bims-placeb Biomed News
on Placental cell biology
Issue of 2025–09–21
nineteen papers selected by
Carlos M Guardia, National Institute of Health
  1. Human Placental Genomic Instability Predicts Adverse Pregnancy Outcomes.
  2. High-elevation adaptation and gestational hypoxia jointly shape vascular development in a rodent placenta.
  3. Transformed bovine trophoblast stem cell lines, characterization, gene editing and secretions.
  4. DUX4-stimulated genes define an antiviral defense program in human placental trophoblasts.
  5. Tumor suppressor protein p53 governs human trophoblast lineage development.
  6. Amino Acid Restriction Impairs Human Endometrial Stromal Cell Decidualization and Is Rescued by Proline Supplementation.
  7. Intercellular highways of viral spread: tunneling nanotubes and extracellular vesicles at the maternal-fetal interface.
  8. Maternal, placental and cord erythrocyte levels of long-chain polyunsaturated fatty acids in full-term and preterm pregnancy.
  9. Interplay of stromal cell-derived factor 2 and endoplasmic reticulum stress in the placenta: A review.
  10. Placentation Disruption by Perfluorooctanoic Acid and Perfluorooctanesulfonate in Human Trophoblast Organoids.
  11. ARIH1 Promotes Preeclampsia by Inducing MFN2-Dependent Hypoxia-Triggered Mitophagy and Endoplasmic Reticulum Stress in Trophoblasts.
  12. Differential susceptibility of human placental trophoblasts to Trypanosoma cruzi infection.
  13. Associations between brominated and organophosphate flame retardant levels and inflammatory biomarkers in maternal blood, cord blood, and placental tissue at mid-gestation.
  14. Aberrant Expression of Gonadotropin-Releasing Hormone Receptor in Human Mast Cells Enhances the Recruitments of Trophoblasts and NK Cells.
  15. Preeclampsia is associated with placental complement C4d deposition.
  16. Extracellular vesicles released from human amniotic fluid stem cells modulate macrophages.
  17. Evaluating the sFlt1 Mouse Model of Preeclampsia: Benefits and Limitations for Understanding Human Disease.
  18. ANXA6 Overexpression Causes Abnormal Decidual Macrophage-Trophoblast Crosstalk in Recurrent Spontaneous Abortion.
  19. Participation of kynurenine pathway metabolites in Trypanosoma cruzi infection of human placenta.
  1. Res Sq. 2025 Sep 08. pii: rs.3.rs-7419733. [Epub ahead of print]
    Human Placental Genomic Instability Predicts Adverse Pregnancy Outcomes.
    Kathleen Fisch, Molly Huang, Cindy Barba, Hector Chavez, Avery Williams, Nicholas Guo, Rhea Robertson, Emily Zhang, Arundhati Calambur, Cayla Mason, Katharine Nelson, Morgan Meads, Omonigho Aisagbonhi, Mariko Horii.
      Preeclampsia is a leading cause of pregnancy-related death, accounting for over 50,000 maternal and 500,000 fetal deaths worldwide each year. Preeclampsia has been linked to confined placental mosaicism, which underscores a potential role of placental genomic instability in driving adverse pregnancy outcomes. Here, using bulk RNA sequencing from 59 preeclamptic and 53 normotensive pregnancies, we explored somatic genomic instability and hypoxia with respect to clinical maternal-placental-neonatal outcomes. We found that genomic instability increased the probability of delivering at an earlier gestational age with a diagnosis of preeclampsia, maternal vascular malperfusion placental lesions, and small for gestational age neonates. Notably, genomic instability and hypoxia are predictive biomarkers for all three adverse pregnancy outcomes. In an induced pluripotent stem cell-derived trophoblast stem cell model, we observed increased genomic instability in trophoblast stem cells obtained from placentas demonstrating maternal vascular malperfusion with preeclampsia. Additionally, increased genomic instability correlated with reduced extravillous trophoblast invasion, implicating a functional role for genomic instability. These findings provide promising insights into the underlying mechanisms of genomic instability in the placenta which may be useful biomarkers for early clinical diagnosis of placental injury underlying preeclampsia.
    DOI:  https://doi.org/10.21203/rs.3.rs-7419733/v1
  2. J Physiol. 2025 Sep 17.
    High-elevation adaptation and gestational hypoxia jointly shape vascular development in a rodent placenta.
    Kathryn Wilsterman, Zachary A Cheviron, Jeffrey M Good, Kai Gurnoe-Brantley, Kylie E Jewett, Katherine Kiel, Ashley M Larson.
