bims-placeb 2025-08-17 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–08–17
fifteen papers selected by
Carlos M Guardia, National Institute of Health

Syncytin-1 deficiency impairs placental nutrient transport via PI3K/Akt/mTOR signaling.
Sex-specific effects of betamethasone on glucocorticoid and apoptotic signalling pathways in the sheep placenta.
ELABELA targets the MEK/ERK axis to enhance trophoblast invasion in early-onset preeclampsia.
Mouse trophectoderm stem cells generated with morula signalling inducers capture an early trophectoderm state.
Human Decidual RUNX1 Promotes Angiogenesis and Trophoblast Differentiation by Regulating Extracellular Vesicle Signaling.
F11r Deficiency-Mediated Disruption of Crosstalk Between Decidual Epithelial Cells and Macrophages is Detrimental to Female Pregnancy.
Pravastatin Mitigates Hypertension, Proteinuria, and Fetal Growth Restriction in an L-NG-Nitro Arginine Methyl Ester (L-NAME)-Induced Rat Model of Preeclampsia.
HIF-1A Expression in Placenta of Pregnancies Complicated with Preeclampsia and Fetal Growth Restriction.
Down-Regulation of Klotho/FGF23 by Low-Expressed VEGFR2 Inhibits the GH/IGF-1/PI3K/AKT Signaling Pathway Inducing Intrauterine Growth Restriction in Rats.
Autophagy in PE: Dispute, Role and Potential Target.
Single-cell RNA sequencing reveals systemic and placental immune landscape in preeclampsia.
Association Between Maternal Dietary Fatty Acid Intake and Fatty Acid Composition of Placental Phospholipids.
Juxtaposition of human pluripotent stem cells with amnion-like cells is sufficient to trigger primitive streak formation.
Pre-pregnancy treatment of semaglutide improves high-fat-diet-induced placental and fetal hypothalamic alterations in a sex-specific manner in rats†.
Association between placental epigenetic age acceleration and early postnatal growth patterns.

J Nutr Biochem. 2025 Aug 08. pii: S0955-2863(25)00222-0. [Epub ahead of print] 110060

Syncytin-1 deficiency impairs placental nutrient transport via PI3K/Akt/mTOR signaling.

Xue-Ling Chen, Xing-Xing Gong, Zhe-Lei Xiong, Da Zhou, Ju Yang, Hai-Feng Zhang, Yun-Shan Xue, Ya-Nan Wang, Hai-Bin Chen.

  The placenta, a vital organ bridging the fetus and mother, governs nutrient exchange. Syncytin-1, an endogenous retroviral envelope protein specifically expressed in placental trophoblasts, is diminished in preeclampsia and fetal growth restriction. This study aimed to investigate the effects of low syncytin-1 expression on placental transport of amino acids, fatty acids and cholesterol, and its implications for fetal and placental development, contributing to fetal growth restriction pathogenesis. Pregnant C57BL/6J mice received tamoxifen-induced conditional syncytin-a gene knockout at embryonic day 11.5, with controls receiving sunflower oil. Placentas and fetuses were collected analyzed for transport efficiency. Parallelly, siRNA-mediacted syncytin-1 knockdown in BeWo cells assessed trophoblast dysfunction. Nutritional content and the expression of relevant transporters for amino acids, fatty acids and cholesterol, were all evaluated in vivo and in vitro. Using conditionally induced syncytin-a gene knockout mouse models, we found that syncytin-A deficiency resulted in decreased fetal and placental weights, reduced placental labyrinthine layer area and syncytiotrophoblast layer structural defects. Placental amino acid (SNAT2, LAT1), fatty acid (CD36, FABP4, FATP4), and cholesterol (LDLR, SR-B1) transporters were dysregulated, aligning with altered nutrient levels in knockout mice. Similar dysfunction in amino acid and fatty acid transport was observed in syncytin-1-silenced BeWo cells. Mechanistically, syncytin-1 deficiency suppressed the PI3K/Akt/mTOR signaling, a key pathway modulating nutrient sensing and transporter activity. Our experiments demonstrate that syncytin-1 regulates the transport of amino acids, fatty acids and cholesterol in placental trophoblastic cells, providing new insights into the pathological role of decreased syncytin-1 in pregnancy-related disorders, particularly in fetal growth restriction.

