bims-placeb 2025-08-31 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–08–31
nineteen papers selected by
Carlos M Guardia, National Institute of Health

Unraveling the role of miRNAs in placental function: insights into trophoblast biology and pregnancy pathology.
The Role of β-Core Fragment hCG in Embryo Implantation and Early Pregnancy.
AMPK function in uterine vasculature and placenta at high altitude.
Therapeutic potential of extracellular vesicles for treating human pregnancy disorders.
Deep genome sequencing reveals extensive genetic heterogeneity in early human placentas.
Gestation-Stage Related Changes in the IGF System Components in the Equine Placenta.
Cripto-1 and Cripto-3 differential expression pattern in human placenta, umbilical cord and fetal tissues suggests new functions for these proteins.
Placental mitochondrial calcium uniporter modulates offspring susceptibility to metabolic dysfunction.
Maternal liver lipid dysregulation mediates fetal developmental impairments induced by gestational co-exposure to ozone and heat in C57BL/6J Mice.
High-resolution MRI reveals uteroplacental flow dynamics in a 3D-printed human placental cotyledon model.
Metformin and insulin exacerbate one-carbon metabolism deficits in pregnant growth restricted rats and impacts the placenta, fetal liver and pancreas.
Study on the relationship between cesarean scar pregnancy and placental accreta using ultrasound monitoring.
Maternal exposure to advanced oxidation protein products induces neurodevelopmental abnormalities in the offspring of mice.
Impact of placenta-derived extracellular vesicles on endothelial function in supraphysiological maternal hypercholesterolemia.
Isorhynchophylline alleviates preeclampsia via PI3K/AKT/mTOR-mediated trophoblast oxidative stress inhibition.
The roles of NLRP3 and prostaglandin E2 in mediating bidirectional cross-talk between bovine endometrial fibroblasts and M2 macrophages.
Lithium Exposure Causes Trophoblast Cuproptosis by Upregulating FOXO1/STEAP4 Axis in Unexplained Miscarriage.
Defining the cell and molecular origins of the primate ovarian reserve.
A call to standardize the nomenclature of human fetal membrane at the feto-maternal interface.

Placenta. 2025 Aug 15. pii: S0143-4004(25)00662-9. [Epub ahead of print]

Unraveling the role of miRNAs in placental function: insights into trophoblast biology and pregnancy pathology.

Yanjie Guo, Cheuk-Lun Lee, Yajing Meng, Yimeng Li, Sam Chak Sum Wong, Hoi Kit Matthew Leung, William S B Yeung, Ka-Wang Cheung, Qingqing Zhang, Philip C N Chiu.

  MicroRNAs (miRNAs) are pivotal regulators of placental development and function, orchestrating critical processes such as trophoblast proliferation, differentiation, invasion, and vascular remodeling. By modulating diverse signaling pathways, these small non-coding RNAs help ensure proper placental formation and optimal maternal-fetal nutrients and gases exchange. Dysregulated miRNA expressions can profoundly affect placental biology, leading to complications such as preeclampsia, fetal growth restriction, and recurrent pregnancy loss. Accumulating evidence implicates abnormal miRNA profiles in defective spiral artery remodeling and impaired trophoblast activity. Notably, circulating miRNAs exhibit high stability and tissue specificity, positioning them as promising noninvasive biomarkers for early detection of pregnancy complications. Recent preclinical studies highlight the therapeutic potential of miRNA-based modulators using mimics or inhibitors to restore normal placental function. However, challenges remain in optimizing placental-targeted delivery systems. Collectively, miRNAs are pivotal in placental health and disease, offering potential as biomarkers and therapeutic targets.

Keywords:  Biomarker; Placental complication; Placental development; Therapeutic target; Trophoblast; miRNA

DOI:  https://doi.org/10.1016/j.placenta.2025.08.327
Int J Mol Sci. 2025 Aug 18. pii: 7974. [Epub ahead of print]26(16):

The Role of β-Core Fragment hCG in Embryo Implantation and Early Pregnancy.

Ji Soo Ryu, Nu Ri Yang, Yu Ha Shim, Yu Jin Kim, Won Jae Kwag, Jin Dong Chang, Jae Ho Lee.