      Gestational hypoxia reduces fetal growth and birth weight across mammals, including humans. Evolutionary adaptation to high-elevation hypoxia mitigates these negative effects, and identifying these protective mechanisms may offer insight into how environmental factors interact with gestational physiology to influence health outcomes. We know that gestational hypoxia modifies development of the placenta, which mediates maternal-fetal exchange, but little is known about how high-altitude adaptation interacts with this developmental plasticity to influence placental exchange capacity. We tested the hypothesis that hypoxia-dependent remodelling of the placental exchange surface is protective for fetal growth and thus will be exaggerated in highland-adapted individuals by using a model rodent system, the North American deer mouse. We acclimated lowland- and highland-ancestry deer mice to normoxia or hypoxia (12.3% O2) during gestation and found that lowland-ancestry deer mice expand their placenta and maternal blood spaces in the placenta in response to environmental hypoxia. Highland-ancestry deer mice produce even larger placentas and maternal blood spaces, suggesting that these hypoxia-driven responses may benefit fetal growth by increasing total exchange capacity. Notably, we also found that the fetal blood spaces in highland-ancestry placentas have increased perimeter (a proxy for surface area) per unit area occupied by blood. Similar changes to fetal vasculature have been observed in high-elevation-adapted human populations, which is suggestive of convergent adaptation. Our results demonstrate that the hypoxia-sensitive development of placental vasculature is remodelled by adaptation to environmental hypoxia and that some of these processes may be points for convergent adaptation across species despite distinct placental architectures. KEY POINTS: Evolutionary adaptation to high elevations provides protection against hypoxia-dependent fetal growth restriction. The placenta is a key determinant of fetal growth because it defines the total surface area available for nutrient and gas exchange between the gestational parent and offspring. We tested the hypothesis that evolutionary adaptation to high elevations protects fetal growth by increasing placental surface area for exchange using acclimation experiments in a model rodent system, the North American deer mouse. As we predicted, high-elevation ancestry increased the size of maternal blood spaces in the placenta, especially under gestational hypoxia; however, highland ancestry was also associated with narrower fetal blood spaces, which could increase exchange efficiency. The patterns observed in deer mice resemble developmental plasticity observed in placentas from humans with high-elevation ancestry, pointing to potential for convergent adaptation across species with distinct placental architectures.
    Keywords:  North American deer mouse; Peromyscus maniculatus; angiogenesis; high altitude; hypoxia; labyrinth; villi
    DOI:  https://doi.org/10.1113/JP289376
  3. Biol Reprod. 2025 Sep 13. pii: ioaf212. [Epub ahead of print]
    Transformed bovine trophoblast stem cell lines, characterization, gene editing and secretions.
    Viju Vijayan Pillai, Prasanthi P Koganti, Shailesh Gurung, Soon Hon Cheong, Vimal Selvaraj.
      Trophoblast stem cells (TSCs) serve as a critical model for understanding placental development, early embryo-maternal interactions, and pregnancy establishment in mammals. In cattle, the developing trophectoderm plays an essential role in conceptus elongation and secretion of factors necessary for maternal recognition of pregnancy. Building on previous work identifying signaling pathways regulating bovine TSC self-renewal and differentiation, we report the generation and characterization of transformed bovine TSC (bTSC) lines derived from blastocysts via lentiviral transduction of simian vacuolating virus 40 large T antigen. These rapidly proliferating TSC cell lines, maintained in the presence of Rho-associated protein kinase (ROCK) inhibition, retain key morphological and transcriptional characteristics of bovine TSCs. Upon transforming growth factor β-induced differentiation, they exhibit morphological and molecular changes consistent with trophoblast maturation. To evaluate their utility for functional studies, we demonstrated stable gene introduction of tdTomato and EGFP using lentiviral vectors and employed CRISPR/Cas9-mediated gene editing to target lentiviral EGFP integration sites, confirming efficient gene deletion. Additionally, proteomic analysis of conditioned medium identified secreted proteins with potential roles in embryo-uterine interactions, aligning with factors previously reported in bovine conceptus secretomes. These findings establish transformed bTSC lines as a valuable model for investigating bovine trophoblast biology, functional gene studies, and trophoblast-endometrial signaling. By providing a renewable in vitro system with stable proliferative capacity, these cell lines enable further exploration of the molecular mechanisms governing early pregnancy in cattle.
    Keywords:  Placenta; embryo; gene editing; secretome; stem cells
    DOI:  https://doi.org/10.1093/biolre/ioaf212
  4. J Exp Med. 2025 Dec 01. pii: e20250448. [Epub ahead of print]222(12):
    DUX4-stimulated genes define an antiviral defense program in human placental trophoblasts.
    Joshua Hatterschide, Liheng Yang, Carolyn B Coyne.
      The placenta combats mother-to-fetus transmission of viruses through the antiviral activities of fetal-derived trophoblasts. Placental trophoblasts employ specialized antiviral strategies to protect against infection while preventing maternal immune rejection of the fetus. However, the full extent of how trophoblasts respond to viral infections is not well understood. To address this, we defined the transcriptional landscape of human trophoblast organoids infected with seven diverse teratogenic viruses. We found that herpesviruses, including HSV-1, HSV-2, and HCMV, did not trigger an IFN response. Instead, they activated the expression of DUX4 and its downstream target genes: DUX4-stimulated genes (DSGs). This program was enriched in trophoblasts and associated with cells containing low HSV-1 gene expression following infection. Screening highly expressed DSGs revealed that many of them exhibited anti-herpesvirus activity, indicating they comprise an alternative antiviral pathway similar to the IFN-stimulated gene response. These findings identify DUX4 as a master regulator of an antiviral program in trophoblasts, specifically targeting a prominent family of teratogenic viruses.