Keywords:  Amino acids; Cholesterol; Fatty acids; Fetal growth restriction; Maternal-fetal interface; Transporters

DOI:  https://doi.org/10.1016/j.jnutbio.2025.110060
J Physiol. 2025 Aug 10.

Sex-specific effects of betamethasone on glucocorticoid and apoptotic signalling pathways in the sheep placenta.

Ashley S Meakin, Mitchell C Lock, Stacey L Holman, Joshua L Robinson, Vicki L Clifton, Claire T Roberts, Michael D Wiese, Kathryn L Gatford, Janna L Morrison.

  Antenatal corticosteroid therapy (ACS, e.g. betamethasone) is standard clinical care for pregnancies at risk of preterm delivery to reduce the incidence of neonatal lung disease and death. Variable and sex-specific impacts of ACS on the placenta have been reported and may reflect differing expression profiles of glucocorticoid receptor (GR) isoforms. We therefore examined placental GR isoforms and molecular and structural responses to betamethasone in the clinically relevant sheep pregnancy. Pregnant Merino ewes at 138 days of gestation (term = 150 days) received i.m. injections of saline or 11.6 mg of betamethasone 48 and 24 h prior to Caesarean section delivery of lambs and tissue collection. Placental glucocorticoid concentrations were measured using liquid chromatography-tandem mass spectrometry. Markers of GR signalling and placental development and function were measured using histology, western blotting and quantitative real-time PCR. Betamethasone increased diffusion barrier thickness in female placentae only and reduced placental cortisol concentrations in both sexes. Betamethasone increased cytoplasmic GRαC, GR-P and GRαD isoforms in female placentae only; neither treatment nor sex impacted nuclear GR isoform expression. Expression of angiogenic genes was higher, whereas that of growth-promoting genes was lower, in betamethasone-exposed placentae, independent of sex. Similarly, expression of endoplasmic reticulum stress genes was lower in betamethasone-exposed than control placentae, whereas those involved in oxidative stress and apoptosis were higher, particularly in females. Betamethasone induced molecular changes in the placenta within 48 h of exposure. The apoptotic response was heightened in female placentae, possibly driven by higher expression of specific GR isoforms, which contributes to a greater risk of ACS-induced placental insufficiency. KEY POINTS: Betamethasone treatment for pregnancies at risk of preterm delivery not only reduces the risk of neonatal death, but also acts on glucocorticoid receptors (GR) in the placenta, inducing sex-specific changes that may impact function and fetal growth. In this study, we explored sex-specific placental molecular responses to betamethasone in the clinically relevant sheep pregnancy. Betamethasone increased markers of angiogenesis and decreased markers of growth and proliferation in placentae of both sexes. In females only, betamethasone increased expression of the pro-apoptotic GR isoform, GRαC, which coincided with an enriched pro-apoptotic response and an increased placental diffusion barrier thickness, indicative of placental insufficiency. Our findings highlight that betamethasone induces several molecular changes in the sheep placenta within 48 h of exposure and supports previous sex-specific findings in other species, indicative of a conserved female response.

Keywords:  betamethasone; fetus; glucocorticoid receptor; placenta; sex differences; sheep

DOI:  https://doi.org/10.1113/JP289044
Sci Rep. 2025 Aug 11. 15(1): 29357

ELABELA targets the MEK/ERK axis to enhance trophoblast invasion in early-onset preeclampsia.

Lijing Wang, Xue Wang, Ningning He, Lin Yang, Yang Zou, Zhanping Weng, Li Guo.