  Human chorionic gonadotropin (hCG) is a pregnancy biomarker, and five forms of this hormone are involved in female physiological regulation. β-core fragment hCG (bcf-hCG) is a fragment of hCG whose biological role in female reproduction has not been completely elucidated. This study aimed to investigate its role in embryo implantation and maintenance of a pregnancy-supportive environment. We analyzed the protein expression pattern of bcf-hCG in the intrauterine environment during early pregnancy by performing western blotting and immunohistochemistry with a monoclonal anti-bcf-hCG antibody. We performed a cell proliferation assay in the presence of bcf-hCG compared with intact hCG. We conducted an ex vivo study by performing intrauterine injection of bcf-hCG or intact hCG in mice. Endometrial thickness was measured using histological methods, and uterine gene and protein expression were analyzed following intrauterine injection of bcf-hCG. We evaluated the effect of bcf-hCG on embryo implantation in the uterus. bcf-hCG was highly abundant in the placenta and epithelial stromal glands of the uterine endometrium during early pregnancy and significantly induced proliferation of a stromal epithelial cell line. Intrauterine injection of bcf-hCG induced expression of specific genes and proteins, including homeobox A10, for embryo implantation and placental development. Upon embryo transfer, the implantation rate of bcf-hCG-treated embryos was higher than that of control embryos. In conclusion, bcf-hCG plays a role in the proliferation of glandular epithelial cells in the endometrium and placenta during early pregnancy. Therefore, bcf-hCG is an early-phase pregnancy biomarker that maintains the initial phase of pregnancy.

Keywords:  endometrium; placenta; pregnancy; proliferation; β-core fragment hCG

DOI:  https://doi.org/10.3390/ijms26167974
Philos Trans R Soc Lond B Biol Sci. 2025 Aug 21. 380(1933): 20240174

AMPK function in uterine vasculature and placenta at high altitude.

Ramón A Lorca.

  The chronic hypoxia of high-altitude (HA, >2500 m) residence reduces uterine artery (UtA) blood flow, contributing to an increased frequency of fetal growth restriction (FGR). FGR pregnancies have reduced UtA blood flow partially owing to impaired myometrial artery (MyoA) vasodilation. However, studies show lower rates of HA-associated reductions in fetal growth in Andeans and describe an association between genetic variants predicted to activate the AMP-activated protein kinase (AMPK) pathway and protection against low birthweight. Vascular function studies show that AMPK-dependent vasodilator responses are amplified in UtA from mice exposed to hypoxia during pregnancy and MyoA from pregnant women at HA, while the response is reduced in MyoA from women with FGR pregnancies. The effect of HA (or gestational hypoxia) on placental AMPK activation needs to be clarified, with some studies showing an effect and others not. There is potential to use AMPK activators as therapeutic targets. However, some drugs (i.e. metformin) approved for use in pregnancy complications cause off-target and adverse metabolic effects in offspring, which discourage their use. Future studies are warranted to elucidate the mechanisms underlying the altitude-dependent activation of AMPK in uncomplicated pregnancies and its reduction in FGR to identify possible vascular-specific targets for therapeutic intervention.This article is part of the discussion meeting issue 'Pregnancy at high altitude: the challenge of hypoxia'.

Keywords:  chronic hypoxia; fetal growth; uterine artery; vasodilation

DOI:  https://doi.org/10.1098/rstb.2024.0174
Extracell Vesicles Circ Nucl Acids. 2025 ;6(2): 287-309

Therapeutic potential of extracellular vesicles for treating human pregnancy disorders.

Shixuan Zheng, Harry M Georgiou, Maria I Kokkinos, Katrina M Mirabito Colafella, Shaun P Brennecke, Bill Kalionis.

  Pregnancy complications such as preeclampsia and fetal growth restriction are major global health concerns, contributing to significant maternal and fetal morbidity and mortality. These disorders also increase the long-term risk of cardiovascular, metabolic, and kidney diseases in both mother and child. Accumulating evidence highlights the important role of placental mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) in both healthy and pathological pregnancies. In healthy pregnancies, EVs support placental development and maternal-fetal communication. In contrast, EVs from diseased placentas can contribute to pregnancy complications. Importantly, EVs from healthy placental MSCs show promise as novel, cell-free therapies. They offer advantages over whole-cell therapies, including lower immunogenicity, no risk of replication, and easier storage and delivery. This review explores the role of placental MSC-derived EVs in pregnancy disorders, preeclampsia, fetal growth restriction, preterm birth, and gestational diabetes, and discusses their potential as targeted therapeutics. It also examines the future of bioengineered EVs and the challenges that must be addressed to bring EV-based therapies into clinical practice.

Keywords:  Pregnancy; exosomes; extracellular vesicles; therapeutics

DOI:  https://doi.org/10.20517/evcna.2025.07
Nat Commun. 2025 Aug 23. 16(1): 7873

Deep genome sequencing reveals extensive genetic heterogeneity in early human placentas.

Ieva Miceikaite, Christina Fagerberg, Charlotte Brasch-Andersen, Pernille M Torring, Britta Schlott Kristiansen, Qin Hao, Lene Sperling, Martin J Larsen.

