bims-placeb 2025-12-21 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–12–21
fifteen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Development of a trophoblast organoid resource in a translational primate model.
Downregulation of the biological macromolecule Spondin-2 disrupts maternal-fetal immune tolerance and trophoblast invasion, driving unexplained recurrent pregnancy loss.
Transcriptomics and metabolomics analysis reveals cell subpopulations of trophoblast cells associated with preeclampsia.
Galectin-3 in endometrial small extracellular vesicles promotes cytotrophoblast cell fusion during the implantation phase.
Three-dimensional visualization of the cytotrophoblast layer of human term chorionic villi.
Placenta-derived extracellular vesicles in fetal health: emerging insights into brain development and environmental interactions.
Dynamic Spiral Artery Remodeling in Early Human Pregnancy: An Analysis of Specimens Collected with a Standardized Protocol†.
Understanding the Causal Impact of Elevated Maternal Stress During Pregnancy: A Systematic Literature Review of Guinea Pig Models.
Obesity concurrent with gestational diabetes mellitus dysregulates mitochondria-endoplasmic reticulum contacts in human placenta.
Spatiotemporal cellular map of the developing human reproductive tract.
Pre-marking chromatin with H3K4 methylation is required for accurate zygotic genome activation and development.
The 3D genome during germline development and meiosis.
Rodents Exposed to Placental Ischemia in Utero Display Sex Differences in Brain miRNA Expression, Mitochondrial Function, and Blood Pressure in Adulthood.
Single-cell transcriptome analyses reveal disturbed decidual microenvironment in women of advanced maternal age.
Oxidative stress, mitochondrial dysfunction, and ferroptosis in the placenta of gestational diabetes mellitus.

Organoids. 2025 Dec;pii: 24. [Epub ahead of print]4(4):

Development of a trophoblast organoid resource in a translational primate model.

Brady M Wessel, Jenna N Castro, Henry F Harrison, Brian P Scottoline, Margaret C Wilcox, Maureen K Baldwin, Victoria H J Roberts.

  First-trimester placental development comprises many critical yet understudied cellular events that determine pregnancy outcomes. Improper placentation leads to a host of health issues that not only impact the fetal period but also influence later-life offspring health. Thus, an experimental paradigm for studying early placental development is necessary and has spurred the development of new in vitro models. Organoid model systems are three-dimensional structures comprising multiple differentiated cell types that originate from a progenitor population. Trophoblasts are the progenitor cells that serve as the proliferative base for the differentiation and maintenance of the placenta. Due to research constraints, experimental studies on the causal mechanisms underlying pathological pregnancies cannot readily be performed in human subjects. The nonhuman primate (NHP) offers a solution to this problem as it circumvents the limitations of human pregnancy sampling. Importantly, NHPs share many developmental features of human pregnancy, including placenta type and a similar fetal growth trajectory, making longitudinal pregnancy studies feasible and relevant. Since perturbations made in vivo can be validated in vitro, an NHP model of early pregnancy would facilitate mechanistic studies of pregnancy disorders. Herein, we describe the methodology for the establishment of a first-trimester NHP placenta trophoblast organoid model system.

Keywords:  3-dimensional culture; first-trimester placenta; nonhuman primate; rhesus macaque; trophoblast organoid

DOI:  https://doi.org/10.3390/organoids4040024
Int J Biol Macromol. 2025 Dec 12. pii: S0141-8130(25)10229-8. [Epub ahead of print]338(Pt 1): 149672

Downregulation of the biological macromolecule Spondin-2 disrupts maternal-fetal immune tolerance and trophoblast invasion, driving unexplained recurrent pregnancy loss.

Xue Zhang, Ping-Fen Li, Yan''e Gao, Peng-Sheng Zheng.