    DOI:  https://doi.org/10.1084/jem.20250448
  5. Cell Rep. 2025 Sep 17. pii: S2211-1247(25)01081-2. [Epub ahead of print]44(10): 116310
    Tumor suppressor protein p53 governs human trophoblast lineage development.
    Yunying Huang, Ling Xu, Haifeng Fu, Wei Zhang, Ming Zeng, Sojung Lee, Shilong Li, Guocheng Lan, Yingzhang Huang, Degong Ruan, Qingqing Zhang, Chunyan Wang, Weiyu Zhang, Andy Chun Hang Chen, Sze Wan Fong, Yin Lau Lee, William Shu Biu Yeung, Jason Wing Hon Wong, Gordon Dougan, Lei Li, Jianqiao Liu, Asif Javed, Pentao Liu.
      Tumor suppressor protein p53 (encoded by Trp53 in mice and TP53 in humans) has important functions in normal development. Dysregulated Trp53 expression in mice causes multiple embryonic developmental defects or even implantation failure. However, how p53 affects these development processes is not entirely clear. Here, we report that p53 is highly expressed in preimplantation embryos. p53 inhibition arrests preimplantation embryonic development with defective trophectoderm (TE) development. Genetic knockout of p53 in human pluripotent stem cells (hPSCs) compromises human trophoblast development. Single-cell transcriptomic analysis further reveals the critical requirement of p53 in trophoblast cell lineage segregation and identifies that the p53-mediated cell cycle state determines trophoblast cell fate propensity. Together, our findings demonstrate that p53 is a potential master regulator in human trophoblast cell fate determination and lineage development, which has important implications for p53 functions in human fertility, reproduction, and tumor suppression.
    Keywords:  CP: Developmental biology; cell cycle; cell fate determination; human expanded potential stem cells; trophoblast lineage; trophoblast stem cell; tumor suppressor protein p53
    DOI:  https://doi.org/10.1016/j.celrep.2025.116310
  6. J Cell Mol Med. 2025 Sep;29(18): e70821
    Amino Acid Restriction Impairs Human Endometrial Stromal Cell Decidualization and Is Rescued by Proline Supplementation.
    Chloe Jang, Cristiana Iosef, Stephen J Renaud, Victor K M Han.
      Decidualization is a critical process for successful pregnancy. It is characterised by the transformation of endometrial stromal cells into decidual cells that support embryo implantation and placental development. Maternal amino acid deficiency is linked to impaired decidualization, which can lead to pregnancy complications such as miscarriage, preeclampsia and fetal growth restriction. Halofuginone (HF), a synthetic alkaloid, induces nutritional stress by triggering the amino acid starvation response. This study investigated the effects of HF-induced nutritional stress and amino acid supplementation on decidualization of human endometrial stromal cells (HESCs). Exposure of HESCs to decidualization agents caused distinct morphological changes and expression of insulin-like growth factor binding protein-1 (IGFBP-1), indicative of successful decidualization. Treatment of HESCs with HF or leucine-deprived media inhibited the expression of key decidualization markers. Interestingly, supplementation with proline, but not leucine, rescued the inhibitory effects of HF on decidualization of HESCs. HF inhibited the expression of genes encoding growth factors crucial for decidualization, highlighting their sensitivity to amino acid availability, and disrupted transforming growth factor β-SMAD signalling, which was restored by proline supplementation. These findings highlight the essential role of amino acids, particularly proline, for proper decidualization and suggest potential therapeutic strategies for improved reproductive health.
    Keywords:  decidua; fetal growth restriction; growth factors; halofuginone; leucine; placenta; preeclampsia; proline
    DOI:  https://doi.org/10.1111/jcmm.70821
  7. Curr Opin Virol. 2025 Sep 16. pii: S1879-6257(25)00040-9. [Epub ahead of print]73 101490
    Intercellular highways of viral spread: tunneling nanotubes and extracellular vesicles at the maternal-fetal interface.
    Long B Tran, Rafael T Michita, Deepak Kumar, Indira U Mysorekar.
      The placenta serves as both a conduit and a barrier, facilitating nutrient exchange while shielding the fetus from pathogens. Despite these defenses, several viruses, including ZIKV, CMV, HSV, HIV, LCMV, and HBV, can breach the placental barrier, while others like SARS-CoV-2 and RSV infect placental cells without consistent vertical transmission. Emerging evidence highlights two underexplored intercellular communication mechanisms, tunneling nanotubes (TNTs) and extracellular vesicles (EVs), as critical pathways exploited by viruses to disseminate, modulate immunity, and disrupt placental homeostasis. This review discusses how virally hijacked TNTs and EVs facilitate transmission and immune evasion at the maternal-fetal interface, emphasizing the need to further understand these mechanisms in the context of pregnancy and fetal health.