Placental biopsy in early pregnancy is widely used in prenatal genetic diagnostics as a surrogate for fetal tissue. Confined placental chromosomal mosaicism is a well-documented phenomenon causing genetic discrepancies between the fetus and placenta. Although comprehensive sequencing methods are becoming popular for prenatal screening of monogenic disorders, knowledge of concordance between the fetus and early placenta at the sequence level remains limited. By deep genome sequencing, we have mapped the mutational landscape across multiple sites and stages of placental development. We have revealed wide-spread mutations, with distinct clusters of postzygotic non-fetal small sequence variants, indicating extensive clonal evolution in all early placental biopsies, including first-trimester chorionic villus samples. Our study illuminates spatial and temporal genetic heterogeneity of the developing placenta. While most clonal sequence variants in placental biopsies exhibit low variant allele frequency, their presence underscores the need for caution when using placental tissue as a fetal proxy for diagnostics. These findings highlight the importance of confirmatory testing using AF in cases where placental mosaicism is suspected to avoid misinterpretation and unnecessary interventions.

DOI: https://doi.org/10.1038/s41467-025-63296-3
Biomolecules. 2025 Aug 06. pii: 1135. [Epub ahead of print]15(8):

Gestation-Stage Related Changes in the IGF System Components in the Equine Placenta.

Kirsten E Scoggin, Fatma Adlan, Carleigh E Fedorka, Shimaa I Rakha, Tom A E Stout, Mats H T Troedsson, Hossam El-Sheikh Ali.

  The insulin-like growth factor (IGF) system regulates implantation, placental development, and angiogenesis in eutherian mammals. However, little is known about the changes in this system in equine placenta (chorioallantois; CA) and the endometrium (EN) during pregnancy, or the relationship to vascular endothelial growth factor (VEGF) expression. The current study investigated the expression of the IGF system components, namely the ligands (IGF1 and IGF2), their receptors (IGF1R, IGF2R, and INSR), and their binding proteins (IGFBPs and IGF2BPs) in equine CA at 45 days, 4, 6, 10, and 11 months of gestational age (GA) and immediately postpartum (PP), and in equine EN at 4, 6, 10, and 11 months GA. IGF1 immunolocalization and serum concentrations were also evaluated across gestation. IGF1 mRNA expression in CA increased from day 45 to peak at 6 months and then gradually declined to reach a nadir in PP samples. This profile correlated positively with the VEGF expression profile (r = 0.62, p = 0.001). In contrast, IGF2 expression in CA was not correlated with VEGF (p = 0.14). Interestingly, IGF2 mRNA was more abundant in equine CA than IGF1 (p < 0.05) throughout gestation. Among the IGFBPs investigated in CA, the expression of IGFBP2 and IGF2BP2 was highly abundant (p < 0.05) at day 45 compared to other GAs. Conversely, mRNA expression for IGFBP3 and IGFBP5 was more abundant (p < 0.05) in PP than at all investigated GAs. Immunohistochemistry revealed that IGF1 is localized in the equine chorionic epithelium (cytoplasm and nucleus). IGF1 serum concentrations peaked at 9 months and declined to their lowest levels PP. In conclusion, this study demonstrates a positive correlation between IGF1 and VEGF expression in equine CA during gestation, suggesting that the IGF system plays a crucial role in placental angiogenesis by regulating VEGF.

Keywords:  IGF system; VEGF; chorioallantois; equine; placenta

DOI:  https://doi.org/10.3390/biom15081135
Sci Rep. 2025 Aug 20. 15(1): 30497

Cripto-1 and Cripto-3 differential expression pattern in human placenta, umbilical cord and fetal tissues suggests new functions for these proteins.

Josune García-Sanmartín, Judit Narro-Íñiguez, María José Puente, Frank Cuttitta, Alfredo Martínez.

  Cripto-1 (CR1) is an oncofetal protein involved in EGF/TGFβ signal transduction, with important functions in development, stem cell biology and cancer. Its homolog, Cripto-3 (CR3), is almost identical, with the exception of six (out of 188) amino acids. Thus, until recently, no antibody could distinguish them. Here, we compare the immunostaining pattern for highly specific monoclonal antibodies against CR1 and CR3 in human samples of placenta, umbilical cord and fetal tissues. Immunoreactivity (IR) for both proteins was found in placenta, umbilical cord, fetal retina, testis, lung, esophagus, pancreas and kidney, but was absent in samples of fetal heart, brain, liver and thymus. Nevertheless, a very different staining pattern emerged for CR1 and CR3 in the positive tissues. For instance, (i) CR1-IR in the placenta, umbilical cord and fetal esophagus was preferently found in cell nuclei whereas CR3-IR was always cytoplasmic; (ii) In endothelial cells, CR1 staining was always stronger than CR3´s; (iii) In the retina and the testes, CR3-IR was stronger than CR1´s in Müller cells and fetal spermatogonias; (iv) The epithelium of the fetal bronchioles was very faint for CR1 and strongly positive for CR3; and (v) Both CR1 and CR3 stained the fetal pancreatic islets, but CR1-IR was stronger than CR3´s in the peripheral cells of the islets. All these morphological differences in staining pattern point to complex nuances in Cripto biology that were not evident previously, including the nuclear localization of CR1, and these need to be addressed through molecular and physiological approaches.