  Recurrent pregnancy loss (RPL) affects approximately 1 %-3 % of couples preparing for pregnancy, of which more than 50 % have unknown etiology, referred to as unexplained recurrent pregnancy loss (URPL). This study aimed to investigate the role of Spondin-2 (SPON2) in the pathogenesis of URPL and to elucidate its underlying molecular mechanisms. Using human trophoblast stem cells (TSCs) and extravillous trophoblast differentiation models, combined with single-cell and spatial transcriptomic analyses, in vitro functional assays, and the abortion-prone mouse model, we systematically evaluated the regulatory function of SPON2 in trophoblast biology and maternal-fetal immune homeostasis. We found that SPON2 was highly expressed in human extravillous trophoblasts but was significantly downregulated in the villus tissue of patients with URPL and in the placenta of an abortion-prone mouse model. Mechanistically, SPON2 deficiency triggered excessive accumulation of reactive oxygen species (ROS), which subsequently activated the NF-κB signaling pathway and upregulated OLR1 transcription. This ROS/NF-κB/OLR1 cascade impaired trophoblast migration and invasion and promoted a proinflammatory microenvironment, characterized by elevated secretion of IL-1β, IL-6, and TNF-α as well as enhanced M1 macrophage polarization. Importantly, the in vivo administration of recombinant SPON2 improved pregnancy outcomes in the abortion-prone mouse model by restoring trophoblast function and local immune balance. Collectively, our findings demonstrate that SPON2 modulates trophoblast function and the maternal-fetal immune microenvironment via the ROS/NF-κB/OLR1 axis, highlighting the crucial role of SPON2 in reproductive health and its potential as a therapeutic target for URPL.

Keywords:  Extravillous trophoblast dysfunction; Inflammation; ROS/NF-κB/OLR1 axis; SPON2; Unexplained recurrent pregnancy loss

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149672
Physiol Genomics. 2025 Dec 17.

Transcriptomics and metabolomics analysis reveals cell subpopulations of trophoblast cells associated with preeclampsia.

Xiaojun Zhu, Ying Jiang, Lilin Wang, Peiyue Jiang, Zixing Zhong, Hetong Li, Caihong Zheng, Lujiao Chen, Juan Wei, Xishi Lin, Peng Ding, Zihua Dong, Xiaosheng Wang, Qiong Luo.

  Placental abnormalities are central to preeclampsia (PE), yet the cellular and molecular mechanisms underlying this dysfunction remain unclear. We applied a multi-layered, integrative approach to investigate placental tissue from PE patients and matched controls. Single-cell RNA sequencing (scRNA-seq, GSE173193) and bulk RNA sequencing (bulk RNA-seq, GSE203507) datasets were obtained from the Gene Expression Omnibus (GEO). The scRNA-seq dataset included two PE and two control samples, while the bulk RNA-seq dataset focused on eight early-onset PE and five uncomplicated term births. Trophoblast subpopulations were identified via scRNA-seq, and pseudotime analysis was used to trace differentiation trajectories. Differential expression and pathway enrichment analyses were performed to elucidate molecular alterations. For metabolomic profiling, plasma samples from six PE patients and six controls (three replicates each) were analyzed. Transcriptomic and metabolomic data were integrated to investigate gene-metabolite interactions and their relevance to PE pathogenesis. Villous cytotrophoblasts (VCTs) and syncytiotrophoblasts (SCTs) were more abundant in PE placentas, whereas extravillous trophoblasts (EVTs) were reduced compared to controls. Five trophoblast subpopulations-SCT-VCT, Mix, EVT, VCT, and SCT-were characterized by distinct marker genes. Pseudotime analysis indicated differentiation from mixed states toward specific trophoblast lineages. Immune-related pathways were significantly enriched in PE. Integrated analysis highlighted key connections between metabolites, gene expression, and PE-related pathways, implicating oxidative stress, inflammation, metabolic dysregulation, and vascular dysfunction. Our study provides novel insights into placental dysfunction in PE, highlighting alterations in trophoblast subpopulations and immune pathways. These findings may inform strategies for early diagnosis, prevention, and therapeutic intervention in PE.

Keywords:  Preeclampsia; metabolomics; placenta; single-cell RNA sequencing; transcriptomics

DOI:  https://doi.org/10.1152/physiolgenomics.00185.2025
Cell Commun Signal. 2025 Dec 20.

