In addition, integrating both MRI and ultrasound can enhance segmentation performance by leveraging complementary information. This review also discusses the challenges associated with the high costs and limited availability of advanced imaging technologies. It provides insights into the current state of placental segmentation techniques and their implications for improving maternal and fetal health outcomes, underscoring the transformative impact of deep learning on prenatal diagnostics.

Keywords:  Deep learning; Magnetic resonance imaging; Placenta; Segmentation; Ultrasound

DOI:  https://doi.org/10.1186/s42492-025-00197-8
Curr Opin Genet Dev. 2025 Jul 10. pii: S0959-437X(25)00071-1. [Epub ahead of print]94 102379

Centromere regulation in the germline and early embryo.

Marta Grzonka, Ben E Black, Michael A Lampson.

Centromeres are essential for genome inheritance, serving as sites for kinetochore assembly and for final sister chromatid cohesion to ensure accurate chromosome segregation during cell division. These roles must persist through radical physical changes to chromosomes and other biological challenges presented by specialized processes in the germlines of both sexes and during early embryonic development. Centromeres in most organisms are epigenetically defined by the presence of a histone H3 variant, CENP-A. Therefore, to maintain centromeres, CENP-A nucleosomes must be inherited across generations through the germline. However, unique aspects of gametogenesis, including asymmetric meiosis and prolonged cell cycle arrest in the female germline and extensive chromatin reorganization in the male germline, introduce additional layers of complexity to the process of centromere inheritance. Here, we review the implications of these processes for centromere regulation during gametogenesis and early embryonic development, drawing on findings from mouse and fruit fly models.

DOI: https://doi.org/10.1016/j.gde.2025.102379
bioRxiv. 2025 May 09. pii: 2025.05.05.652287. [Epub ahead of print]

Mesenchymal-epithelial transition serves to rapidly, yet transiently, restore the endometrial epithelium during postpartum murine uterine regeneration.

Zidao Wang, Kimberly M Davenport, Susanta K Behura, Amanda L Patterson.

The uterus is a remarkable organ in its ability to undergo extensive tissue damage during menstruation and parturition, yet achieves efficient, scar-free repair. Coordinated regulation of this regenerative process is essential for uterine homeostasis and fertility; however, the underlying mechanisms remain incompletely understood. Here, we demonstrate that mesenchymal-epithelial transition (MET) contributed to postpartum endometrial re-epithelialization using Pdgfrα CreERT2/+ ; Rosa26-tdTomato fl/+ lineage tracing mice. Flow cytometry revealed a marked increase in mesenchymal-derived (MD) epithelial cells during active tissue repair. Notably, these cells were transient, undergoing clearance primarily via apoptosis following completed epithelial restoration. We also identified a migratory population of transitional cells of mesenchymal origin within the mesometrial stroma that incorporated into the luminal epithelium, consistent with an active MET program. Single-nucleus RNA sequencing (snRNA-seq) revealed that MD epithelial cells exhibited gene expression profiles associated with cell adhesion and cytoskeletal remodeling, while transitional cells were enriched for genes involved in junctional assembly and actin dynamics. MET-associated genes were significantly upregulated in both transitional and MD epithelial populations. Cell-cell communication analysis highlighted WNT, BMP, and EPHA signaling as candidate regulators of MET during regeneration. Together, these findings provide confirmation of MET as a physiologic mechanism of postpartum endometrial epithelial repair and uncover a coordinated signaling network that facilitates this process. Perturbations in MET may contribute to pathologies such as endometriosis or endometrial cancer, underscoring the importance of understanding mesenchymal-epithelial plasticity in both normal and disease states.
Significance: The mammalian endometrium undergoes repeated injury and repair during menstruation (women) and pregnancy (most eutherians), yet exhibits a remarkable capacity for rapid, scar-free healing that mediates infection, inflammation and hemorrhage. Despite its clinical relevance, the molecular regulation of endometrial regeneration remains poorly defined. Using a transgenic lineage-tracing mouse model, we identified mesenchymal-derived (MD) epithelial and transitional cells during the regenerative window and revealed a critical role for mesenchymal-epithelial transition (MET) in this process. Single-nucleus RNA sequencing further uncovered functional characteristics of these cells and highlighted WNT, BMP, and EPHA signaling as potential regulators of MET. These findings provide new insight into the cellular and molecular framework of endometrial regeneration and have important implications for diseases involving aberrant tissue repair.

DOI: https://doi.org/10.1101/2025.05.05.652287
J Vis Exp. 2025 Jun 27.

Mouse Model of Surgical Uterine Injury and Subsequent Pregnancy Outcomes.

Nathan Lee Ng, Elisa T Zhang.

Uterine injury from Cesarean sections (C-sections) and other procedures (dilation and curettage, myomectomies, etc.) can lead to several morbidities in subsequent pregnancies, including placenta previa, placenta accreta spectrum (PAS), Cesarean scar pregnancy, and uterine rupture. C-sections account for approximately 30% of deliveries in the US, with rates projected to rise. Therefore, a deeper understanding of the mechanisms by which injury-associated pregnancy disorders arise and a platform for testing possible interventions are essential. To achieve these objectives, there is a critical need for animal models of uterine injury, particularly those that address the impact of injury on subsequent in utero outcomes. This protocol describes a novel surgical procedure for a model of mechanically induced uterine injury in the laboratory mouse (Mus musculus). Steps taken in preparation for surgery, induction of the uterine injury itself, and post-surgical recovery procedures are demonstrated. Additional information is provided regarding the downstream dissection of both non-pregnant and pregnant mice. Overall, by detailing a set of procedures for inducing uterine injury in an in vivo model, this protocol presents a tractable method for elucidating the molecular and cellular events of uterine wound healing and its effects on subsequent pregnancy.

DOI: https://doi.org/10.3791/67977