  The study aimed to investigate the role of ELABELA (ELA) in early-onset preeclampsia (EOPE), a condition characterized by dysregulated trophoblast invasivity leading to inadequate remodeling of uterine spiral arteries and shallow placental implantation. Using immunohistochemical staining, quantitative PCR (qPCR), and Western immunoblotting, placental ELA levels were evaluated in tissue samples. The invasive and migratory potential of trophoblastic cells in vitro was assessed using a Transwell system. Additionally, key kinases associated with the MEK (Mitogen-activated protein kinase kinase)/ERK (Extracellular-regulated protein kinases) signaling pathway in trophoblasts were examined through Western immunoblotting. The findings revealed that ELA was present in both cytotrophoblasts and syncytiotrophoblasts of the placenta. There were no significant differences in ELA mRNA or protein levels between normal pregnancies and preterm births; however, ELA levels were significantly lower in the EOPE group compared to the normal pregnancy group. Silencing of ELA in HTR-8/SVneo trophoblastic cells notably impaired their invasive and migratory abilities, accompanied by reduced levels of key kinases linked to the MEK/ERK pathway. Conversely, overexpression of ELA enhanced these cellular functions. The repression of MEK also inhibited HTR-8/SVneo cell migration and invasion while decreasing related kinase levels. The study concluded that ELA plays a critical role in promoting trophoblastic cell migration and invasion through the activation of the MEK/ERK signaling pathway. The observed decrease in ELA levels in EOPE suggests its potential involvement in the pathogenesis of this condition. These findings underscore the potential for novel therapeutic strategies targeting ELA and the MEK/ERK signaling pathway to address early-onset preeclampsia, a condition with significant maternal and fetal health implications. Further research into ELA's mechanisms and its regulatory pathways may offer insights for effective interventions.

Keywords:  ERK; Invasion; MEK; Placenta; Preeclampsia

DOI:  https://doi.org/10.1038/s41598-025-15533-4
Nat Cell Biol. 2025 Aug 14.

Mouse trophectoderm stem cells generated with morula signalling inducers capture an early trophectoderm state.

Yake Gao, Mingying Li, Wei Guan, Wei Guo, Shu Wei, Fang Yan, Wenrui Han, Xueting Zhang, Tong Yin, Yunkun Dang, Huanhuan Li, José C R Silva, Jian Zhang.

The first embryonic cell differentiation in mice segregates the trophectoderm and the inner cell mass. Successful derivation of mouse trophoblast stem cells (TSCs) and trophectoderm stem cells (TESCs) has greatly facilitated the understanding of trophoblast differentiation. However, our understanding of early trophectoderm differentiation remains incomplete. Here we report the establishment of a morula-derived trophectoderm stem cell (MTSC) line from 32-cell embryos that show enhanced and uniform trophoblast core gene expression. Importantly, distinct from TSCs or TESCs, MTSCs represent a much earlier trophectoderm state (E3.5) than that of TSCs (E5.5-6.5) and TESCs (E4.5-5.5). MTSCs can robustly integrate into all cell lineages of the placenta. Moreover, MTSCs can self-organize to form placenta organoids. When partially differentiated MTSCs aggregate with embryonic stem cells, they form blastoids that efficiently implant uteruses. Finally, MSTC medium can efficiently convert embryonic stem cells, TSCs and TESCs into MTSC-like cells. Thus, MTSCs capture an early blastocyst trophectoderm state and provide a research model for studying trophoblast development.

DOI: https://doi.org/10.1038/s41556-025-01732-8
bioRxiv. 2025 Jul 14. pii: 2025.07.09.663949. [Epub ahead of print]

Human Decidual RUNX1 Promotes Angiogenesis and Trophoblast Differentiation by Regulating Extracellular Vesicle Signaling.

Jacob R Beal, Xiangning Song, Athilakshmi Kannan, Indrani C Bagchi, Milan K Bagchi.

During early pregnancy, human endometrial stromal cells differentiate into secretory decidual cells via a process regulated by ovarian steroid hormones. Decidual cells play a crucial role by secreting various factors that support essential events in forming a functional placenta, including uterine angiogenesis and the differentiation and development of trophoblasts. We previously reported that the conditional ablation of the transcription factor RUNX1 in the mouse uterus leads to subfertility due to insufficient maternal angiogenesis and impaired trophoblast differentiation. In this study, we examined the role of RUNX1 in facilitating communication mechanisms among human decidual cells and other cell types present in the pregnant uterus. We demonstrated that RUNX1 regulates the conserved HIF2α-RAB27B pathway in primary human endometrial stromal cells (HESC) during decidualization, which promotes the secretion of extracellular vesicles (EVs) by these cells. Consequently, the depletion of RUNX1 in HESC led to reduced EV secretion. Mass spectrometry identified several cargo proteins in decidual EVs, including ANGPTL2 and IGF2, which could regulate angiogenesis or trophoblast differentiation. We found that RUNX1 directly regulates their expression, resulting in partial changes to these cargoes when it is absent. We observed that delivering EVs lacking ANGPTL2 or IGF2 to human endothelial cells significantly decreased the formation of vascular networks compared to introducing control EVs carrying these factors. Furthermore, adding IGF2-depleted EVs to human trophoblast cells inhibited their differentiation into the extravillous trophoblast lineage. These findings collectively highlight the crucial role of decidual RUNX1 in promoting essential cell-cell interactions for angiogenesis and trophoblast differentiation during placenta formation.

