bims-placeb Biomed News
on Placental cell biology
Issue of 2025–10–26
seventeen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences
  1. Functional Interaction of GCM1 and LINC01118 Regulates Syncytiotrophoblast Differentiation.
  2. Activity of the SWI/SNF complex is indispensable for syncytiotrophoblast formation.
  3. Spatial metabolomics and transcriptomics reveal cell type-specific dynamics in the placenta of patients with late-onset preeclampsia.
  4. The regulation of placental pericyte function through transforming growth factor β-1 signalling.
  5. Chronic mild maternal stress modulates the immune response at the maternal-fetal interface and affects the growth and mortality of the offspring.
  6. Non-Enzymatic Generation of Placenta Single Cells From Third Trimester Human Placenta.
  7. Utility of Placental Growth Factor (PlGF) for preeclampsia prediction in pregnancies complicated by Sickle Cell Disease.
  8. Expression pattern of the HIFα-family in equine chorioallantois during pregnancy and placental pathology.
  9. Placental transfer of quercetin and its metabolites to fetuses in pregnant mice.
  10. Live imaging of late-stage preimplantation human embryos reveals de novo mitotic errors.
  11. Differential lipid and metabolic profiles of embryonic inner cell mass and trophectoderm.
  12. Elevated serum sFlt-1 at 18-20 weeks in advanced maternal age: a key difference from younger pregnancies.
  13. Possible involvement of a ZC3H4 gene splicing defect in the etiology of pre-eclampsia.
  14. Establishment of sex-specific liver transcriptomes and H3K9me3 profiles during sexual maturity: the impact of maternal obesity.
  15. Artificially induced torpor during pregnancy impairs fetal growth in mice.
  16. Maternal-fetal conflict and the timing of birth.
  17. Pregnancy-to-lactation transition remodels mammary adipocytes via p38 MAPK-dependent adipogenesis.
  1. FASEB J. 2025 Oct 31. 39(20): e71161
    Functional Interaction of GCM1 and LINC01118 Regulates Syncytiotrophoblast Differentiation.
    Liang-Jie Wang, Yu-Hsuan Pao, Yen-Jhen Tseng, Pui-Sze Ng, Yun-Shien Lee, Hungwen Chen.
      Human trophoblast stem (TS) cells differentiate into syncytiotrophoblasts (STBs) through cell-cell fusion, forming the outermost layer of the placental villus to enable nutrient and gas exchange between the mother and fetus. GCM1 (glial cells missing 1) is a placenta-specific transcription factor that regulates STB differentiation by activating the transcription of syncytin and hCGβ genes. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that do not encode proteins. While recent studies suggest that lncRNAs regulate cell differentiation, their role in STB differentiation remains unclear. In this study, we analyzed the transcriptomics of TS cells, as well as TS cell-derived STBs and extravillous trophoblasts, and identified a correlation between the expression of LINC01118 lncRNA and STB-related genes. LINC01118 is highly expressed in first-trimester STBs in the human placenta and is upregulated in BeWo and TS cells upon induction of STB differentiation. Notably, LINC01118 directly interacts with GCM1, enhancing its protein stability and thereby its transcriptional activity, which supports GCM1 autoregulation and the expression of downstream target genes involved in trophoblast fusion and hormone production. In conclusion, we identify LINC01118 as a novel lncRNA that positively regulates GCM1 activity, playing a key role in STB differentiation through its direct interaction with GCM1.
    Keywords:  GCM1; long‐noncoding RNA; placenta; syncytiotrophoblast
    DOI:  https://doi.org/10.1096/fj.202501013RR
  2. Development. 2025 Oct 22. pii: dev.204770. [Epub ahead of print]
    Activity of the SWI/SNF complex is indispensable for syncytiotrophoblast formation.
    Henrieta Papuchova, Andreas Lackner, Terezia Vcelkova, Petra Tolp, Sandra Haider, Vasileios Gerakopoulos, Paulina A Latos.