    DOI:  https://doi.org/10.1016/j.coviro.2025.101490
  8. J Neonatal Perinatal Med. 2025 Sep 18. 19345798251380113
    Maternal, placental and cord erythrocyte levels of long-chain polyunsaturated fatty acids in full-term and preterm pregnancy.
    Akshaya P Meher, Manasi Kathaley.
      BackgroundLong-chain polyunsaturated fatty acids (LCPUFAs) are biologically active fatty acids which regulate placental as well as fetal development. Abnormalities in these fatty acids have implications in adverse pregnancy outcomes like preterm birth. In the current study, we examined the maternal and cord erythrocyte LCPUFA levels along with the regional placental LCPUFA levels in women delivering preterm as compared with the women delivering at term.MethodsIn this cross-sectional study, we recruited 93 women delivering at term and 93 women delivering preterm. Fatty acid levels were analyzed from maternal erythrocyte, placental and cord erythrocyte samples. Samples from two different regions of placenta, maternal and fetal region were studied.ResultsWe observed lower (p = 0.001) cord erythrocyte docosahexaenoic acid (DHA) levels, lower (p = 0.000) maternal erythrocyte arachidonic acid (ARA) levels and higher (p = 0.002) cord erythrocyte ARA levels in women delivering preterm as compared to those delivering full-term. The placental DHA levels were higher (p = 0.002) on the maternal side of women delivering preterm as compared to women delivering full-term. There was a positive association (p = 0.000) between cord erythrocyte DHA levels with all the newborn characteristics. There was a negative association (p = 0.000) between placental DHA levels from the maternal side with all the newborn characteristics.ConclusionThe imbalance in the levels of maternal DHA and ARA in addition to differential pattern of DHA distribution across the maternal and fetal regions of the placenta may have affected materno-fetal transfer of these fatty acids, therefore responsible for the adverse fetal outcome.
    Keywords:  arachidonic acid; docosahexaenoic acid; placenta; preterm birth
    DOI:  https://doi.org/10.1177/19345798251380113
  9. Placenta. 2025 Sep 05. pii: S0143-4004(25)00681-2. [Epub ahead of print]
    Interplay of stromal cell-derived factor 2 and endoplasmic reticulum stress in the placenta: A review.
    E Bevilacqua, C R R Rocha, H W Yung, G J Burton, A R Lorenzon.
      Disruption of endoplasmic reticulum (ER) homeostasis causes a condition known as "ER stress" that triggers a finely regulated response, the unfolded protein response (UPR), primarily associated with the restoration of normal ER function. Although the UPR is principally a pro-survival process, sustained and/or prolonged stress can induce cell death. ER stress has been observed in various gestational diseases and is associated with poor pregnancy outcomes. In this review, we examined the role of stromal cell-derived factor 2 (SDF2) in the UPR, particularly in placental cells. We highlight recent findings that enhance our understanding of the underlying molecular mechanisms and their influence on the balance between cell survival and death. Exploring how SDF2 affects cell survival and death during ER stress may be vital for developing therapeutic strategies aimed at preventing adverse disease outcomes during pregnancy.
    Keywords:  ER stress; Placenta; SDF2; Trophoblast cell lines; UPR
    DOI:  https://doi.org/10.1016/j.placenta.2025.09.004
  10. Environ Sci Technol. 2025 Sep 15.
    Placentation Disruption by Perfluorooctanoic Acid and Perfluorooctanesulfonate in Human Trophoblast Organoids.
    Mingzhu Li, Chenke Xu, Linwan Li, Fumei Gao, Cheng Xu, Yafei Yu, Chong Huang, Yanan Liu, Xinming Shen, Jianying Hu.
      Prenatal exposure to perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) is associated with low birth weight, a condition often resulting from placental dysfunction. However, whether and how PFOA and PFOS affect human placentation and placental-specific functions remains unclear. In this study, we reconstructed a human trophoblast organoid model, incorporating a near-physiological proportion of extravillous trophoblast (EVT). The organoids were exposed to PFOA or PFOS for 7 days. Exposure to PFOA at 10 nM significantly increased the proportion of villous cytotrophoblast (CTB) cells, while reducing the proportion of EVT and syncytiotrophoblast (STB) cells at 10 and 100 nM, respectively. A similar pattern was observed with PFOS, albeit at concentrations 10 times higher than those of PFOA. Mechanistically, both PFOA and PFOS inhibited trophoblast differentiation by antagonizing the transcriptional activity of cAMP response element-binding protein (CREB). This disruption in placentation impaired placental function, as evidenced by significantly decreasing hormone secretion and invasion potential. Our investigation may provide mechanistic insight into the association of PFOA and PFOS with low birth weight observed in epidemiological studies, with PFOA demonstrating a stronger effect than PFOS. These findings may aid in evaluating the toxicity of emerging PFAS and support the development or selection of safer chemical alternatives.