DOI: https://doi.org/10.1101/2025.07.09.663949
FASEB J. 2025 Aug 31. 39(16): e70887

F11r Deficiency-Mediated Disruption of Crosstalk Between Decidual Epithelial Cells and Macrophages is Detrimental to Female Pregnancy.

Xiangming Tian, Shuai Li, Wenhui Zhou.

  Complex intercellular interactions occur at the maternal-fetal interface during pregnancy. Human uterine decidual epithelial cells play a crucial role in maternal immune tolerance and placental development. Macrophages are major cells at the maternal-fetal interface regulating tissue remodeling and immune response. The role of F11 receptor (F11r) in regulating the biological functions of epithelial cells and immune cells is particularly prominent. Thus, this study was to determine the mechanism by which F11r mediates the interaction of decidual epithelial cells with macrophages. F11r knockout (KO) mice were obtained using CRISPR/Cas9 technology. On Day 12.5 of gestation, single-cell RNA sequencing (scRNA-seq) was performed and reproduction was recorded at the uterine implantation sites in the WT and the KO groups, respectively. F11r KO mice have increased embryo resorption after natural mating. Decidual epithelial cells were classified into three subtypes based on scRNA-seq data: Epi1, Epi2, and Epi3. In F11r KO mice, Epi2, located at an early stage of differentiation, prematurely differentiates to an immunoregulatory cell fate and participates in the regulation of the immune response. In addition, the interaction between epithelial cell subpopulations and macrophage subpopulations was disturbed in the KO group. Specifically, Csf1-Csf1r interactions between Epi1 and C1q+ macrophages were reduced in the F11r KO group. However, Spp1-cd44 interactions were enhanced between subclusters of decidual epithelial cells (Epi1, 2, and 3) and macrophage subclusters (C1q+, Cxcl10+, and Spp1+ macrophages). In conclusion, we elucidated the immunomodulatory mechanisms by which F11r mediates decidual epithelial-macrophage interactions at the maternal-fetal interface from cellular and molecular perspectives.

Keywords:  F11r; epithelial cells; macrophages; maternal–fetal; pregnancy

DOI:  https://doi.org/10.1096/fj.202403397RR
Cureus. 2025 Jul;17(7): e87663

Pravastatin Mitigates Hypertension, Proteinuria, and Fetal Growth Restriction in an L-NG-Nitro Arginine Methyl Ester (L-NAME)-Induced Rat Model of Preeclampsia.

Hind A Elamin, Amal M Saeed, Magbola M Sharif, AhmedElharith ElMahdi.

   BACKGROUND: Preeclampsia is a common pregnancy complication characterized by the abrupt onset of hypertension and proteinuria occurring after the midpoint of gestation. If left untreated, it can severely threaten the health of both the mother and the infant. This study aimed to evaluate the potential therapeutic effects of pravastatin in a rat model of preeclampsia. The study examined the efficacy of its ability to modulate key clinical and biochemical parameters, including blood pressure, proteinuria, nitric oxide concentrations, and the weights of the fetus and placenta.
METHODS: A total of 21 pregnant Wistar rats were divided into three groups: (1) a normal pregnant group; (2) a preeclamptic group (induced by a subcutaneous injection of L-NG-Nitro arginine methyl ester (L-NAME)); and (3) a preeclamptic group treated with pravastatin. The effects of pravastatin were evaluated on blood pressure and proteinuria, as well as its impact on endothelial function (serum nitric oxide) and birth outcomes (fetal and placental weights).
RESULTS: The results showed that L-NAME successfully created a preeclampsia model, which was marked by a notable rise in blood pressure and protein levels in urine, as well as a decrease in the weights of the fetus and placenta. The L-NAME group had reduced serum levels of nitric oxide, but the difference was not statistically significant. Conversely, pravastatin therapy entirely mitigated the detrimental effects of L-NAME. It resulted in significant reductions in blood pressure and proteinuria, along with increases in fetal and placental weights, plus an insignificant increase in nitric oxide levels.
CONCLUSION: Pravastatin demonstrates significant promise as a therapeutic intervention that can mitigate pathophysiological changes of an L-NAME-induced preeclampsia, such as hypertension, proteinuria, and diminished fetal and placental weights. Although the increase in serum nitric oxide levels did not reach statistical significance, the observed upward trend may reflect a partial restoration of endothelial function, which is typically impaired in this model. This suggests that pravastatin may exert a protective effect on the endothelium, at least in part, through modulation of NO pathways. Additional research, including clinical trials, is necessary to ascertain safety, optimal dosage, and long-term effects.