      Developmental transitions are characterized by coordinated changes in lineage-specific gene expression programs and chromatin states. Yet, how these shifts in cell fate occur during placental development remains largely unknown. Here, we used human trophoblast stem cells (hTSCs), genetic depletion, and small-molecule inhibition of the SWI/SNF remodelling complex activity to address its role during syncytiotrophoblast (ST) differentiation. We found that SWI/SNF inhibition has a massive impact on gene expression, chromatin accessibility, and histone modifications, particularly H3K27ac, resulting in ST differentiation failure. We also observed cell cycle defects, indicating that SWI/SNF is required for hTSCs to exit the cell cycle, a prerequisite for ST commitment. In addition, based on motif analysis of SWI/SNF target regions, we genetically tested several early ST candidate transcription factors. While GCM1, CEBPB, and TBX3 are vital for ST differentiation, only GCM1 is sufficient to induce ST fate. Together, our results demonstrate that SWI/SNF activity is essential for lineage specification during placental development.
    Keywords:  Placenta; SWI/SNF; Trophoblast stem cells
    DOI:  https://doi.org/10.1242/dev.204770
  3. Front Cell Dev Biol. 2025 ;13 1659880
    Spatial metabolomics and transcriptomics reveal cell type-specific dynamics in the placenta of patients with late-onset preeclampsia.
    Xiaowei Wei, Qian Li, Chuanmei Qin, Weihong Zeng, Yuxu Liu, Jiawei Lu, Jiuming He, Cailian Chen, Xiaoqing Zhang, Yi Lin.
       Introduction: The placenta is vital for fetal development, but its growth can become disordered in pregnancy complications, particularly at the maternal-fetal interface. Preeclampsia, a severe condition that arises after the 20th week of pregnancy, is characterized by hypertension and other complications, posing significant risks to both mother and fetus. Despite its importance, the underlying mechanisms of preeclampsia remain poorly understood. Unraveling these mechanisms is essential for improving outcomes and advancing treatment strategies.
    Objectives: This study aimed to explore the spatial heterogeneity of the placenta and investigate the pathogenesis of late-onset preeclampsia (LOPE).
    Methods: We employed spatial transcriptomics (ST) and spatial metabolomics (SM) to map trophoblasts, fibroblasts, and immune cells, and analyze their transcriptomic and metabolomic profiles. A "spot-match" method was developed to integrate ST and SM data, revealing cell type-specific gene and metabolite changes during trophoblast differentiation.
    Results: The preeclamptic placenta showed increased fibroblasts and VCT proportions but a reduced SCT proportion. Complex interactions among trophoblasts, fibroblasts, and macrophages were observed in LOPE patients. Major metabolic reprogramming, particularly in glycerophospholipid and sphingolipid metabolism, was identified, potentially influencing trophoblast differentiation.
    Conclusion: Our ST and SM data offer new insights into LOPE mechanisms, providing valuable information for its prevention and treatment.
    Keywords:  placenta; preeclampsia; spatial metabolomics; spatial transcriptomics; trophoblast
    DOI:  https://doi.org/10.3389/fcell.2025.1659880
  4. Sci Rep. 2025 Oct 21. 15(1): 36668
    The regulation of placental pericyte function through transforming growth factor β-1 signalling.
    Caelan A MacPhee, Bryony V Natale, Curtis Noordhof, Sophia Wang, Patricia D A Lima, David R C Natale.
      In the placenta, fetal-derived pericytes wrap the villous capillaries, directly interacting with endothelial cells to orchestrate the branching angiogenesis required to meet the demands of the growing fetus. In animal models of preeclampsia (PE), there is a positive correlation between reduced αSMA-expressing pericyte coverage and reduced vascular branching. Transforming Growth Factor β-1 (TGFβ-1) signalling is critical to placental development, is altered in placental pathology and alters pericyte function in other organs. However, the factors that influence placental pericyte function are under-investigated. In the present study, we investigated the in vitro effects of TGFβ-1 signalling on the population dynamics and functional measures of isolated term human placental pericytes, including angiogenic and inflammatory secretions, extracellular matrix (ECM) production, and phagocytic capacity. TGFβ-1 treatment promoted a proangiogenic phenotype with increased pro-angiogenic secretion of VEGFA and MMP-2 and reduced vessel stabilizing secretion of (ANG-1), without affecting the production of ECM components. Pericyte secretion of inflammation-associated adhesion molecule sVCAM-1, cytokine IL-6, chemokine MCP-1, and their phagocytosis capacity were attenuated with TGFβ-1 treatment. While some effects were mediated via the type I receptor ALK5, others were not, suggesting that TGFβ-1 signalling in placental pericytes may additionally occur via ALK1. Thus, it is likely that locally secreted TGFβ-1, contributes to the regulation of villous pericyte properties and their barrier function, and may implicate dysregulated TGFβ-1 signalling as a mechanism for the compromised placental fetal vascular branching observed in many placental pathologies. These findings are timely with emerging evidence that TGFβ is involved in the pathogenesis of PE.