    Keywords:  low birth weight; perfluorooctanesulfonate; perfluorooctanoic acid; placentation; trophoblast organoid
    DOI:  https://doi.org/10.1021/acs.est.5c07230
  11. FASEB J. 2025 Sep 30. 39(18): e71060
    ARIH1 Promotes Preeclampsia by Inducing MFN2-Dependent Hypoxia-Triggered Mitophagy and Endoplasmic Reticulum Stress in Trophoblasts.
    Hongyu Liu, Yali Deng, Mei Peng, Yanting Nie, Jingfei Chen.
      The pathogenesis of preeclampsia (PE) involves endoplasmic reticulum stress (ERS) and the subsequent induction of mitophagy. Ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) is a key factor regulating mitophagy, but its role in PE has not been reported. In this study, we aimed to analyze the role of ARIH1 in the pathogenesis of PE. The role of ARIH1 in the pathogenesis of PE was investigated in a PE rat model and in an in vitro hypoxia/reoxygenation (H/R) model using HTR8 trophoblast cells. The study revealed that ARIH1 was upregulated while Mitochondrial fusion protein 2 (MFN2) was downregulated in PE rats and H/R-treated HTR8 cells. Inhibition of ARIH1 reversed the suppressed proliferation and invasion capacities of HTR8 cells under H/R conditions, reduced intracellular reactive oxygen species (ROS) and calcium ions (Ca2+), and modulated the protein expression of LC3II/LC3I, p62, glucose-regulatory protein 78 (GRP78), and C/EBP homologous protein (CHOP). Additionally, mitochondrial membrane potential was improved. Interestingly, treatment with Tunicamycin or Thapsigargin could reverse the inhibitory effects of ARIH1 downregulation on trophoblastic cells by activating endoplasmic reticulum stress (ERS) and mitophagy. Notably, the study identified for the first time that ARIH1 mediates the ubiquitination degradation of MFN2. Inhibition of MFN2 abolished the regulatory effects of ARIH1 downegulation on ERS and mitophagy in trophoblast cells, as well as the associated damage in PE rats. Overall, the findings underscore the crucial role of ARIH1 in regulating mitophagy and ERS through MFN2, highlighting its significance in the pathogenesis of PE.
    Keywords:  ARIH1; MFN2; endoplasmic reticulum stress; mitophagy; preeclampsia; trophoblast
    DOI:  https://doi.org/10.1096/fj.202500821R
  12. Parasitol Res. 2025 Sep 16. 124(9): 104
    Differential susceptibility of human placental trophoblasts to Trypanosoma cruzi infection.
    Paula Andrea Marín, Ana Milena Murillo Giraldo, Ana María Mejia-Jaramillo, Omar Triana-Chávez, Santiago Pemberty, Ana María Vásquez.
      Congenital transmission is a key route for Trypanosoma cruzi infection, yet the cellular mechanisms enabling congenital transmission remains poorly understood. This study evaluated the susceptibility of different trophoblast cell line models to T. cruzi infection and compared infectivity patterns among TcI strains compared to Y strain (TcII). The BeWo cell line was used to model cytotrophoblast (CT) and syncytiotrophoblast (ST) cells, while the HTR-8/SVneo cells modeled extravillous trophoblasts (EVTs). Three Colombian TcI strains and one TcII strain were cultured and differentiated into infective trypomastigotes. Infection rates, intracellular parasite replication, trypomastigote release, cell viability, hormone secretion, apoptosis, and ultrastructural characteristics were studied. Significant differences in infection susceptibility among trophoblast types were observed. BeWo CT-like cells were highly permissive to infection, whereas ST-like cells exhibited strong resistance, potentially due to intrinsic defense mechanisms. HTR-8/SVneo showed moderate susceptibility, supporting persistent replication and trypomastigote release. Infection impaired cell viability and disrupted endocrine functions such as hCG secretion, with cell-type-specific effects. Parasite strains also differed in infectivity. Strain Υ demonstrated high infectivity and cytotoxic effects. In contrast, SN3 and GAL61S strains exhibited slower intracellular development and lower release of trypomastigotes. Strain SA showed early infectivity but limited replication. These findings highlight the differential susceptibility of trophoblast subtypes to T. cruzi infection and the variability in strain virulence. Further insight into placental defense mechanisms and parasite-host interactions is essential for understanding congenital transmission and developing targeted preventive strategies.
    Keywords:   Trypanosoma cruzi ; Cell culture; Congenital Chagas disease; Cytotrophoblast; Extravillous trophoblast; In vitro assay; Syncytiotrophoblast
    DOI:  https://doi.org/10.1007/s00436-025-08552-7
  13. Sci Total Environ. 2025 Sep 16. pii: S0048-9697(25)02141-2. [Epub ahead of print]1001 180501
    Associations between brominated and organophosphate flame retardant levels and inflammatory biomarkers in maternal blood, cord blood, and placental tissue at mid-gestation.