Galectin-3 in endometrial small extracellular vesicles promotes cytotrophoblast cell fusion during the implantation phase.

Tsutomu Ohara, Akihito Horie, Mitsuhiro Nakamura, Sachi Imakita, Asami Ikeda, Shimpei Shitanaka, Akihiro Yanai, Baku Nakakita, Yoshimi Kitawaki, Yusuke Sagae, Shinji Ito, Asuka Okunomiya, Masaki Mandai.

   BACKGROUND: Small extracellular vesicles (sEVs) mediate intercellular communication by transporting microRNAs and proteins. Endometrial sEVs have been implicated in embryo implantation due to their content of implantation-related molecules; however, their precise functions and underlying mechanisms remain unclear. This study aimed to identify proteins in endometrial sEVs that contribute to embryo implantation and to clarify their functional significance.
METHODS: Uterine fluid (UF) samples were collected from five women in each of the ovulatory and implantation phases. UF-derived sEVs (UF-sEVs) were isolated using a combination of size-exclusion chromatography and ultrafiltration, and their proteomic profiles were compared between phases. In parallel, hormone-treated Ishikawa cells-a human endometrial adenocarcinoma cell line-were used to model the proliferative and implantation phases in vitro, and sEVs derived from these cells (Ishikawa-sEVs) were similarly analysed. Galectin-3, a protein upregulated in both UF-sEVs and Ishikawa-sEVs during the implantation phase and known to be involved in cytotrophoblast (CT) cell fusion, was selected for functional validation. CT cell fusion assays were performed using Ishikawa-sEVs from galectin-3 knockdown (Gal3-KD) and non-target knockdown (NT-KD) cells.
RESULTS: We identified 2,041 and 1,386 proteins in UF-sEVs from the ovulatory and implantation phases, respectively. Comparative analysis revealed 318 differentially expressed proteins (140 upregulated and 178 downregulated) during the implantation phase, including proteins related to immune response, cell adhesion, and migration. In Ishikawa-sEVs, we identified 913 and 915 proteins in the proliferative and implantation phases, respectively, with 68 differentially expressed proteins (44 upregulated and 24 downregulated). Implantation-phase Ishikawa-sEVs significantly promoted CT cell fusion compared with proliferative-phase sEVs. Moreover, Gal3-KD in Ishikawa cells significantly reduced the fusion-promoting effect of the sEVs, suggesting that galectin-3-enriched endometrial sEVs may facilitate CT fusion and subsequent differentiation into syncytiotrophoblast (ST) during implantation.
CONCLUSIONS: Our findings demonstrate that endometrial sEVs enriched in galectin-3 during the implantation phase promote CT differentiation into ST, underscoring a novel role for sEV-mediated protein delivery in regulating early placental development and suggesting potential diagnostic and therapeutic applications in reproductive medicine.

Keywords:  Embryo implantation; Galectin-3; Human uterine fluid; Proteomics; Small extracellular vesicles

DOI:  https://doi.org/10.1186/s12964-025-02586-1
Histochem Cell Biol. 2025 Dec 15. 163(1): 122

Three-dimensional visualization of the cytotrophoblast layer of human term chorionic villi.

Haruki Shimada, Shiori Suga, Manabu Ogoyama, Yuuki Yamaguchi, Takami Takizawa, Shigeki Matsubara, Akihide Ohkuchi, Hironori Takahashi, Toshihiro Takizawa.