    DOI:  https://doi.org/10.1038/s41598-025-20432-9
  5. Placenta. 2025 Oct 03. pii: S0143-4004(25)00711-8. [Epub ahead of print]
    Chronic mild maternal stress modulates the immune response at the maternal-fetal interface and affects the growth and mortality of the offspring.
    F L De la Cruz Borthiry, J S Beltrame, V A Cañumil, F Scheffer, M E Bogetti, M Cella, M Vermeulen, L Gimenez, M Negri Malbrán, E M Repetto, C Cymeryng, G F Leguizamon, A M Franchi, M L Ribeiro.
      Maternal lifestyle influences the health of both the mother and fetus. Acute stress is detrimental to health and increases the risk of obstetric complications. However, the consequences of chronic mild stress are less understood. We investigated the effect of chronic mild maternal stress on gestation and its influence on the immune response at the maternal-fetal interface. BALB/c female mice were exposed to a model of mild stress involving reduced litter material compared with the control condition. Also, a shaking protocol of 1 min every other day was initiated two weeks before mating and continued until euthanasia (days 7 or 15 of pregnancy) or term labor. The stressor stimulus increased the level of serum corticosterone. Furthermore, higher concentrations of total cholesterol and triglycerides were detected in the serum of stressed pregnant mice. Stressed mothers presented lower weight gain. The offspring born to stressed mothers showed lower weight on postnatal day one, and higher early neonatal mortality. No changes were observed in the number of implantation sites, the resorption rate, ovarian architecture, and histology. However, fetuses from stressed mice exhibited lower weights. Moreover, IL-6, IL-17, and TGF-β levels increased in the amniotic fluid of stressed mothers, while no changes were detected systemically. In addition, the protein expression of TLR-4 was increased in the uterus. Moreover, cyclooxygenase-2 and prostaglandin E2 were decreased in the placenta. In conclusion, chronic mild maternal stress induces immunological alterations at the maternal-fetal interface affecting the health of the mothers during gestation and the development of the offspring.
    Keywords:  Chronic mild maternal stress; Inflammatory mediators; Maternal and offspring health; Maternal-fetal interface
    DOI:  https://doi.org/10.1016/j.placenta.2025.10.003
  6. Curr Protoc. 2025 Oct;5(10): e70237
    Non-Enzymatic Generation of Placenta Single Cells From Third Trimester Human Placenta.
    Joy U Ameloko, Idowu A Aimola, Hanneda A Fomukong, Aliyu Salihu, Abdullahi B Salau, Zeenat B Kudan, Ruben S Baba, Solomon Dunason, Habiba H Abubakar, Kalen E Audu, Joy B Karma, Peculiar N Okoro, Abduljabar Musa, Musa Kana, Benedict Anchang.
      The placenta is a heterogeneous and complex organ with multiple cell types, posing a challenge for the maternal-fetal medicine field to implement single-cell technologies for a deeper characterization of this essential organ. Several protocols use enzymes to digest the tissue and generate single-cell suspensions, but this approach has several shortcomings, including the loss and reduced viability of cells. In this article, we describe a non-enzymatic approach to generate single-cell suspensions from placental tissue with high yield and viability for single-cell RNA sequencing. © 2025 Wiley Periodicals LLC. Basic Protocol 1: Preparation of single-cell suspension from freshly collected third trimester human placental sections Basic Protocol 2: Visualization and determination of cell viability Alternate Protocol: Counting cells using a hemocytometer.
    Keywords:  non‐enzymatic; placenta cell viability; single‐cell RNA sequencing; single‐cell genomics; third trimester placenta; transcriptomics
    DOI:  https://doi.org/10.1002/cpz1.70237
  7. Blood Adv. 2025 Oct 21. pii: bloodadvances.2025016821. [Epub ahead of print]
    Utility of Placental Growth Factor (PlGF) for preeclampsia prediction in pregnancies complicated by Sickle Cell Disease.