    Vince Nguyen, Neha Sehgal, Lin Li, Dana E Goin, Rachel Morello-Frosch, Tracey J Woodruff, Julia Varshavsky, June-Soo Park, Stephanie L Gaw, Joshua F Robinson, Stephanie M Eick.
       OBJECTIVE: Prenatal exposures to flame retardants (FRs), including legacy polybrominated diphenyl ethers (PBDEs) and alternative organophosphate FRs (OPFRs), are associated with adverse pregnancy outcomes. In animal and cell models, inflammation has been proposed as a potential pathway of FR-toxicity; however, data in humans is limited. In this study, we assessed whether levels of FRs are associated with diverse inflammatory biomarkers, reflecting potential mediating pathways. We leveraged mid-gestation maternal and fetal biospecimens, a timepoint that is often difficult to study due to ethical challenges.
    MATERIAL AND METHODS: Participants in this study included a demographically diverse group of pregnant women undergoing elective mid-pregnancy terminations and for whom measurements of maternal OPFRs and PBDEs and maternal and fetal inflammation biomarkers were available (N = 65). Four PBDEs (BDE-47, BDE-99, BDE-100, BDE-153) and four OPFRs (BCEP, BCIPP, BDCIPP, DPHP) were quantified via mass spectrometry in mid-gestation maternal serum and urine samples, respectively. We measured 20 unique cytokines in matched maternal serum, cord blood, and placental tissue. We used quantile g-computation to assess mixture effects and linear regression to assess associations between individual FRs and cytokines. All models were adjusted for gestational age at time of sample collection, maternal age, education, and insurance.
    RESULTS: A one-quartile increase in the mixture of PBDEs alone was positively associated with most maternal inflammatory mediators, including CCL-17 (Ѱ = 0.22, 95 % CI = 0.02, 0.42) and CCL-2 (Ѱ = 0.21, 95 % CI = 0.06, 0.37). Additionally, a one-quartile increase in the combined mixture of PBDEs and OPFRs was associated with increases in maternal serum levels of CCL-2, CCL-3, CC-17, and CCL-22. In contrast, BDE-47 and BDE-100 were individually associated with reductions in placental CCL-2 (β = -0.59, 95 % CI = -1.08, -0.1; β = -0.46, 95 % CI = -0.84, -0.07, respectively). No significant associations between levels of FRs in cord blood and cytokines were observed.
    CONCLUSION: Prenatal exposure to FRs, particularly PBDEs, was significantly associated with differences in biomarkers of inflammation in maternal serum during mid-pregnancy.
    Keywords:  Biomarkers of exposure; Flame retardants; Inflammation; Mixtures; Pregnancy
    DOI:  https://doi.org/10.1016/j.scitotenv.2025.180501
  14. Am J Reprod Immunol. 2025 Sep;94(3): e70168
    Aberrant Expression of Gonadotropin-Releasing Hormone Receptor in Human Mast Cells Enhances the Recruitments of Trophoblasts and NK Cells.
    Takashi Matsuzaki, Hiroaki Hamaguchi, Ken R Ito, Ryota Nakagawa, Hiroya Nakamura, Hiroaki Ito, Chiyuki Ueshima, Akihiko Yoshizawa, Hironori Haga, Tatsuki R Kataoka.
       PROBLEM: Gonadotropin-releasing hormone (GnRH), primarily known for its hypothalamic role in regulating gonadotropin secretion, is also expressed in extra-hypothalamic tissues, including trophoblasts at implantation sites. We investigated the association between trophoblasts and mast cells, demonstrating their role in producing leukemia inhibitory factor (LIF) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesized an additional interaction between trophoblasts and mast cells mediated by GnRH.
    METHOD OF STUDY: Immunohistochemical analysis was conducted to investigate GnRH receptor (GnRHR) expressing mast cell in endometrial and tubal tissues from both pregnant and non-pregnant conditions (2005-2018). We established a human mast cell line LAD2 with forced expression of GnRHR expression (GnRHR-expressing LAD2) via lentiviral transfection method. The cells were stimulated with or without leuprorelin (1 µM) and transcriptomic analysis and cell migration assays were conducted.
    RESULTS: GnRHR is expressed in decidual mast cells during uterine pregnancy and in mast cells adjacent to or embedded in trophoblasts of tubal pregnancy. Notably, GnRHR expression was also observed in endometrial mast cells in non-pregnancy conditions. The levels of transcripts encoding LIF, MMP-9, and a natural killer (NK) cell attractant C-X-C motif chemokine ligand 16 (CXCL16) were significantly upregulated in GnRHR-expressing LAD2 than in control cells. In addition, culture supernatants from GnRHR-expressing LAD2 cells enhanced the migration of the trophoblast cell line HTR-8/SVneo and the NK cell line NK-92 MI.
    CONCLUSIONS: These findings suggest that GnRHR expression in mast cells promotes their supportive role in pregnancy establishment by increasing the LIF, MMP-9, and CXCL16 productions, recruiting trophoblasts and NK cells.