  In the human placenta, trophoblast cells give rise to two unique cell layers that envelop the surface of chorionic villi: the outer syncytiotrophoblast (STB) layer and the inner cytotrophoblast (CTB) cell layer. The structural changes in CTB cells during gestation are still not fully understood. This study examined the ultrastructural integrity of the CTB layer within chorionic villi of the human term placenta using Fast Red immunohistochemistry in conjunction with proteinase K/Triton X-100 tissue-clearing and serial block-face scanning electron microscopy (SBF-SEM). Visualization of the CTB layer in whole-mount peripheral villous trees was facilitated by Fast Red immunohistochemistry of SPINT1, a marker specific to CTB cells, under both bright-field and fluorescence imaging modes in light microscopy. CTB cells displayed a thin, flattened morphology and extended multiple cellular projections, resulting in a spider-like transformation that envelops grape-like terminal villi. In contrast, in more proximal villi (e.g., stem villi), CTB cells showed a thick, cuboidal, or polygonal appearance, covering the villous subsurface. SBF-SEM imaging demonstrated the structure of a thin, mesh-like CTB layer, where the basal domain of the villous surface STB infiltrated through the small gaps of the CTB layer and contacted fetal capillaries via the basal lamina in terminal villi. Our data suggest that terminal villi undergo structural changes to facilitate fetomaternal exchange.

Keywords:  Cytotrophoblast; Fast Red; Human term placenta; Immunohistochemistry; Serial block-face scanning electron microscopy; Tissue-clearing

DOI:  https://doi.org/10.1007/s00418-025-02443-9
Exp Mol Med. 2025 Dec 17.

Placenta-derived extracellular vesicles in fetal health: emerging insights into brain development and environmental interactions.

Ethan Lewis, So Jeong Lee, Hae-Ryung Park.

Placenta-derived extracellular vesicles (EVs) are emerging as critical regulators of maternal-fetal communication during pregnancy. These lipid bilayer-enclosed particles, primarily secreted by trophoblasts, transport bioactive cargos-including RNAs, proteins, lipids and neurotransmitters-that influence a wide range of developmental and immunological processes. While much attention has been given to their roles in maternal adaptation and health outcomes, recent studies highlight their direct impact on fetal development, particularly fetal brain development. Emerging evidence suggests that placental EVs may traverse both the placental and blood-brain barriers, thereby contributing to signaling processes that influence neurogenesis, cell fate specification and regional brain patterning. Their cargo composition is dynamic, modulated by gestational age and environmental factors such as air pollution, viral infection and chemical toxicants. These stressors can alter EV secretion and molecular content, contributing to adverse fetal outcomes including impaired organogenesis and neurodevelopmental delays. In this review, we synthesize current knowledge on placental EV biology, examine their roles in maternal and fetal health with an emphasis on neurodevelopment and evaluate how environmental exposures reshape EV-mediated signaling. We also discuss emerging technologies and translational opportunities, including EV-based diagnostics and therapeutic delivery systems. Collectively, placenta-derived EVs represent a vital yet underexplored mechanism in fetal programming, offering novel insights into the developmental origins of health and disease.

DOI: https://doi.org/10.1038/s12276-025-01601-2
Biol Reprod. 2025 Dec 16. pii: ioaf279. [Epub ahead of print]

Dynamic Spiral Artery Remodeling in Early Human Pregnancy: An Analysis of Specimens Collected with a Standardized Protocol†.

Shenglong Ye, Yeling Ma, Wenlong Li, Linjing Qi, Xiao Fang, Xin Yu, Duo Yu, Xiaoye Wang, Dong-Bao Chen, Yan-Ling Wang.

  Human uterine spiral artery remodeling (SAR) is a tightly regulated process involving complex interactions between interstitial and endovascular extravillous trophoblasts (iEVTs and enEVTs) and diverse maternal decidual cell populations. However, the intrinsic spatiotemporal dynamics of SAR in human placentation remain poorly understood, largely due to the limited availability of high-quality maternal-fetal interface specimens. Electively terminated early pregnancies offer a valuable resource for studying SAR in situ, yet inconsistent methods for distinguishing fragmented villous and decidual tissues have hindered reproducibility and interpretation. Herein we present a standardized protocol for the classification and characterization of high-quality maternal-fetal interface specimens from elective terminations by integrating stereomicroscopic evaluation with confirmation by immunohistochemistry and immunofluorescence microscopy. Combined with multiplex immunofluorescence imaging with cell-type-specific markers, this approach enabled precise spatial mapping and quantification of key morphological and cellular events in SAR from gestational weeks 5 to 10. Our analyses reveal that SAR initiates as early as week 5 with extraluminal recruitment of natural killer (NK) cells, followed by the formation of tightly packed EVT plugs within the lumens of spiral arteries in the decidua compacta; these plugs progressively extend deeper into the vessels and gradually loosen as gestation progresses. Notably, enEVTs appear to acquire NK cell-like phenotypes that may facilitate the displacement of endothelial and smooth muscle cells, promoting progressive vessel dilation. In summary, we provide a robust and reproducible method for assessing physiological SAR in early human pregnancy, promoting the adoption of our methodology in future studies of pathological SAR and related pregnancy disorders.