    Evangelia Vlachodimitropoulou, Tharshini Balasubramaniam, Nadine Shehata, Richard Ward, Kevin H M Kuo, John Charles Kingdom, Kinga Malinowski.
      Outside of pregnancy, Placental Growth Factor (PlGF), is produced by erythroid cells in typically undetectable levels. In pregnancy, PlGF is strongly expressed by the trophoblast layer covering the placental villi. PlGF levels rise progressively due to placental growth, peak at 28-30 weeks' gestation, then slowly decline towards term. Low PlGF has emerged as a powerful diagnostic test for preterm preeclampsia. However its interpretation in context of sickle cell disease (SCD) is potentially confounded by: upregulation of cellular PlGF expression in non-pregnant SCD individuals, and higher 3rdtrimester circulating PlGF levels documented in healthy Black compared with Caucasian individuals. Primary objectives were to determine the distribution of PlGF at mid-trimester in pregnant individuals with SCD compared to unaffected Black controls and to explore the diagnostic accuracy of PlGF in the context of suspected preeclampsia in SCD pregnancies. Secondary objective was to examine the relationship between low PlGF and placental disease in SCD pregnancies. Pregnant individuals with SCD at Mount Sinai Hospital in Canada (Jan. 2017-Sept. 2021) with at least one PlGF measurement 20+0 - 35+6 weeks' gestation and pregnant Black controls without SCD, with suspected preeclampsia or growth restriction, were included in this retrospective study. Maternal and neonatal outcomes were extracted from medical records. For early-onset, but not late-onset, preeclampsia, a PlGF cut-off <100 pg/mL demonstrated 100% sensitivity and specificity at 20-24 weeks' gestation. This study is the first to demonstrate the utility of PlGF in predicting early-onset preeclampsia in SCD pregnancies, allowing clinicians to anticipate and mitigate adverse pregnancy outcomes.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016821
  8. Theriogenology. 2025 Oct 16. pii: S0093-691X(25)00440-6. [Epub ahead of print]250 117714
    Expression pattern of the HIFα-family in equine chorioallantois during pregnancy and placental pathology.
    Yatta Boakari, Hossam El-Sheikh Ali, Gustavo Henrique Doná Rodrigues Almeida, Kirsten E Scoggin, Claudia Barbosa Fernandes, Sophia Panelli Marchio, Mats H T Troedsson, Ana Claudia Oliveira Carreira.
      Equine placental dysfunction impairs fetal growth and disrupts pregnancy outcomes. Despite many advances in diagnosis, the molecular pathophysiology of equine placentitis and premature placental separation remains poorly understood. However, the hypoxia-inducible factor (HIF-α) pathway is related to placental hypoxia, and its modulation in placental diseases has been shown in other species. Therefore, we hypothesized that in conditions marked by equine placental dysfunction, oxygen deprivation in the chorioallantois membrane triggers the activation of the HIF-α pathway, which is related to molecular alterations associated with placental insufficiency. Accordingly, we compared the expression of HIF1A, HIF2A, HIF3A, and HIF1AN genes in equine chorioallantois 1) at various points during normal gestation, and in mares with 2) ascending placentitis (AP), 3) nocardioform placentitis (NP), and 4) premature placental separation (PPS), compared to mares with normal pregnancies (controls). During normal pregnancy, expression of HIF-related genes remained low until a significant post-partum increase, suggesting a balanced regulatory state under normoxic conditions. In contrast, the three pathological conditions exhibited a distinct expression profile: AP was marked by HIF1A upregulation and concurrent suppression of HIF3A and HIF1AN; NP showed reduced HIF2A and HIF3A expression without changes in HIF1A; and PPS was characterized by HIF1A upregulation with HIF1AN, HIF2A, and HIF3A downregulation. Our findings reveal that although AP, NP, and PPS all involve oxygen deprivation, the molecular hypoxia response is disease specific. This study provides novel insight into the equine placental hypoxic response. This warrants further research to elucidate these mechanisms and explore them as potential diagnostic targets for equine placental dysfunctions.
    Keywords:  Equine reproduction; Hypoxia; Mare; Placental dysfunctions
    DOI:  https://doi.org/10.1016/j.theriogenology.2025.117714
  9. Biochem Biophys Res Commun. 2025 Oct 17. pii: S0006-291X(25)01543-8. [Epub ahead of print]788 152827
    Placental transfer of quercetin and its metabolites to fetuses in pregnant mice.