Keywords:  Cripto-1; Cripto-3; Fetal tissue; Placenta; Umbilical cord

DOI:  https://doi.org/10.1038/s41598-025-14201-x
Mol Metab. 2025 Aug 21. pii: S2212-8778(25)00143-7. [Epub ahead of print]100 102236

Placental mitochondrial calcium uniporter modulates offspring susceptibility to metabolic dysfunction.

Seokwon Jo, Grace Chung, Yu-Jin Youn, Charlotte Hunt, Ava Hill, Megan Beetch, Brian Akhaphong, Elizabeth A Morgan, Perrie F O'Tierney-Ginn, Sarah A Wernimont, Emilyn U Alejandro.

  Mitochondria are crucial for regulating metabolism, but their role in the placenta and how they may shape offspring metabolism and long-term health remains unclear, despite being commonly associated with pregnancy complications. To investigate this, we used a genetic model with placenta-specific deletion of the mitochondrial calcium uniporter (Pl-MCUKO) and assessed the metabolic trajectory of adult offspring. We found that, at baseline, female placental trophoblasts in wild-type animals exhibited higher respiration rates than males. MCU deletion impaired mitochondrial function specifically in female placentas and was accompanied by distinct changes in the metabolomic profiles of protein and lipid metabolism. Transcriptome analysis revealed reduced placental cellular growth pathways, consistent with smaller placentas and reduced embryonic body weights in Pl-MCUKO. Although in utero MCU deletion affected fetal growth, it was insufficient to cause permanent postnatal changes in body weight, as these deficits normalized in adulthood, with normal glucose homeostasis in Pl-MCUKO offspring. However, when challenged with a high-fat diet, Pl-MCUKO females exhibited reduced weight gain, improved glucose and insulin tolerance, smaller fat depots, and increased ambulatory activity compared to controls. This improved metabolic profile was associated with reduced pancreatic β-cell mass but preserved β-cell function. These findings provide direct evidence that placental mitochondrial function can influence the long-term metabolic health of female offspring by modulating key metabolic tissues.

Keywords:  DOHaD; Metabolic health; Mitochondria; Mitochondrial calcium uniporter; Obesity; Placenta; Sexual dimorphism

DOI:  https://doi.org/10.1016/j.molmet.2025.102236
Ecotoxicol Environ Saf. 2025 Aug 20. pii: S0147-6513(25)01242-4. [Epub ahead of print]303 118897

Maternal liver lipid dysregulation mediates fetal developmental impairments induced by gestational co-exposure to ozone and heat in C57BL/6J Mice.

Yuzhi Guo, Jiahao Zhang, Xinhang Jiang, Miao Li, Wenxue Li, Yahan Yang, Liping Chen, Xiumei Xing, Qing Wang, Yongmei Xiao, Daochuan Li, Chunyang Liao, Wen Chen, Shen Chen.

  Global warming has increased the frequency of simultaneous ozone and heat exposure, raising significant public health concerns. This study investigates the impacts of gestational exposure to ozone (1 ppm) and heat (34°C) under real-world conditions on fetal and placental development in C57BL/6 J mice, with a particular focus on the role of maternal hepatic lipid metabolism. Pregnant mice were exposed from gestational day (GD) 0 to GD17. Co-exposure to ozone and heat significantly reduced fetal birth weight and crown-rump length, and exacerbated adverse pregnancy outcomes, while exposure to ozone or heat alone did not significantly reduce fetal birth weight or crown-rump length. Placental development was impaired in the co-exposure group, particularly in the trophoblast zone. Ex vivo cell experiments revealed that plasma from co-exposed pregnant mice induced functional impairment in HTR-8/SVneo trophoblast cells. Maternal plasma analysis revealed a strong association between impaired placental and fetal development and abnormal lipid levels, which play a key role in causing developmental toxicity. Transcriptomic analysis of maternal liver tissue revealed that ozone exposure suppressed LDL and VLDL absorption, while heat promoted triglyceride synthesis. Co-exposure further exacerbated disruptions in hepatic lipid homeostasis. These findings highlight the detrimental effects of ozone and heat co-exposure on maternal and fetal health, suggesting that fetal impairments may be mediated by maternal hepatic lipid metabolism dysregulation.

Keywords:  Air pollution; Co-Exposure to ozone and heat; Development toxicity; Global warming; Lipid metabolism; Placenta

DOI:  https://doi.org/10.1016/j.ecoenv.2025.118897
Sci Adv. 2025 Aug 22. 11(34): eadw9753

High-resolution MRI reveals uteroplacental flow dynamics in a 3D-printed human placental cotyledon model.

Nirav Barapatre, David Frank, Franz Edler von Koch, Sven Grundmann, Hans-Georg Frank, Martin Bruschewski.