Keywords:  hypertension; l-name; pravastatin; preeclampsia; rat model

DOI:  https://doi.org/10.7759/cureus.87663
Diagnostics (Basel). 2025 Jul 22. pii: 1843. [Epub ahead of print]15(15):

HIF-1A Expression in Placenta of Pregnancies Complicated with Preeclampsia and Fetal Growth Restriction.

Choo Xiang Tan, Hannah Xin Yi Yeoh, Nur Aqilah Amani Mohamad Tazilan, Jonathan Wei De Tan, Nurwardah Alfian, Haliza Zakaria, Shamsul Azhar Shah, Rahana Abd Rahman, Yin Ping Wong, Geok Chin Tan.

  Background: The worldwide prevalence of FGR is about 13% and can lead to various adverse perinatal outcomes, including preterm birth, stillbirth, and neonatal mortality. Hypoxia-Inducible Factor-1 (HIF-1) is an important regulator of oxygen homeostasis in humans and is crucial for placental development. The aim of this study is to determine the pattern of HIF-1A expression in placenta, and to correlate its association with preeclampsia, fetal growth restriction and adverse perinatal outcomes. Methods: This study comprised a total of 158 cases with 42 cases of mother having babies with fetal growth restriction (FGR), 39 cases of mother with preeclampsia (PE), 35 cases of mother with preeclampsia and fetal growth restriction and 42 controls. The expression of HIF-1A was evaluated in various placental cell types, including cytotrophoblasts, syncytiotrophoblasts, fetal endothelial cells, maternal endothelial cells, and decidual cells. Results: The expression of HIF-1A in placental decidual cells of mother with FGR (21/42, 50%, p < 0.0001), PE (25/39, 64.1%, p < 0.0001) and PE with FGR (12/35, 34.3%, p < 0.0001) were significantly increased compared to controls (1/42). Intriguingly, HIF-1A expression was significantly reduced in the placental cytotrophoblasts and syncytiotrophoblasts of mother with PE and FGR (2/35, 5.7%) compared to PE alone (11/39, 28.2%) (p = 0.0142). Conclusions: We found that increased HIF-1A expression in the nuclei of decidual cells was observed in the mothers of babies with FGR, both with and without PE. While HIF-1A expression in the cytotrophoblasts and syncytiotrophoblasts was significantly reduced between mothers with PE and mothers with PE and FGR. This suggests HIF-1A expression might play a role in the pathogenesis of FGR.

Keywords:  HIF-1A; fetal growth restriction; hypertension; placenta; pregnancy

DOI:  https://doi.org/10.3390/diagnostics15151843
Am J Reprod Immunol. 2025 Aug;94(2): e70110

Down-Regulation of Klotho/FGF23 by Low-Expressed VEGFR2 Inhibits the GH/IGF-1/PI3K/AKT Signaling Pathway Inducing Intrauterine Growth Restriction in Rats.

Li Zhang, Linlu Zheng, Yaying Cheng.