    Nao Fujiwara, Kyoka Matsubara, Rie Mukai, Miyu Nishikawa, Shinichi Ikushiro, Akira Murakami, Akari Ishisaka.
      Quercetin (QUE), a flavonoid widely found in vegetables and fruits, is primarily metabolized through phase II conjugation pathways and circulates as various conjugates. We previously showed that QUE and its metabolites are transferred to neonatal mice via breast milk. However, as the dams in that study ingested QUE during pregnancy, placental transfer may also had occurred. Thus, this study aimed to investigate the placental transfer of QUE and its metabolites by quantifying their concentrations before parturition. ICR mice were fed a standard AIN-93G diet and mated, with gestational day 0 defined as the day of mating. On gestational day 14, the diet was switched to 1 % (w/w) QUE-supplemented AIN-93G. On gestational day 17, blood, liver, and placenta samples were collected from pregnant dams and fetuses. QUE and its metabolites were quantified using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. QUE and its metabolites were detected in the placenta and maternal liver, as well as in the fetal liver. The proportions of heteroconjugates (e.g., quercetin glucuronide sulfate and isorhamnetin glucuronide sulfate) in the placenta (59 %) and fetal liver (43 %) were lower than in maternal plasma (94 %). In contrast, monoconjugates (e.g., quercetin glucuronide, quercetin sulfate) and particularly free QUE were relatively abundant in both placenta and fetal liver. These findings suggest that heteroconjugates from maternal blood may be deconjugated in the placenta. To our knowledge, this is the first study to comprehensively analyze the placental transfer of QUE and its metabolites to fetuses in pregnant mice.
    Keywords:  Fetus; Flavonoid metabolism; LC-QTOF-MS; Placenta transfer; Quercetin
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152827
  10. Nat Biotechnol. 2025 Oct 23.
    Live imaging of late-stage preimplantation human embryos reveals de novo mitotic errors.
    Ahmed Abdelbaki, Afshan McCarthy, Anita Karsa, Leila Muresan, Kay Elder, Athanasios Papathanasiou, Phil Snell, Leila Christie, Martin Wilding, Benjamin J Steventon, Kathy K Niakan.
      Existing methods to image chromosome segregation errors are not suitable for studying human embryos at advanced preimplantation stages. As chromosomal errors are a leading cause of miscarriage and infertility, it remains unclear whether missegregation arises postfertilization. Here we optimize nuclear DNA labeling via messenger RNA electroporation and apply light-sheet live imaging to reveal chromosome segregation errors immediately before implantation. We show that embryos at advanced preimplantation stages display missegregation, including multipolar spindle formation, lagging chromosomes, misalignment and mitotic slippage. Most lagging chromosomes are passively inherited rather than reincorporated. To trace individual nuclei, we developed an open-source, semi-automated segmentation method using a customized deep learning model optimized for variability in embryo size, shape and signal. With this approach, we find most labeled cells remain externally positioned, consistent with placental rather than inner cell mass fate. Our findings raise questions about clinical uses of preimplantation genetic testing for aneuploidy, while providing broadly applicable imaging and segmentation methods for studying diverse cellular structures in human embryos.
    DOI:  https://doi.org/10.1038/s41587-025-02851-1
  11. Dev Biol. 2025 Oct 18. pii: S0012-1606(25)00302-1. [Epub ahead of print]529 188-199
    Differential lipid and metabolic profiles of embryonic inner cell mass and trophectoderm.
    Thamiris Vieira Marsico, Andressa Minozzo Oliveira, Roniele Santana Valente, Kelly Annes, Christina Ramires Ferreira, Mateus José Sudano.