Doppler measurements of the uterine arteries are indirect measures of the uteroplacental blood flow. Given that the intervillous flow cannot be resolved by clinical imaging, theoretical models are used to study the flow dynamics in the intervillous space (IVS). We propose an experimental method to visualize the flow within the IVS of a single placental cotyledon postpartum. At first, a cotyledon is measured by micro-computed tomography imaging. The reconstructed volume is then used to create a near-realistic placenta model. Four variations of arterial inlets are designed to simulate both normal and abnormal flow patterns. A scaled version of the model is printed in three dimensions. Magnetic resonance imaging-based velocity measurements inside the printed model, which is perfused with a Newtonian fluid at two Reynolds numbers, revealed that the flow patterns are primarily influenced by the Reynolds number and the dilation of the arterial inlet. The spiralization of the arterial pathway had only a minimal impact.

DOI: https://doi.org/10.1126/sciadv.adw9753
J Physiol. 2025 Aug 26.

Metformin and insulin exacerbate one-carbon metabolism deficits in pregnant growth restricted rats and impacts the placenta, fetal liver and pancreas.

Dayna A Zimmerman, Jessica F Briffa, Dewei Kong, Sogand Gravina, Dara Daygon, Vinod Kumar, Karen M Moritz, Lillian Y Lim, Adrian K K Teo, Shiao-Yng Chan, Mary E Wlodek, James S M Cuffe.

  Fetal growth restriction increases the risk of metabolic conditions such as gestational diabetes mellitus (GDM). One-carbon metabolite and nutrient concentrations are dysregulated in GDM and influenced by antihyperglycaemic medications. However, it remains unclear whether disrupted one-carbon metabolism contributes to GDM onset in growth restricted offspring and whether antihyperglycaemic medications exacerbate this dysregulation. We investigated the effects of growth restriction and antihyperglycaemic treatment on one-carbon metabolism in pregnant rats and their fetuses. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was performed on embryonic day (E)18 in Wistar-Kyoto rats. Female F1 offspring were mated and Restricted dams received daily metformin, insulin or vehicle from E13. Although restricted dams did not develop metabolic dysfunction during pregnancy, they exhibited reduced one-carbon metabolism and a lower S-adenosylmethionine:S-adenosylhomocysteine (SAM:SAH) ratio, indicating reduced methylation capacity. These changes were exacerbated by both metformin and insulin. In F2 fetuses, plasma one-carbon metabolites were unaffected despite changes in expression of genes involved in one-carbon metabolism and DNA methylation in the placenta and fetal liver. F2 fetuses displayed an elevated pancreatic β-cell:islet ratio. Antihyperglycaemic medications altered the expression of multiple one-carbon metabolising enzymes in the maternal liver, the placenta junctional zone and the fetal liver. Metformin also increased pancreatic α-cell area. This study suggests disrupted one-carbon metabolism may underly programmed metabolic dysfunction and highlights the need for monitoring females born small. Both metformin and insulin induced similar physiological changes indicating that one is not safer than the other. Treatment decisions should consider potential impacts on long-term health. KEY POINTS: Being born growth restricted predisposes females to develop gestational diabetes (GDM) contributing to intergenerational transmission of disease. GDM is often treated with metformin or insulin. Disruptions to one-carbon metabolism caused by growth restriction, insulin or metformin may explain transmission of disease. This study investigated the effects of growth restriction, metformin and insulin on one-carbon metabolism and subsequent fetal outcomes in rats. Growth restriction impaired one-carbon metabolism in mothers resulting in a reduced S-adenosylmethionine:S-adenosylhomocysteine ratio, changes to expression of associated enzymes in the placenta and fetal liver and an increase in the fetal β-cell: pancreatic islet ratio. Metformin and insulin exacerbated deficits in one-carbon metabolism in growth restricted dams and their fetuses, whereas metformin also increased pancreatic α-cell area. This study demonstrates one-carbon metabolism as a key regulator of programmed metabolic disease in pregnancy and informs about the appropriate treatment of GDM in women born growth restricted.

Keywords:  B12; GDM; SAM:SAH ratio; beta cell; methionine

DOI:  https://doi.org/10.1113/JP289453
Medicine (Baltimore). 2025 Aug 22. 104(34): e44091

Study on the relationship between cesarean scar pregnancy and placental accreta using ultrasound monitoring.

Yiwen Chong, Aiqing Zhang, Yangyu Zhao.

