bims-placeb Biomed News
on Placental cell biology
Issue of 2025–12–28
fifteen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences
  1. Modeling human embryo implantation in vitro.
  2. Toxoplasma gondii infection inhibits invasion and migration of human extravillous trophoblasts through dysregulation of FOXO1- and FOXO3a-dependent and -independent mechanisms.
  3. Liraglutide-Driven Weight Loss Modulates Placental Remodeling in Obese Pregnancies in Mice.
  4. Extracellular adenosine mediated activation of the A2B adenosine receptor increases human syncytiotrophoblast formation.
  5. Distinct transcriptional and epigenomic programs define Hofbauer cells in term placenta.
  6. HIF-2α / HILPDA promotes ferroptosis sensitivity in placenta trophoblast cells of early-onset preeclampsia.
  7. Sex-specific associations between hypertensive disorders in pregnancy and fetal and placental weight.
  8. Sex-specific placental transcriptome alterations in late-onset preeclampsia reveal male-biased immune and metabolic dysregulation.
  9. Comparative analysis of lipid metabolism in trophoblast subpopulations in preeclampsia and in vitro hypoxia model.
  10. Research Progress on RNA m6A Methylation Modification Mediating Placental Disorders Induced by Maternal Stress.
  11. A 3D in vitro model for studying human implantation and implantation failure.
  12. 3D post-implantation co-culture of human embryo and endometrium.
  13. Fetoplacental circadian rhythms develop and then synchronize to the mother in utero.
  14. Isolation Strategy Matters: How Tissue Processing Shapes the Composition of Placental Extracellular Vesicles.
  15. Announcing the Lancet Commission on Maternal and Newborn Health.
  1. Cell. 2025 Dec 23. pii: S0092-8674(25)01232-2. [Epub ahead of print]
    Modeling human embryo implantation in vitro.
    Matteo A Molè, Sarah Elderkin, Irene Zorzan, Christopher Penfold, Nicole Horsley, Alexandra Pokhilko, Max Polanek, Andrea Palomar, Molika Sinha, Yang Wang, Alicia Quiñonero, Charalampos Androulidakis, Richard Acton, Kathryn Balmanno, Anneliese Jarman, Jhanavi Srinivasan, Adam Bendall, Sara Morales-Álvarez, Roberto Yagüe-Serrano, Katie Heywood, Stephen Harbottle, Mina Vasilic, Suzanne Cawood, Srividya Seshadri, Paul Serhal, Lauren Weavers, Ippokratis Sarris, Anastasia Mania, Rachel Gibbons, Lucy Laurier, Immaculada Sánchez-Ribas, Amparo Mercader, Pilar Alamá, Anthony Hoa Bui, Graham J Burton, Tereza Cindrova-Davies, Ridma C Fernando, Afshan McCarthy, Lusine Aghajanova, Liesl Nel-Themaat, Ruth B Lathi, Simon J Cook, Kathy K Niakan, Alexander R Dunn, Francisco Domínguez, Peter J Rugg-Gunn.
      Implantation of a human embryo into the endometrium is a crucial event in gestation, as it marks the initiation of a pregnancy and is prone to high failure rates. We have limited understanding of these stages because of the inaccessibility of implanting embryos and the lack of suitable model systems. Here, we establish an in vitro model that recapitulates the luminal, glandular, and stromal compartments of the superficial layer of receptive human endometrium. Human embryos and blastoids implant into the endometrial model, achieving post-implantation hallmarks including advanced trophoblast structures that underlie early events in placental development. Single-cell RNA sequencing of the embryo-endometrial interface at day 14 uncovers predicted molecular interactions between conceptus and endometrium. Disrupting signaling interactions between extravillous trophoblast and endometrial stromal cells caused defects in trophoblast outgrowth, demonstrating the importance of crosstalk processes to sustain embryogenesis. This platform opens the opportunity to investigate early stages of human embryo implantation.
    Keywords:  development; embryo; embryogenesis; endometrium; human; implantation; in vitro model; placenta; reproduction; trophoblast
    DOI:  https://doi.org/10.1016/j.cell.2025.10.027
  2. Front Cell Infect Microbiol. 2025 ;15 1651142
    Toxoplasma gondii infection inhibits invasion and migration of human extravillous trophoblasts through dysregulation of FOXO1- and FOXO3a-dependent and -independent mechanisms.
    Aurore Lebourg, Louis-Philippe Leroux, Visnu Chaparro, Sophie Chagneau, Cathy Vaillancourt, Maritza Jaramillo.