      The initial development of mammalian embryos represents a highly intricate and meticulously orchestrated process. This journey encompasses distinct cellular fate determinations and complex regulatory mechanisms. In the scope of our study, we conducted a comprehensive examination of the lipid and metabolic profiles characterizing these distinct cell populations within bovine embryos. In vitro-produced embryos, were submitted to microsurgery and/or immunosurgery techniques to recover trophectoderm (TE) and inner cell mass (ICM) cells. After different cell type obtaining ICM and TE samples underwent lipid and metabolic profiling utilizing multiple reaction monitoring (MRM) profiling mass spectrometry. We unveiled clear and distinct patterns of metabolites expression, including lipids, with TE cells demonstrating a heightened abundance of a variety classes of lipids, whereas ICM cells exhibited specific abundance increase of amino acids. The substantial presence of amino acids in ICM cells aligns with their pivotal role in orchestrating the development of diverse tissues and organs within the emerging organism. Conversely, TE cells are primarily dedicated to preparations for placentation, maternal recognition, and providing essential support to the ICM throughout the developmental process. In summary, our study furnishes valuable insights into the intricate metabolic dynamics that underlie early embryonic development in bovine embryos. It underscores the unique lipidomic and metabolic signatures of ICM and TE cells, reflecting their respective roles in shaping the developmental trajectory. These findings significantly contribute to our deeper understanding of the molecular mechanisms governing embryonic development, offering potential implications for bovine reproduction and broader insights into mammalian embryology.
    Keywords:  Differentiation; Early embryo development; Embryonic competence; Lipid profiles; Metabolic profiles
    DOI:  https://doi.org/10.1016/j.ydbio.2025.10.016
  12. Hypertens Pregnancy. 2025 Dec 31. 44(1): 2565501
    Elevated serum sFlt-1 at 18-20 weeks in advanced maternal age: a key difference from younger pregnancies.
    Kazunari Nemoto, Keiichi Kumasawa, Motoaki Kinugawa, Keisuke Nakajima, Kei Inaba, Mari Ichinose, Masatake Toshimitsu, Seisuke Sayama, Takayuki Iriyama, Yutaka Osuga, Yasushi Hirota.
      Advanced maternal age (AMA) is associated with preeclampsia (PE). Although serum sFlt-1 levels at term are lower in PE cases among AMA women compared to those in PE cases among non-AMA women, evidence from mid-pregnancy remain limited. Since the clinical phenotype of PE has not yet emerged at 18-20 weeks of gestation, assessing angiogenic markers during this period may lead to a better understanding of the pathophysiology of PE. We retrospectively analyzed singleton pregnancies delivered at The University of Tokyo Hospital between January 2022 and March 2024. Serum sFlt-1 and PlGF levels were measured at 18-20 weeks of gestation, and their associations with PE were assessed based on maternal age (<35 years: non-AMA; 35-44 years: AMA). In non-AMA pregnancies, serum sFlt-1 levels tended to be lower in PE cases compared to normotensive (NT) cases. Conversely, in AMA pregnancies, PE cases showed significantly higher serum sFlt-1 levels and sFlt-1/PlGF ratios than NT cases. Serum PlGF levels did not differ significantly between any of the groups. These findings highlight differences in PE-associated markers between AMA and non-AMA pregnancies at mid-pregnancy. Clarifying these differences is essential for optimizing early risk stratification and management strategies in AMA populations.
    Keywords:  Advanced maternal age; normotensive; placental growth factor; preeclampsia; soluble fms-like tyrosine kinase-1
    DOI:  https://doi.org/10.1080/10641955.2025.2565501
  13. Placenta. 2025 Oct 15. pii: S0143-4004(25)00721-0. [Epub ahead of print]172 44-50
    Possible involvement of a ZC3H4 gene splicing defect in the etiology of pre-eclampsia.
    Hikari Yoshizawa, Hidehito Inagaki, Rei Yoshimoto, Ken-Ichi Fujita, Asuka Kato, Yoshiko Sakabe, Akiko Ohwaki, Mayuko Ito, Ryoko Ichikawa, Haruki Nishizawa, Akila Mayeda, Hiroki Kurahashi.
       INTRODUCTION: Alternative RNA splicing adds diverse variations to gene function, and its abnormalities are occasionally associated with the etiology of disease. We examined this possibility in pre-eclampsia.
    METHODS: We performed transcriptome analysis of placentas from pre-eclamptic and normotensive pregnancies and screened for disease-specific aberrant splicing.