Keywords:  Standardized protocol; electively aborted materials; maternal-fetal interface; multiplex immunofluorescence imaging; spiral artery remodeling

DOI:  https://doi.org/10.1093/biolre/ioaf279
bioRxiv. 2025 Nov 24. pii: 2025.07.30.667555. [Epub ahead of print]

Understanding the Causal Impact of Elevated Maternal Stress During Pregnancy: A Systematic Literature Review of Guinea Pig Models.

Rebecca L Wilson, Caitlin Messiah, Adetola F Louis-Jacques.

Increased maternal stress during pregnancy has been linked to numerous adverse pregnancy outcomes, including preterm birth and impaired fetal development. While clinical studies have established strong associations between maternal stress and adverse pregnancy outcomes, understanding the biological mechanisms is crucial for developing effective preventive intervention. Rodent models have provided valuable insights, however physiological differences from humans limit translational relevance. This systematic review evaluated and synthesized experimental models of increased maternal stress during pregnancy in guinea pigs. Guinea pigs share key pregnancy characteristics with humans, including relevant placental structure, maternal hormonal recognition of pregnancy and precocial offspring development. We identified 43 studies using various experimental approaches categorized into three main types: behavioral models, drug/substance exposure models, and physiological challenge models. These studies demonstrated significant fetal and offspring effects, particularly sex-specific neurodevelopmental outcomes. However, maternal physiological adaptations were often superficially characterized, focusing primarily on weight gain and occasional stress hormone measurements. Most studies began interventions during established pregnancy, potentially missing critical pre-pregnancy and early pregnancy periods. Overall, this review highlights the need for future studies to consider pre-conception interventions to better model human conditions and more comprehensively examine maternal adaptations.

DOI: https://doi.org/10.1101/2025.07.30.667555
Sci Rep. 2025 Dec 13.

Obesity concurrent with gestational diabetes mellitus dysregulates mitochondria-endoplasmic reticulum contacts in human placenta.

Ruofan Wang, Jianying Liu, Qian Li, Xiaoyi Yin, Niannian Li, Guanglei Wang, Yuchun Zhu, Hong Jiang.

  Obesity concurrent with gestational diabetes mellitus (GDM) markedly increases the risk of adverse pregnancy outcomes, wherein placental dysfunction acts as a key mediating factor, however, the underlying mechanisms involved remain elusive. This pilot study was designed to focus on the role of mitochondria-endoplasmic reticulum contacts (MERCs) in obesity with GDM-induced placental dysfunction. Term placental tissues from pregnant women with obesity and GDM or healthy control were analyzed. Reduced cell count of placental trophoblasts, disorganized cell arrangement, and higher apoptosis rate were observed in placental tissue from women with obesity and GDM. In addition, oxidative stress levels and protein expression levels of endoplasmic reticulum (ER) stress markers phosphorylated inositol-requiring enzyme 1 (pIRE1α) and CCAAT/enhancer-binding protein homologous protein (CHOP) were both markedly upregulated compared to the healthy controls. Of note, proximity ligation assay (PLA) revealed increased formation of MERCs core complexes mitofusin 1 (MFN1)-mitofusin 2 (MFN2) and inositol 1,4,5-trisphosphate receptor type 1 (IP3R1)-glucose-regulated protein 75 (GRP75)-voltage-dependent anion channel 1 (VDAC1) in obesity and GDM group. These findings suggest that obesity comorbid with GDM may induce MERCs restructuring via oxidative stress and ER stress, thereby triggering trophoblast apoptosis and subsequent placental dysfunction. Our study sheds light on the underlying mechanisms driving placental pathology in women with obesity and GDM.