    Keywords:  CXCL16; GnRH; GnRH receptor; LIF; MMP9; mast cell; pregnancy
    DOI:  https://doi.org/10.1111/aji.70168
  15. Placenta. 2025 Sep 02. pii: S0143-4004(25)00678-2. [Epub ahead of print]171 45-51
    Preeclampsia is associated with placental complement C4d deposition.
    E Pierik, M H de Jong-Schoots, M Bulthuis, M R Daha, J van den Born, S J Gordijn, J R Prins.
       INTRODUCTION: Preeclampsia complicating pregnancy can be life-threatening for both mother and infant, often resulting in maternal and neonatal morbidity. Previous studies have related changes in specific immune factors to preeclampsia; however, the role of the complement system in preeclampsia remains understudied. Therefore, this study aims to examine differences in placental complement deposition in pregnancies complicated by preeclampsia and healthy term control pregnancies. In addition, we compared early and late preeclampsia with healthy term and spontaneous preterm births.
    METHODS: Placentas from pregnancies complicated by early onset preeclampsia (n = 26), late onset preeclampsia (n = 26), healthy term controls (n = 24), and spontaneous preterm births (n = 14) were investigated for the presence of complement using immunohistochemistry for C1q, C4d, C3d, C5b-9, and CD59.
    RESULTS: Deposition of C4d was observed at the trophoblast in 25.5 % of all preeclampsia cases and differed from healthy term controls (p = 0.029). C4d was observed in 12.0 % of late onset preeclampsia and 38.5 % of early onset preeclampsia placentas. None or minimal C4d was found in placentas of healthy term and preterm births. C4d trophoblast deposition significantly differed between early onset preeclampsia and healthy term (p = 0.002) and spontaneous preterm births (p = 0.022). With respect to C1q, C3d, C5b-9 and CD59, no significant differences were observed between the groups.
    CONCLUSION: Our data demonstrate an increase in C4d deposition in placentas of early onset preeclampsia compared to healthy term controls and spontaneous preterm births, suggesting a possible role for the complement system in preeclampsia. Our findings underscore the complexity of preeclampsia pathophysiology and highlight the need for more refined, subtype-specific investigations.
    Keywords:  C4d; Complement system; Early onset preeclampsia; Placenta; Preeclampsia
    DOI:  https://doi.org/10.1016/j.placenta.2025.09.001
  16. Mol Biol Rep. 2025 Sep 18. 52(1): 924
    Extracellular vesicles released from human amniotic fluid stem cells modulate macrophages.
    Yushi Abe, Daigo Ochiai, Yosuke Matsumiya, Seiji Kanzaki, Mamoru Tanaka, Manu Vatish.
       BACKGROUND: Human amniotic fluid stem cells (hAFSCs) secrete extracellular vesicles (EVs) that modulate fetal immunity. Because fetal and neonatal macrophages largely rely on innate responses, development of a targeted method to switch their inflammatory phenotype would fill a critical therapeutic gap in perinatal medicine. We therefore elucidated whether the hAFSC-EV surface marker CD44 functions as a "delivery code" for preferential uptake by inflammatory macrophages.
    METHODS AND RESULTS: hAFSCs and hAFSC-EVs were isolated and characterized by performing flow cytometry, transmission electron microscopy, nanoparticle tracking analysis, and western blotting. The hAFSC-EVs were co-cultured with macrophages derived from the human monocytic leukemia cell line THP-1. The uptake of hAFSC-EVs was evaluated using fluorescence microscopy and flow cytometry. The effects of hAFSC-EVs on macrophages were analyzed by western blotting and real-time quantitative polymerase chain reaction. Our analyses revealed that inhibiting CD44 expression with a functional antibody blocked hAFSC-EV uptake by macrophages and led to changes in the cellular phenotype. Furthermore, inhibiting the uptake of CD44-positive hAFSC-EVs suppressed the expression of some pro-inflammatory cytokines. These findings suggest that CD44-positive hAFSC-EVs play a crucial role in the anti-inflammatory effects of hAFSCs.
    CONCLUSIONS: Our study provides insights into the specific delivery of hAFSC-EVs into inflammatory macrophages and sheds light on the potential therapeutic applications of these EVs for regulating inflammatory macrophage phenotypes.
    Keywords:  Amniotic fluid stem cell; CD44; Extracellular vesicle; Immunomodulation; Inflammatory cytokine; Macrophage
    DOI:  https://doi.org/10.1007/s11033-025-10945-x
  17. Fetal Pediatr Pathol. 2025 Sep 19. 1-10
    Evaluating the sFlt1 Mouse Model of Preeclampsia: Benefits and Limitations for Understanding Human Disease.
    David M Aronoff, Jean W Wassenaar, Meena S Madhur.