  Placental accreta (PLA) has increased and is identified as a significant risk factor for PLA. Clinical approaches for treating cesarean scar pregnancy (CSP) varied, there is still controversy over whether CSP patients can continue pregnancy. This study aimed to use ultrasound monitoring to explore the connection between CSP and PLA. We retrospectively analyzed 24 patients diagnosed with CSP at the obstetrics and gynecology department of our hospital from 2015 to 2022. Patients were categorized into low-risk (CSPI and CSPII) and high-risk (CSPIII) groups based on ultrasound findings, and continuous ultrasound assessment was performed to gauge the severity of PLA. Pregnancy outcomes of both the groups were then compiled. Among the 24 patients, 22 were in the low-risk group, with 13 of them suspected of having placental increta or percreta prior to surgery. Ultimately, surgery confirmed 1 case without accreta, 2 cases of PLA, 7 cases of placental increta, and 3 cases of placental percreta. The ultrasound diagnostic sensitivity was 77% (10/13). The remaining 9 patients, initially suspected to have only PLA or none, were all confirmed during surgery, aligning with preoperative assessments. Ultrasound diagnostic specificity was 100%. Within the low-risk group, 20 patients had live births and 20 retained their uterus. In the high-risk group, 2 patients were preoperatively diagnosed with placenta percreta, both confirmed during surgery. Results indicated 1 termination at 16 weeks and another at 33 weeks with a live fetus, with both cases requiring uterine removal. The study suggests that invasive placenta might be an outcome of CSP, and ultrasound-based classification of CSP could forecast pregnancy outcomes, offering clinical direction for CSP patients opting to continue pregnancy.

Keywords:  cesarean scar pregnancy; cesarean section; connection; placental accreta; ultrasonics

DOI:  https://doi.org/10.1097/MD.0000000000044091
Brain Behav Immun. 2025 Aug 22. pii: S0889-1591(25)00326-5. [Epub ahead of print]130 106091

Maternal exposure to advanced oxidation protein products induces neurodevelopmental abnormalities in the offspring of mice.

Jiexing He, Qian Chen, Mingzheng Zhu, Yanxuan Xiao, Qiuyu Huang, Ailan Yin, Sijia Jiang, Pei Zhu, Tingyu Xiang, Jing Li, Zhongjun Li, Xinping Yang, Mei Zhong.

  Preeclampsia (PE) not only causes multi-organ damage to the mother but also exerts long-term effects on the development of the offspring. Prenatal exposure to PE has been demonstrated to result in deleterious neurodevelopment and behavioral abnormalities in the offspring. Our prior research has evidenced that advanced oxidation protein products (AOPPs), both the biomarker and promoter of oxidative stress, contribute to the pathogenesis of preeclampsia by inducing trophoblast dysfunction and systemic inflammation. However, it remains unclear whether offspring mice exposed to placental oxidative stress and dysfunction induced by AOPPs will exhibit abnormal neurodevelopment and the underlying mechanisms involved. In this study, we found pregnant mice injected with AOPPs and AOPPs-induced sEVs exhibited PE-like symptoms with elevated blood pressure and reduced fetal weight. Furthermore, behavioral detection showed that male and female adult offspring mice exposed to AOPPs prenatally displayed impairments in learning and memory. Placental and hippocampal transcriptome sequencing revealed that inflammation and immune response may play a pivotal role in this process. Our study provides valuable insights into the pathogenesis of adverse neurodevelopment and cognitive dysfunction in offspring exposed to placental oxidative stress induced by AOPPs and the search for effective preventive and therapeutic measures.

Keywords:  AOPPs; Cognitive dysfunction; Immune response; Inflammation; Offspring; Preeclampsia

DOI:  https://doi.org/10.1016/j.bbi.2025.106091
Placenta. 2025 Aug 21. pii: S0143-4004(25)00664-2. [Epub ahead of print]170 53-63

Impact of placenta-derived extracellular vesicles on endothelial function in supraphysiological maternal hypercholesterolemia.

Claudette Cantin, Jaime Gutiérrez, Reyna Peñailillo, Matthew W Kemp, Ling-Jun Li, Lara J Monteiro, Sebastián E Illanes, Andrea Leiva.

  Maternal physiological hypercholesterolemia (MPH; total cholesterol (TC)≤280 mg/dL) occurs during pregnancy to support fetal growth. When TC exceeds this threshold, this condition is recognized as maternal supraphysiological hypercholesterolemia (MSPH), which is associated with endothelial dysfunction in the maternal and fetoplacental vasculature. Placenta-derived extracellular vesicles (EVs), which mediate intercellular communication during pregnancy, may contribute to MSPH by affecting endothelial cells.
AIM: To characterize EVs isolated from MPH and MSPH term placentas and assess their effects on endothelial function in vitro.
METHODS: EVs from term MPH (n = 10) and MSPH (n = 10) placental explants were purified by differential ultracentrifugation. EVs were characterized by nanoparticle tracking analysis (NTA), transmission electron microscopy, and analysis of protein markers and content. MPH- and MSPH-EVs were labeled to assess their uptake by endothelial cells (HMEC-1). Their effects on angiogenesis, endothelial activation, endothelial nitric oxide (NO) synthase (eNOS) protein expression and NO levels were evaluated.
RESULTS: The concentration and morphology of placental EVs from MPH and MSPH were comparable. When HMEC-1 were exposed to placenta-derived EVs, MSPH-EVs increased angiogenic capacity. Intercellular adhesion molecule-1 (ICAM-1) expression was induced regardless of whether vesicles were originated from MPH or MSPH placentas. No differences were observed in eNOS expression or NO production when cells were incubated with placenta-derived EVs from both conditions.
CONCLUSION: In our in vitro model, MSPH placenta-derived EVs adjusted angiogenesis but did not alter eNOS expression or activity in endothelial cells. Our findings suggest that placental EVs could have a protective role in the NO-associated endothelial dysfunction described in MSPH pregnancies.