Keywords:  Apoptosis; Gestational diabetes mellitus; Mitochondria-endoplasmic reticulum contacts; Obesity; Oxidative stress; Placenta

DOI:  https://doi.org/10.1038/s41598-025-31193-w
Nature. 2025 Dec 17.

Spatiotemporal cellular map of the developing human reproductive tract.

Valentina Lorenzi, Cecilia Icoresi-Mazzeo, Charlotte Cassie, Nadav Yayon, Elias R Ruiz-Morales, Carmen Sancho-Serra, Ryan Colligan, Frederick C K Wong, Magda Marečková, Elizabeth Tuck, Kenny Roberts, Tong Li, Marc-Antoine Jacques, James Ashcroft, Xiaoling He, Berta Crespo, Batuhan Cakir, Simon Murray, Yong Gu, Alexander V Predeus, Martin Prete, Iva Kelava, Roger Barker, Luz Garcia-Alonso, John C Marioni, Roser Vento-Tormo.

The human reproductive tract is essential for species perpetuation and overall health. Its development involves complex processes of sex specification, tissue patterning and morphogenesis, the disruption of which can cause lifelong issues, including infertility1-5. Here we present an extensive single-cell and spatial multi-omic atlas of the human reproductive tract during prenatal development to provide insights beyond those that are possible with smaller-scale, organ-focused studies. We describe potential regulators of sexual dimorphism in reproductive organs and pinpoint previously unknown genes involved in Müllerian duct emergence and regression and urethral canalization of the penis. By combining histological features with gene expression and chromatin accessibility data, we define transcription factors and signalling events potentially involved in the regionalization of the Müllerian and Wolffian ducts. We also refine how the HOX code is established in distinct reproductive organs and reveal that the expression of thoracic HOX genes is increased in the rostral mesenchyme of the fallopian tube and epididymis. Our findings further indicate that epithelial regionalization of the fallopian tube and epididymis, which probably contribute to sperm maturation and capacitation, is established during development. By contrast, later events are necessary for regionalization of the uterocervical canal epithelium. Finally, on the basis of single-cell data and fetal-derived organoids, we show that the fetal uterine epithelium is vulnerable to oestrogen-mimicking endocrine disruptors. By mapping sex-specific reproductive tract regionalization and differentiation at the cellular level, our study provides valuable insights into causes and potential treatments of developmental reproductive disorders.

DOI: https://doi.org/10.1038/s41586-025-09875-2
Nat Commun. 2025 Dec 19.

Pre-marking chromatin with H3K4 methylation is required for accurate zygotic genome activation and development.

Meghana S Oak, Marco Stock, Ana Janeva, Matthias Mezes, Antony M Hynes-Allen, Tobias Straub, Ignasi Forné, Andreas Ettinger, Stephan Hamperl, Axel Imhof, Jelle van den Ameele, Antonio Scialdone, Eva Hörmanseder.

In vertebrate embryos, gene expression is first initiated at zygotic genome activation (ZGA). Maternally expressed transcription factors are essential for this process. However, it is unknown whether active chromatin modifications established in gametes are present in early embryos and contribute to ZGA and embryonic development. Here, we show that in Xenopus laevis, H3K4me3 occurs at common genomic loci in gametes, in transcriptionally quiescent pre-ZGA embryos, and in transcriptionally active ZGA embryos. These loci exhibit high H3K4me3 intensities and breadth, DNA hypomethylation, and elevated CpG content. We show that H3K4 methylation pre-marking is required for successful ZGA and development, including expression of the key ZGA transcription factor Pou5f3.2. We demonstrate that the H3K4 methyltransferase Cxxc1 ensures establishment of H3K4me3 and proper ZGA. These findings reveal a role for H3K4 methylation in defining active chromatin states in Xenopus laevis embryos and highlight its importance for accurate ZGA and embryonic development.