    RESULTS: We identified aberrant splicing at exon 14 in the ZC3H4 gene. This in-frame exon is generally skipped in placentas from normal pregnancies but often observed in those from pre-eclampsia patients. The level of exon inclusion did not correlate with disease severity, such as blood pressure or fetal weight, but showed an association with the decrease in placental weight. Significantly, placental blood flow resistance measured by Doppler ultrasound correlated with the level of ZC3H4 exon 14 inclusion, suggesting that this retention leads to the onset and/or symptoms of pre-eclampsia. ZC3H4 is known to act on transcriptional regulation via suppression of lncRNA expression. Moreover, the SOD1 gene, encoding superoxide dismutase that eliminates toxic free superoxide radicals, was identified in the downstream gene group for ZC3H4. Indeed, the expression of SOD1 was found in this current study to be decreased in the pre-eclamptic placenta in correlation with the levels of ZC3H4 exon 14 retention.
    DISCUSSION: Aberrant splicing of ZC3H4 gene may induce excessive oxidative stress in the placenta via the downregulation of downstream SOD1 expression thereby leading to the onset and development of pre-eclampsia.
    Keywords:  Alternative splicing; Exon skip; Pre-eclampsia; SOD1; ZC3H4
    DOI:  https://doi.org/10.1016/j.placenta.2025.10.013
  14. Biol Sex Differ. 2025 Oct 21. 16(1): 81
    Establishment of sex-specific liver transcriptomes and H3K9me3 profiles during sexual maturity: the impact of maternal obesity.
    Ajay K Yadav, Arianna Harris-Kawano, Romil Saxena, Guanglong Jiang, Jia Ji, Hongyu Gao, Kok Lim Kua, Núria Morral.
       BACKGROUND: The escalating prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to rising obesity rates. Maternal obesity (MO) is associated with increased susceptibility to metabolic disorders, including MASLD, in the offspring. This elevated risk could be a consequence of epigenetic modifications established during fetal development, a period highly sensitive to the maternal diet. H3K9me3, a hallmark of heterochromatin, plays a vital role in development by silencing gene programs dispensable for differentiated cell types. This study investigated how MO influences gene expression and chromatin architecture in male and female offspring liver, in early postnatal live and upon sexual maturity.
    METHODS: Female mice were fed a Western-style diet or a control diet before and throughout pregnancy and lactation. The offspring were weaned at 3 weeks and subsequently transitioned to a standard chow diet for 5 weeks.
    RESULTS: At 3 weeks, the liver transcriptomes of control offspring were similar between sexes. However, MO disrupted hepatic gene expression in both sexes, leading to the dysregulation of hundreds of genes and alterations in H3K9me3 binding patterns. By 8 weeks, as the mice reached sexual maturity, control offspring showed considerable sex-based gene expression divergence, with over 1,800 genes showing differential expression. These genes were predominantly involved in immune response regulation, cell adhesion and extracellular matrix organization, xenobiotic and glutathione-mediated detoxification, cholesterol metabolism, and lipid partitioning. Furthermore, thousands of differentially bound H3K9me3 peaks were observed between the 3- and 8-week time points. A significant fraction of these peaks were located on the X chromosome in females, suggesting a role in X inactivation. Remarkably, MO offspring displayed incomplete normalization of gene expression, H3K9me3 profiles, and hepatic lipid classes by week 8, underscoring the long-term impact of maternal diet on the genomic and metabolic landscape.
    CONCLUSIONS: Collectively, this study highlights inherent sex differences in liver gene expression, and suggests that H3K9me3 plays a role in establishing sex-specific liver function during sexual maturation. Moreover, MO disrupts these patterns, which are not fully corrected by 5 weeks of postnatal dietary normalization.
    Keywords:  Cellular differentiation; Heterochromatin; Histone methylation; Liver; Maternal obesity; Sex dimorphism; Western-style diet
    DOI:  https://doi.org/10.1186/s13293-025-00767-8
  15. Sci Rep. 2025 Oct 23. 15(1): 37069
    Artificially induced torpor during pregnancy impairs fetal growth in mice.
    Mitsue Hagihara, Takeshi Sakurai, Kazunari Miyamichi, Kengo Inada.