Keywords:  Cholesterol; Endothelial function; Extracellular vesicles; Placental explants; Pregnancy

DOI:  https://doi.org/10.1016/j.placenta.2025.08.329
Eur J Pharmacol. 2025 Aug 18. pii: S0014-2999(25)00830-1. [Epub ahead of print]1005 178076

Isorhynchophylline alleviates preeclampsia via PI3K/AKT/mTOR-mediated trophoblast oxidative stress inhibition.

Jie Wang, Xin'an Li, Yaru Zhu, Xier Zhang, Chunying Ye, Qinhong Zhuang, Zhiyin Wang, Dan Liu, Guangfeng Zhao.

  Preeclampsia (PE) is a severe pregnancy complication characterized by new-onset hypertension after 20 weeks of gestation, posing significant risks to maternal and fetal health. Placental ischemia-hypoxia-induced oxidative stress has been recognized as a central pathological mechanism underlying PE. Isorhynchophylline (IRN), a natural indole alkaloid, exhibits potent anti-inflammatory and antioxidant properties in multiple disease models. This study aims to systematically investigate the regulatory effects of IRN on oxidative stress in extravillous trophoblast (EVT) cells and elucidate its molecular mechanisms. In vitro experiments revealed that IRN markedly alleviated H2O2-induced oxidative stress injury in HTR-8 cells, primarily through the activation of the PI3K/AKT/mTOR signaling pathway. Specifically, IRN enhanced mitochondrial functions as evidenced by restoration of mitochondrial membrane potential, reduction in mitochondrial reactive oxygen species (ROS) levels, and an upregulation of mRNA expression of ATP6, CO1, and Cytb. Moreover, IRN inhibited the expression of apoptosis-related markers, underscoring its potent anti-apoptotic effects. In an L-NAME-induced PE rat model, IRN intervention effectively lowered maternal blood pressure, reduced proteinuria, and improved fetal survival rates. Collectively, this study reveals for the first time that IRN mitigates PE-associated pathological phenotypes by activating the PI3K/AKT/mTOR pathway, thereby ameliorating mitochondrial dysfunction and inhibiting oxidative stress and apoptosis in trophoblast cells. These findings provide critical theoretical support for the clinical translation of IRN as a potential therapeutic agent for PE.

Keywords:  Apoptosis; Isorhynchophylline; Oxidative stress; PI3K/AKT/mTOR; Preeclampsia

DOI:  https://doi.org/10.1016/j.ejphar.2025.178076
Anim Reprod Sci. 2025 Sep;pii: S0378-4320(25)00211-8. [Epub ahead of print]280 107972

The roles of NLRP3 and prostaglandin E2 in mediating bidirectional cross-talk between bovine endometrial fibroblasts and M2 macrophages.

Jiamin Zhao, Haixia Bao, Wenhui Bao, Zhiguo Gong, Yunhe Fu, Xiaoyu Hu, Yanqin Dong, Wei Mao, Shuang Feng, Shuangyi Zhang.

  The bovine endometrium undergoes dynamic structural and functional changes during the estrous cycle, driven by intricate cellular interactions and a complex network of chemokines, cytokines, and growth factors. Among the key cell types, endometrial stromal fibroblasts and M2 macrophages are essential for anti-inflammatory responses and tissue remodeling. However, their bidirectional cross-talk remains poorly characterized. In this study, we investigated fibroblast-macrophage interactions using a conditioned medium-based co-culture system. M2 macrophages were treated with myofibroblast-conditioned medium (MFbCM), while myofibroblasts were treated with M2 macrophage-conditioned medium (M2ø CM), allowing detailed analysis of reciprocal regulatory effects. M2ø CM significantly upregulated fibroblast expression of fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-9 (MMP-9), suggesting M2 macrophage-mediated modulation of fibroblast remodeling activity. Conversely, MFbCM enhanced interleukin-10 (IL-10) and arginase expression in M2 macrophages, supporting fibroblast-driven polarization. Notably, both conditioned media increased expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) in target cells. Inhibition of NLRP3 using the selective inhibitor MCC950 revealed that the NLRP3-prostaglandin E2 (PGE2) axis plays a pivotal role in mediating the cross-talk between these cell types. Collectively, our findings reveal a pivotal NLRP3-PGE2 signaling axis in the regulation of fibroblast-macrophage interactions, offering novel insights into the mechanisms underlying bovine endometrial homeostasis and remodeling.