DOI: https://doi.org/10.1038/s41467-025-67692-7
Trends Genet. 2025 Dec 16. pii: S0168-9525(25)00286-0. [Epub ahead of print]

The 3D genome during germline development and meiosis.

Yuka Kitamura, Satoshi H Namekawa.

  Germ cell development involves extensive remodeling of the 3D genome architecture, which is tightly coupled to transcriptional programs, meiotic chromosome dynamics, and re-establishment of totipotency in the next generation. Recent advances in chromosome conformation capture methods have uncovered stage-specific alterations in chromosome organization during spermatogenesis and oogenesis, including germline-specific 3D genome features. These distinctive nuclear configurations orchestrate gene expression programs essential for each developmental stage and meiosis, contribute to epigenetic inheritance, and shape genome evolution. In this review, we synthesize recent progress in understanding 3D genome organization in male and female germlines, and highlight emerging principles, unresolved questions, and innovative approaches that will advance our understanding of germline biology and the principles of genome architecture.

Keywords:  3D genome; epigenetic priming; germ cells; germline; meiosis; oogenesis; spermatogenesis

DOI:  https://doi.org/10.1016/j.tig.2025.11.004
Physiol Genomics. 2025 Dec 17.

Rodents Exposed to Placental Ischemia in Utero Display Sex Differences in Brain miRNA Expression, Mitochondrial Function, and Blood Pressure in Adulthood.

Savanna Leigh Smith, Angie Castillo, Jonna Smith, Kylie Jones, Kumudu Subasinghe, Robert Barber, Nicole R Phillips, Ahfiya Howard, Allison Burkes, Harlan Jones, Mark W Cunningham.

  Placental ischemia (PI), a prenatal stressor, affects ~1 in 10 human pregnancies worldwide and is associated with several pregnancy complications such as preeclampsia, placental abruption, and intrauterine growth restriction (IUGR). Both human and animal IUGR fetuses have an increased risk of developing hypertension (HTN) in adulthood, with males having a higher risk. Furthermore, multiple studies suggest that changes in brain function and molecular markers may contribute to HTN development. However, the alterations in brain mitochondrial dysfunction (MtDys), oxidative stress (OS), and epigenetic changes (miRNAs) in forebrain and midbrain collectively have not been investigated. Thus, we hypothesize that the sex difference in high blood pressure (HBP) is due to changes in miRNAs, brain MtDys, and increased OS in IUGR males (M) but not IUGR females (F). To test this hypothesis, IUGR and control (CON) M and F Sprague Dawley rats were evaluated at 16-18 weeks (adulthood). IUGR adults were generated from PI dams, and CON adults from normal pregnant dams. Results identified 11 differentially expressed miRNAs in IUGR vs CON, with let-7d-3p miRNA being upregulated in IUGR M. IUGR M also displayed HBP, MtDys (decreased ATP), and OS (~50% increase in H2O2). Conversely, mitochondrial elongation factor (GFM-1), a protein regulated by let-7d-3p, and electron transport chain (ETC) proteins were increased with no changes in ATP production in IUGR F. In summary, our data suggests that increases in let-7d-3p will inhibit the compensatory increase in GFM-1 and ETC proteins needed to prevent HBP and cerebral OS in IUGR M. However, unchanged let-7d-3p may increase GFM-1 and ETC proteins in IUGR F to inhibit brain MtDys, OS, and HBP. Findings from this study provide insights into the mechanisms linking epigenetic changes to brain MtDys and OS along with HTN in adults born IUGR.

Keywords:  Epigenetics; Hypertension; Intrauterine Growth Restriction (IUGR); Mitochondrial Dysfunction; Oxidative Stress

DOI:  https://doi.org/10.1152/physiolgenomics.00086.2025
Clin Transl Med. 2025 Dec;15(12): e70541

Single-cell transcriptome analyses reveal disturbed decidual microenvironment in women of advanced maternal age.