      Fetal development in endothermic mammals relies on a tightly regulated maternal body temperature. In animal models, deviations from normothermia during gestation cause fetal developmental abnormalities. However, the direct and physiological manipulation of the maternal core temperature has been technologically challenging, as traditional methods involve the imposition of external thermal stress. Recent advances in the identification of thermoregulatory neurons in the mouse preoptic area have allowed precise control of maternal body temperature without altering environmental conditions. Here we show that the activation of excitatory neurons in the medial preoptic area (MPO) induces a torpor-like hypothermic state in pregnant mice. When induced during early gestation, this state resulted in pregnancy loss, likely due to implantation failure. Hypothermia in mid- and late-gestation reduced fetal liver and kidney size and caused severe growth retardation. Similar outcomes were observed following pyroglutamylated RFamide peptide (Qrfp)-expressing neuron activation in the MPO, whereas inhibitory neuron activation had minimal effect. Furthermore, activating MPO excitatory neurons projecting to the dorsomedial hypothalamic nucleus reproduced both the torpor-like state and fetal growth retardation. These results underscore the importance of a stable maternal body temperature in fetal development and establish a new model for studying the effects of altered maternal temperature on embryogenesis.
    Keywords:  Development; Hypothalamus; Hypothermia; Organogenesis; Pregnancy; Torpor
    DOI:  https://doi.org/10.1038/s41598-025-21115-1
  16. Evol Med Public Health. 2025 ;13(1): 292-306
    Maternal-fetal conflict and the timing of birth.
    Andrew I Furness.
      Evolutionary theory predicts mammalian offspring will favor greater investment than parents are willing to provide, leading to conflict over resource transfer. This theory of parent-offspring conflict has been applied to resource transfer across the placenta. Birthweight and gestation length are functionally linked, suggesting that the timing of birth might also represent a focal point of maternal-fetal conflict. This hypothesis relies on two assumptions: mother and offspring have different fitness optima and both parties exert partial control over the timing of birth. It is argued, and evidence is reviewed, that suggests offspring benefit from slightly longer gestation than the maternal optimum, and that fetal and maternal genes both influence gestation length. We might therefore expect an evolutionary history of maternal-fetal conflict over the control of parturition. Evidence consistent with this hypothesis includes the effect of imprinted genes, as revealed through imprinting disorders, on gestation length; the wide variability in parturition mechanism(s) among mammalian species; and the complex physiology of human parturition including initiation by multiple different pathways with inputs from both mother and offspring. One potential consequence of a history of maternal-fetal conflict over control of the mechanisms of parturition is that the timing of birth may be subject to a greater degree of dysregulation than simpler physiological systems subject to single-party control.
    Keywords:  birthweight; gestation length; parent-offspring conflict; parturition; pregnancy; preterm birth
    DOI:  https://doi.org/10.1093/emph/eoaf023
  17. J Dairy Sci. 2025 Oct 21. pii: S0022-0302(25)00833-1. [Epub ahead of print]
    Pregnancy-to-lactation transition remodels mammary adipocytes via p38 MAPK-dependent adipogenesis.
    Tao Luo, Nannan Jiang, Chaoqun Wu, Wenying Zhang, Jianxin Liu, Juan J Loor, Hengbo Shi.
      Adipose tissue remodeling is essential for mammary gland development and functional restoration. The dry period represents a pivotal phase characterized by extensive tissue remodeling as the gland transitions from pregnancy to lactation. However, the morphological and molecular mechanisms underlying mammary adipose tissue remodeling during this stage remain poorly understood. In this study, we investigated adipose remodeling in the mammary gland of dairy goats during this transitional period. An integrative multi-omics approach combining transcriptomics, lipidomics, and metabolomics was employed to comprehensively characterize the molecular changes of mammary tissue. Histological analysis and transmission electron microscopy revealed a substantial increase in both the proportion and size of adipocytes at 4 weeks before prepartum. RNA sequencing of isolated mammary adipose cells indicated that the p38 mitogen-activated protein kinase (MAPK) pathway may play a key regulatory role in this process. To further dissect its function, we established an immortalized goat mammary preadipocyte cell line. Pharmacological inhibition of p38 MAPK significantly impaired adipocyte differentiation and hypertrophy. Furthermore, our findings suggested that p38 MAPK modulates adipogenesis in mammary adipocytes through downstream effectors, including APOE. These findings highlight a critical role for the p38 MAPK signaling pathway in orchestrating mammary adipose tissue remodeling during the dry period. This work provides novel insights into the molecular regulation of mammary gland renewal and offers potential targets to manipulate mammary gland development in ruminants.
    Keywords:  adipogenesis; adipose tissue; mammary gland; tissue remodeling
    DOI:  https://doi.org/10.3168/jds.2025-27033
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