Keywords:  Endometrium; Fibroblast; Macrophage; NLRP3; PGE(2)

DOI:  https://doi.org/10.1016/j.anireprosci.2025.107972
Adv Sci (Weinh). 2025 Aug 25. e02139

Lithium Exposure Causes Trophoblast Cuproptosis by Upregulating FOXO1/STEAP4 Axis in Unexplained Miscarriage.

Shuaishuai Xing, Yanbing Lin, Yi Sun, Xiaoping Yue, Qigang Fan, Jisheng Nie, Zhihong Zhang, Yajing Liu, Juntang Yang, Qingzheng Kang, Yanxin Wang, Haijun Yan, Chan Tian, Ying Chang, Huidong Zhang.

  Lithium (Li) batteries have been used worldwide, but few are recycled, thus, the waste Li has been widely spread into the environment and finally accumulated in human body. Cuproptosis is a newly reported Cu-dependent and programmed cell death form. The unclear pathogenesis of unexplained miscarriage (UM) largely restricts its clinical treatment and global human reproduction. In this study, a UM case-control study shows that Li levels in serum or villous tissues, the levels of cuproptosis in villous tissue, and UM are positively associated. Li-exposed mouse models further confirm that Li exposure causes placental cuproptosis to induce miscarriage. Mechanistically, Li exposure up-regulates FOXO1 expression levels and thus promotes FOXO1-mediated STEAP4 transcription, up-regulating STEAP4 levels. STEAP4 up-regulates intracellular Cu+ ion levels and causes cuproptosis, which further induces miscarriage. The cellular mechanisms are consistent with those in UM villous tissues and Li-exposed mouse placental tissues. Finally, treatment with TTM to suppress cuproptosis or the therapeutic down-regulation of FOXO1 or STEAP4 could efficiently suppress placental cuproptosis and alleviate mouse miscarriage in the Li-exposed mouse models. Collectively, this study not only discovers new healthy risks of Li exposure and novel pathogenesis of Li-induced unexplained miscarriage but also reveals new biological targets for treatment against miscarriage.

Keywords:  FOXO1; Li exposure; STEAP4; cuproptosis; trophoblast cells, unexplained miscarriage

DOI:  https://doi.org/10.1002/advs.202502139
Nat Commun. 2025 Aug 26. 16(1): 7539

Defining the cell and molecular origins of the primate ovarian reserve.

Sissy E Wamaitha, Ernesto J Rojas, Francesco Monticolo, Fei-Man Hsu, Enrique Sosa, Amanda M Mackie, Kiana Oyama, Maggie Custer, Melinda Murphy, Diana J Laird, Jian Shu, Jon D Hennebold, Amander T Clark.

The primate ovarian reserve is established during late fetal development and consists of quiescent primordial follicles in the ovarian cortex each composed of granulosa cells surrounding an oocyte in dictate. As late stages of fetal development are not routinely accessible using human tissues, the current study exploits the evolutionary proximity of the rhesus macaque to investigate follicle formation in primates. Like in humans, the rhesus prenatal ovary develops multiple types of pre-granulosa cells in time and space, with primordial follicles deriving from later emerging pre-granulosa subtypes. In addition, our work shows that activated medullary follicles recruit fetal theca cells to establish a two-cell system for sex-steroid hormone production prior to birth, providing a cell-based explanation for mini puberty.

DOI: https://doi.org/10.1038/s41467-025-62702-0
Placenta. 2025 Aug 10. pii: S0143-4004(25)00659-9. [Epub ahead of print]170 42-52

A call to standardize the nomenclature of human fetal membrane at the feto-maternal interface.

Fetal Membrane Society Consortium

  Despite being one of the largest intrauterine tissues in surface area, the fetal membrane that lines the intrauterine cavity is often overlooked, forgotten, or misidentified in clinical and basic science research. The feto-maternal interface is comprised of the fetal membrane (fetal component) and decidua parietalis (maternal component), which lines the intrauterine cavity and provides essential mechanical, immune, hormonal, and transport support to maintain pregnancy. Fetal membrane plays an important role in triggering and regulating labor via complex signaling cascades. Whilst several researchers have investigated the membranes world-wide, nomenclature remains inconsistent, leading to widespread ambiguity across inter-disciplinary disciplines involving science, bioengineering, and reproductive medicine. The ongoing confusion regarding its terminology, origins, structure, and function has resulted in several significant issues, including diagnostic errors and misrepresentation clinically, limitations and inaccuracies in scientific research, and regulatory and clinical miscommunication. Therefore, the Fetal Membrane Society (FMS) calls upon the field to standardize fetal membrane nomenclature, define its architecture, and summarize its region-specific differences to facilitate understanding of its biological role. Clear and consistent identification of the fetal membrane is essential in improving research accuracy, clinical outcomes, and effective communication within and between the medical and scientific communities.

Keywords:  Amniochorionic membrane; Amnion; Chorioamniotic membrane; Chorion; Decidua; Extracellular matrix; Gestational membrane; Nomenclature

DOI:  https://doi.org/10.1016/j.placenta.2025.08.324