      Preeclampsia (PE) remains a leading cause of maternal and neonatal morbidity and mortality globally. Among several experimental models developed to interrogate the pathogenesis of PE, the mouse model employing systemic infusion or transgenic overexpression of soluble fms-like tyrosine kinase-1 (sFlt1) has gained widespread use due to its capacity to induce cardinal features of the human disease. These include maternal hypertension, renal injury, endothelial dysfunction, placental abnormalities, fetal growth restriction, and adverse long-term outcomes. This review critically evaluates the sFlt1-based mouse model of PE, highlighting its utility for understanding the pathogenesis of angiogenic imbalance and its sequelae. We contrast findings from this model with clinical observations in human PE and discuss applications for studying early-onset versus late-onset forms. Finally, we address limitations and propose strategies to enhance its translational relevance. Placing the model in the context of human disease helps guide its use in future preclinical and translational research.
    Keywords:  fetal growth restriction; hypertension; mouse model; preeclampsia; sFlt1
    DOI:  https://doi.org/10.1080/15513815.2025.2558605
  18. Int J Biol Sci. 2025 ;21(12): 5206-5222
    ANXA6 Overexpression Causes Abnormal Decidual Macrophage-Trophoblast Crosstalk in Recurrent Spontaneous Abortion.
    Xin Chen, Xue Yao Li, Xue Qin Ma, Yan Zhang, Qian Lin Song, Jing Yang.
      ANXA6 is involved in numerous biological processes; however, its association with recurrent spontaneous abortion (RSA) remains poorly understood. In this study, we observed significant upregulation of ANXA6 expression in decidual macrophages from RSA patients. Functional analysis revealed that ANXA6 overexpression enhanced reactive oxygen species (ROS) generation and reduced mitochondrial membrane potential, thereby promoting pyroptosis and upregulating M1 macrophage polarization markers. Mechanistically, inhibition of NLRP3 rescued ANXA6 overexpression-induced elevation of M1 polarization and pyroptosis in macrophages. In addition, inhibition of ROS alleviated the decreased mitochondrial membrane potential, aggravated macrophage pyroptosis, and exacerbated inflammatory response, as well as the promoted macrophage M1 polarization caused by ANXA6 overexpression. Further mechanisms suggest that overexpression of ANXA6 in macrophages could promote the accumulation of mitochondrial ROS and inhibit mitochondrial membrane potential through the NF-κB signaling pathway, exacerbating macrophage pyroptosis and amplifying the resulting inflammatory response, thereby promoting macrophage M1 polarization. Besides, ANXA6 overexpressing macrophages showed an inhibitory effect on trophoblast function in vitro, a process mediated through TNF-α inhibition of the PI3K/AKT axis. Collectively, our study reveals that ANXA6 is a key mediator of immune dysregulation at the maternal-fetal interface in RSA patients.
    Keywords:  ANXA6; Macrophage; NF-κB/ROS; PI3K/AKT; Recurrent spontaneous abortion; Trophoblast
    DOI:  https://doi.org/10.7150/ijbs.111791
  19. Placenta. 2025 Sep 13. pii: S0143-4004(25)00692-7. [Epub ahead of print]
    Participation of kynurenine pathway metabolites in Trypanosoma cruzi infection of human placenta.
    María José Moreira-Espinoza, Luciana Mezzano, Martin G Theumer, Graciela María Panzetta-Dutari, María Fernanda Triquell, Cintia María Díaz-Luján, Ricardo E Fretes.
       INTRODUCTION: The kynurenine pathway is a major route of tryptophan (Trp) metabolism, an essential amino acid. This pathway, mediated by Indoleamine 2,3-dioxygenase (IDO), contributes to maternal-fetal tolerance by depletion Trp and generating kynurenines (Kyn). Among the Kyns produced in the placenta, 3-hydroxykynurenine (3-HK) and 3-hydroxy-anthranilic acid (3-HAA) have been shown to affect T. cruzi replication. This study aimed to evaluate the role of kynurenine pathway metabolites in Trypanosoma cruzi (T. cruzi) infection of the human placenta.
    METHODS: Term human placental explants (n = 8) were infected with 105 T. cruzi trypomastigotes/mL for 24 h. The explants were treated with L-Trp, L-1-methyl-tryptophan (L-1MT), IFN-γ, 3-HK and 3-HAA for 72 or 96 hpi. IDO expression was assessed by immunohistochemistry, and IDO activity was measured in homogenates. L-Kyn concentration was quantified in culture supernatants, while infection levels were determined by qPCR. Statistical analysis included ANOVA with Tukey's post hoc test and Student's t-test (p < 0.05).
    RESULTS: L-Trp increased IDO expression and activity, elevating L-Kyn production in both infected and non-infected explants. L-1MT reduced L-Kyn production, whereas IFN-γ stimulated it. Additionally, 3-HK significantly impaired trypomastigotes motility. Both 3-HK and 3-HAA decreased placenta explant infection by T. cruzi.
    CONCLUSION: Metabolites of the kynurenine pathways reduced T. cruzi infection in placental explants, suggesting a potential role in limiting congenital transmission of Chagas disease by modulating parasitic load in human placenta.
    Keywords:  Human placenta; Infection; Kynurenine pathways; T. cruzi; Tryptophan
    DOI:  https://doi.org/10.1016/j.placenta.2025.09.008
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