   PROBLEM: Intrauterine growth restriction (IUGR) is a pregnancy complication characterized by failure of the fetus to reach its genetic growth potential. We established the association Klotho, fibroblast growth factor 23 (FGF23), and vascular endothelial growth factor receptor 2 (VEGFR2) with IUGR for the first time, hoping to provide new insights for its diagnosis and treatment.
METHOD OF STUDY: Sixteen pregnant rats were randomly divided into a low-protein diet group (IUGR group) and a control group. Placental tissues were sampled to detect Klotho, FGF23, VEGFR2 mRNA, and protein expression in placental tissues of pregnant rats using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Bioinformatics methods were also used to predict the signaling pathways involved in Klotho, FGF23, and VEGFR2.
RESULTS: The weight and crown-rump length of fetal rats in the IUGR group were significantly lower than those in the control group (p < 0.05). The expression levels of Klotho, FGF23, and VEGFR2 in IUGR group placental tissues were significantly lower than those in the control group (p < 0.05). Meanwhile, based on bioinformatics, it was predicted that VEGFR2 might affect the activation of the PI3K/AKT signaling pathway by growth hormone (GH)/insulin-like growth factor-1(IGF-1) through Klotho/FGF23 axis inhibition.
CONCLUSIONS: IUGR caused by a low protein diet reduced birth weight and crown-rump length and low expression of Klotho, FGF23, and VEGFR2 in placental tissues, which may inhibit fetal growth through the VEGFR2-Klotho-FGF23-GH-IGF-1-PI3K-AKT signaling axis.

Keywords:  FGF23; Klotho; PI3K/AKT; VEGFR2; intrauterine growth restriction (IUGR)

DOI:  https://doi.org/10.1111/aji.70110
Cell Prolif. 2025 Aug 12. e70102

Autophagy in PE: Dispute, Role and Potential Target.

Miao Xu, Qi Wang, Fang Wang, Li Kang, Huijing Ma, Mengnan Li, Zhuanghui Hao, Zhengrui Li, Ji'an Liu, Xufeng Huang, Hengrui Liu, Shouxin Wei, Hailan Yang.

  PE is a life-threatening pregnancy disorder that can lead to adverse events for both the fetus and the mother. Autophagy is a cellular process involved in cellular renovation and maintaining homeostasis. There is a growing body of evidence suggesting that autophagy in trophoblasts plays a significant role in the development and pathogenesis of PE. However, the exact mechanisms are not yet fully understood. This article provides an overview of recent evidence regarding the role of autophagy in trophoblast invasion, vascular remodelling, inflammation, immune response, and maternal factors in the context of PE. It is believed that impaired or excessive autophagy can contribute to placental ischaemia and hypoxia, thereby exacerbating PE progression. Therefore, understanding the molecular mechanisms that regulate autophagy in PE is crucial for the development of targeted therapeutic interventions in the future.

Keywords:  PE; autophagy; immune response; inflammation; placental development; trophoblast invasion; vascular remodelling

DOI:  https://doi.org/10.1111/cpr.70102
Placenta. 2025 Aug 08. pii: S0143-4004(25)00660-5. [Epub ahead of print]170 26-35

Single-cell RNA sequencing reveals systemic and placental immune landscape in preeclampsia.

Xingyu Wei, Kun Li, Shijing Lu, Fenxia Li, Min Zhang, Yuming Liu, Shi Weng, Yuxuan Yang, Zhenjie Tang, Xiaowei Qiu, Liping Huang, Zhiwei Guo, Chunling Li, Fang Yang, Chao Sheng, Xuexi Yang.

   BACKGROUND: Preeclampsia (PE) is one of the most severe complications of pregnancy characterized by systemic and placental inflammation. Recently, studies have characterized the immune landscape in preeclampsia at single-cell level, further investigation is needed to understand spatial differences across placental compartments and disease subtypes.
METHODS: We utilized single-cell RNA sequencing to profile the immune cells of peripheral blood and placenta compartments from early- and late-onset PE (EPE/LPE), as well as normotensive controls.
RESULTS: Our data revealed significant differences in immune cell composition and proportions across peripheral blood and various placenta compartments. Additionally, we found that PE patients exhibited distinct immune cell distributions and gene expression profiles compared to normotensive controls. Moreover, the frequencies and functional states of immunocytes varied between EPE and LPE patients. When subclustered major immune cells, we discovered a reduction of regulatory T cells in peripheral blood of PE patients. Hofbauer cells were almost absent in placental villi of EPE pregnancies. Furthermore, we identified a novel subset of CD8+ naïve T cells in peripheral blood, exclusively present in EPE, and a new subset of dNK4 cells in basal plate, which were significantly decreased in EPE.
CONCLUSIONS: Our study offers a comprehensive single-cell immune profile of peripheral blood and placental compartments, reinforcing the heightened pro-inflammatory environment observed in PE pregnancies. Furthermore, our analysis reveals distinct immunological differences between EPE and LPE. These findings provide potential insights for early prediction and therapeutic interventions in these disordered pregnancies.