Hongliang Xie, Yu Lu, Aolin Zhang, Anqi Zheng, Baofeng Rao, Cuiyu Yang, Anyao Li, Wenbo Guo, Linhua Hu, Xiaoling Huang, Chi Chiu Wang, Songying Zhang, Xiaohui Fan, Lu Li.

   BACKGROUND: Advanced maternal age (AMA) increases pregnancy risk. However, uterine-specific mechanisms independent of oocyte and embryo quality remain poorly defined. This study aimed to characterise the decidual microenvironment in women with AMA to identify key pathological changes and regulatory pathways.
METHODS AND RESULTS: Through integrated histology, organoid modelling, and high-resolution scRNA-seq of first-trimester decidua from women of AMA and controlled reproductive age, we uncovered a pathologically remodelled decidual microenvironment characterised by aberrant cellular states and pathological differentiation pathways, leading to a pro-fibrotic state and accompanied by immune cell dysfunction, and disrupted intercellular communication in the AMA decidua. Central to this pathology was hyperactivated TGF-β signalling, driving fibroblast-to-myofibroblast transition and extracellular matrix overproduction, thereby fuelling fibrosis. Aberrant TGF-β further impaired decidual stromal cell (DSC) differentiation, leading to the failure of the essential mesenchymal-to-epithelial transition. We identified PRR15 as a novel DSC-specific regulator that is markedly suppressed in AMA. PRR15 deficiency unleashed hyperactive TGF-β/SMAD signalling, directly causing decidualisation failure, enhanced fibrosis, and aborted DSC differentiation. Epithelial-mesenchymal transition and immune cell reprogramming towards pro-fibrotic transcriptional signatures further amplify the fibrotic pathology.
CONCLUSION: This study established the aged decidual microenvironment, orchestrated by dysregulated TGF-β signalling and PRR15 loss, as a critical independent determinant of reproductive failure in AMA. Thus, it unveils novel diagnostic and therapeutic targets and strategies.
KEY POINTS: We provide the first single-cell atlas of the human decidua in advanced maternal age (AMA). A novel PRR15-TGF-β axis is identified, where PRR15 loss drives stromal fibrosis and decidualisation failure. This study reveals that AMA-associated uterine fibrosis begins in the first trimester, shifting focus to maternal factors.

Keywords:  advanced maternal age, decidualisation; decidua fibrosis, epithelial–mesenchymal transition, fibroblast–myofibroblast transition, PRR15‐TGF‐β axis, single cell RNA sequencing

DOI:  https://doi.org/10.1002/ctm2.70541
J Mol Med (Berl). 2025 Dec 18. 104(1): 8

Oxidative stress, mitochondrial dysfunction, and ferroptosis in the placenta of gestational diabetes mellitus.

Xuan Zhou, Huiting Zhang, Lijie Wei, Zizhuo Wang, Shenglan Zhu, Jun Yu, Shaoshuai Wang, Wencheng Ding, Ling Feng, Jianli Wu.

  Gestational diabetes mellitus (GDM) has become a significant concern in the domain of women's health. The pathophysiology of GDM is complicated and not entirely understood. As a functional interface of the maternal and fetal metabolisms, it is evident that the placenta exerts an effect on the development of GDM. The placenta not only involves itself in insulin resistance via the production of hormones, but also serves as an organ abundant in mitochondria and exhibits intense metabolic activities, rendering it particularly vulnerable to the adverse effects of oxidative stress. In the high-glucose environment, excessive oxidative damage leads to mitochondrial dysfunction and further induces ferroptosis by facilitating lipid peroxidation. The objective of this review is to predominantly assess recent research, published within the last five years, that investigates the roles of placental oxidative stress, mitochondrial dysfunction, and ferroptosis as pathological mechanisms influencing the development of GDM. Understanding these pathological changes may help to better explore novel therapeutic strategies for GDM.

Keywords:  Ferroptosis; Gestational diabetes mellitus; Mitochondrial dysfunction; Oxidative stress; Placenta

DOI:  https://doi.org/10.1007/s00109-025-02629-7