Keywords:  Immune dysregulation; Immune landscape; Preeclampsia; Pregnancy; Pro-inflammation; Single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.placenta.2025.08.325
Nutrients. 2025 Jul 22. pii: 2394. [Epub ahead of print]17(15):

Association Between Maternal Dietary Fatty Acid Intake and Fatty Acid Composition of Placental Phospholipids.

Liliana Ladino, Hans Demmelmair, María Teresa Segura, Mireia Escudero-Marin, Veit Grote, Berthold Koletzko, Cristina Campoy.

  Background: Fatty acid status during the perinatal period is important for optimal offspring growth and development. Objectives: We aimed to test the association between maternal fatty acid (FA) intake during the third trimester of pregnancy and the FA composition of placental phospholipids, a marker of maternal fatty acid status. Methods: This cohort study was performed on 54 mothers participating in the PREOBE study. Maternal dietary intake was assessed with prospective 7-day food diaries at 34 weeks of gestation. Placenta samples were collected immediately after delivery and phospholipid FA was quantified with established methods. Data were analyzed with Pearson correlations and linear regression models, with adjustment for confounding factors. Results: Total energy intake was 2019 ± 527 kcal/d (mean ± SD) and total fat intake of the mothers was 87 ± 35 g/day. Myristic, stearic, oleic, and α-linolenic acid intakes were modestly correlated with placental percentages, with r-values ≤ 0.33. Only docosahexaenoic (DHA) acid intake (%-energy, %-fat, and g/d) showed r-values > 0.4 for the correlation with placenta phospholipids. Intake of other fatty acids, including arachidonic acid, was not associated with the placenta percentage. Linear regression models considering confounders showed only dietary DHA intake significant associations. Total fat intake did not interfere with the association of DHA intake with placental incorporation. Conclusions: DHA and arachidonic acid are enriched in the placenta, but only placental DHA content seems modifiable by maternal dietary DHA intake.

Keywords:  dietary intake; docosahexaenoic acid; fatty acids; placenta; pregnancy

DOI:  https://doi.org/10.3390/nu17152394
bioRxiv. 2025 Jul 14. pii: 2025.07.11.664380. [Epub ahead of print]

Juxtaposition of human pluripotent stem cells with amnion-like cells is sufficient to trigger primitive streak formation.

Xiangyu Kong, Anastasiia Nemashkalo, M Cecilia Guerra, Miguel Angel Ortiz-Salazar, Elena Camacho-Aguilar, Aryeh Warmflash.

Studies in the mouse have established that communication between the trophectoderm and the epiblast is crucial for initiating gastrulation. In the primate embryo, the amnion rather than the trophectoderm is directly juxtaposed to the epiblast and may play this role. To model the interactions between the amnion and epiblast, we differentiated human pluripotent stem cells (hPSCs) to amnion-like cells (AMLCs) and juxtaposed them in a controlled manner with undifferentiated hPSCs, which represent the epiblast. We found that juxtaposition between these cell types is sufficient to initiate a range of cell behaviors associated with gastrulation including organized differentiation to primitive streak and downstream mesendodermal cell fates and directed cell migration out of the primitive streak region. Performing knockout experiments specifically in either the epiblast or amnion compartment revealed intricate crosstalk that is required to properly initiate gastrulation. In particularly, using knockouts of NODAL we show that Nodal signaling in both the amnion and epiblast is required for gastrulation patterning. Finally, we show that inductive ability is a transient property acquired during amnion differentiation, and that cells that differentiate from this inductive state acquire an extraembryonic mesenchyme identity. This study establishes a system to study epiblast-amnion communication and shows that this communication is sufficient to initiate gastrulation in the epiblast.

DOI: https://doi.org/10.1101/2025.07.11.664380
Biol Reprod. 2025 Aug 06. pii: ioaf178. [Epub ahead of print]

Pre-pregnancy treatment of semaglutide improves high-fat-diet-induced placental and fetal hypothalamic alterations in a sex-specific manner in rats†.

Jingyue Wang, Ning Wang, Haonan Guo, Xinyi Niu, Shuyuan Hu, Xingyan Pan, Mingxi Wang, Duowen Zhang, Lin Song, Bo Sun.

   INTRODUCTION: The impact of obesity on pregnancy outcomes and offspring health has received increasing attention. Semaglutide have been shown to have significant effects on weight management. This study aims to evaluate whether Pre-pregnancy Semaglutide Intervention (PpSI) improves maternal metabolic disorders before and during pregnancy, affects placental function and fetal hypothalamic neuropeptide expression during late-gestation and its underlying mechanisms.
METHODS: In this study, female SD rats were divided into three groups: control diet (CHOW), high-fat diet (HFD), and high-fat diet with pre-pregnancy semaglutide intervention (PpSI). After mating with males, maternal metabolic outcomes, placental morphology, nutrient transport, and fetal hypothalamic gene expression were assessed on gestational day 20.
RESULTS: PpSI significantly reduced pre-pregnancy weight gain and gestational weight gain of the dams compared with the HFD group. It also reduced maternal blood lipid levels before and during pregnancy. In male placentas of HFD group, the thickness of the labyrinth was decreased, the mRNA expression of amino acid transporters was upregulated, and the phosphorylation of STAT3 and ERK1/2 was increased, while PpSI normalized these changes. In male fetuses, maternal HFD decreased plasma leptin levels, reduced hypothalamic STAT3 signaling and appetite-related gene expression, while pre-pregnancy semaglutide intervention improved these changes. Compared with males, maternal HFD had less effect on placenta or fetal hypothalamic leptin signaling in females.
CONCLUSION: PpSI improves maternal lipid metabolism before and during pregnancy, and improves placental nutritional transport and fetal hypothalamic appetite-related gene expression, which provides a potential strategy for pre-pregnancy intervention in obese women.

Keywords:  Hypothalamus; Obesity; Placenta; Semaglutide; Sex difference

DOI:  https://doi.org/10.1093/biolre/ioaf178
Sci Rep. 2025 Aug 12. 15(1): 29597

Association between placental epigenetic age acceleration and early postnatal growth patterns.

Priyadarshni Patel, Angela Shen, Cynthia Perez, Elizabeth M Kennedy, Kartik Shankar, Kevin J Pearson, Aline Andres, Todd M Everson.

  Placental gestational age acceleration (GAA) is the difference between the actual gestational age (GA) at birth and their estimated epigenetic gestational age (EGA), which is calculated from placental DNA methylation. Understanding the role of placental GAA in postnatal growth trajectories is crucial for early identification of infants at risk of altered growth patterns and associated long-term health outcomes. The objective of this study is to investigate the association between placental GAA and longitudinal growth trajectories specifically weight, height, fat mass, and lean mass gain in early childhood. This study uses placental DNA methylation at birth to calculate epigenetic GAA and longitudinal measures of weight, height, fat mass, and lean mass to generate growth trajectory characteristics. Higher placental GAA was significantly associated with slower weight gain (95% CI [- 0.03, - 0.001]) and fat mass (95% CI [- 0.08, - 0.02]) gain, as well as reduced average fat mass (95% CI [add this]) over the follow-up period. However, no significant associations were found between GAA and height or lean mass gain. Placental GAA can give early insights into altered postnatal growth trajectories, particularly for weight and fat mass where an increase in GAA is associated with decreased weight and fatmass gain over time while we observed no effect on height and lean mass. Understanding these associations offers insights into early developmental patterns and long-term health outcomes in children, highlighting the importance of perinatal factors in shaping growth trajectories in early childhood.

Keywords:  CPC clock; Epigenetic age; Epigenomics; Gestational age; Gestational age acceleration; Growth; Metabolic health; Placenta

DOI:  https://doi.org/10.1038/s41598-025-13951-y