      The protozoan parasite Toxoplasma gondii causes severe pathologies in the infected fetus following vertical transmission during pregnancy. Primary T. gondii infection increases the risk of miscarriage during the first trimester of gestation; however, the cellular and molecular mechanisms are not fully understood. Extravillous trophoblasts (EVTs) are fetal cells that migrate and invade the maternal decidua to allow placenta formation and embryo implantation. The transcription factors Forkhead box O3a (FOXO3a) and FOXO1 play a central role in the regulation of EVT migration and invasion. Hence, impairment of EVT functions is associated with FOXO3a/FOXO1 dysregulation and poor pregnancy outcomes. Interestingly, T. gondii-driven inactivation of FOXO3a and FOXO1 was reported in fibroblasts and macrophages. Using a combination of cell imaging, reverse genetics and biochemical approaches in the human trophoblast cell line HTR-8/SVneo, herein we provide evidence that infection with type I RH T. gondii strain inhibits invasiveness and migratory activities in EVTs by repressing FOXO3a-and FOXO1-dependent and independent gene expression. Indeed, either T. gondii infection or single knockdown of FOXO3a and FOXO1 reduced invasion and migration properties in EVTs. Selective chemical blockade of parasite motility and host cell entry indicates that active infection is indispensable for reduced EVT migration but is only partially required for T. gondii-driven repression of EVT invasiveness. Mechanistically, T. gondii infection led to AKT-sensitive phosphorylation and nuclear exclusion of FOXO3a and FOXO1 in EVTs. An RT-qPCR-based screening identified a subset of invasion-and migration-associated genes downregulated in T. gondii-infected EVTs (MMP2, MMP3, MMP14, TIMP2, MUC1, and ITGB3). Transcription of genes encoding MMP3 and integrin β3 decreased in FOXO3a KD and FOXO1 KD EVT cell lines, respectively. These data along with pharmacological inhibition of AKT in infected cells provide evidence that T. gondii downregulates MMP3 and ITGB3 gene expression in EVTs in an AKT-FOXO3a/FOXO1-dependent fashion. In all, we have uncovered a novel regulatory mechanism involved in the repression of EVT migration and invasion properties during T. gondii infection. Further investigation using in vivo and ex vivo models of placental infection is required to determine whether T. gondii-driven dysregulation of EVT functions contributes to pregnancy complications associated with congenital toxoplasmosis.
    Keywords:  AKT; FOXO1; FOXO3a; Toxoplasma gondii; extravillous trophoblasts; invasion; migration
    DOI:  https://doi.org/10.3389/fcimb.2025.1651142
  3. Cells. 2025 Dec 17. pii: 2009. [Epub ahead of print]14(24):
    Liraglutide-Driven Weight Loss Modulates Placental Remodeling in Obese Pregnancies in Mice.
    Natassia Rodrigo, Dunja Aksentijevic, Nikayla Patel, Carol A Pollock, Lana McClements, Sarah J Glastras.
       BACKGROUND: The placenta stands at the maternal-fetal interface and is a key organ regulating the intrauterine environment. In pregnancies exposed to obesity, placental function, signaling, and nutrient handling are adversely altered. Pre-conception weight loss is a potential intervention to alter an obesogenic milieu of pregnancy, which we investigated in a mouse model of maternal obesity using diet or administration of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide.
    METHODS: Pre-pregnancy weight loss in C57BL/6 high-fat diet (HFD)-fed dams was induced in the pre-pregnancy period by switching diet from HFD to chow diet or administering liraglutide (0.3 mg/kg/day subcutaneously for 4 weeks) whilst continuing HFD. In addition, a group of HFD-fed dams were switched to chow diet post-conception. The metabolomic profile and gene expression within the placenta was compared at day 18-20 of gestation.
    RESULTS: 1H NMR spectroscopy metabolomic analysis of placenta of HFD mice showed an altered amino acid metabolomic profile, with lower aspartate, glutamate, and glutamine levels compared to the placenta of chow-fed mice (p < 0.05). Meanwhile, gene expression analysis identified both oxidative stress and inflammation in the placentas of HFD-fed dams. Whilst dietary modification alone was sufficient to reduce markers of oxidative stress and inflammation, liraglutide treatment modulated pathological changes, including placental metabolic stress but not inflammation.
    CONCLUSIONS: These findings highlight the importance of dietary or pharmacological interventions in the pre- or immediate post-conception period, with pre-conception offering a critical window to reduce aberrant placental changes induced by obesity.
    Keywords:  diet; liraglutide; placenta; pre-conception; reproductive health
    DOI:  https://doi.org/10.3390/cells14242009
  4. Biochem Biophys Res Commun. 2025 Dec 16. pii: S0006-291X(25)01858-3. [Epub ahead of print]796 153142
    Extracellular adenosine mediated activation of the A2B adenosine receptor increases human syncytiotrophoblast formation.
    Nisha Kushwaha, Santosh Kumar Verma, Shakti Kumar, Amrit Gupta, Swasti Tiwari.
      Trophoblast fusion is crucial in developing multinucleated syncytiotrophoblast (STB) that form the placenta. Reports suggest that adenosine and adenosine triphosphate (ATP) plasma levels are elevated in preeclampsia compared to normal pregnant women. Plasma adenosine level is also reported to increase during normal gestation. In the cellular milieu, extracellular ATP is inflammatory, while adenosine has an immunosuppressive role. The present study provides evidence of the absolute requirement of cell-extracellular adenosine in STB reshaping. Under in-vitro conditions, fusion of the human choriocarcinoma cell line mimics the in-vivo syncytialization of placental villous cytotrophoblast cells. Cultured BeWo cells are committed to the placentogensesis pathway by being treated with forskolin (FSK), which forms multinucleated STB. Under culture conditions, cell extracellular adenosine boosts the STB formation process. Antagonists targeting CD39 (E-NTPDase1) and CD73 (ecto-5'-nucleotidase) modulate STB formation by preventing extracellular ATP dephosphorylation. Further scavenging extracellular adenosine by targeting adenosine deaminase (ADA) enzyme, STB formation accentuates by maintaining cell extracellular adenosine pool. Overall, this suggests CD39, CD73, and ADA activity are critical in maintaining normal STB formation. Further, a genetic knockdown approach and antagonist targeting A2B adenosine receptors (A2B-R) suppress STB formation, suggesting a specific role of cell-extracellular adenosine receptors during placenta development. Extracellular adenosine alone does not induce trophoblast differentiation, but its combination with FSK promotes robust STB formation, suggesting the promising role of extracellular adenosine during trophoblast fusion. These data suggest a potential role of the purinergic signalling pathway in maintaining the delicate balance of extracellular ATP and adenosine molecules regulating STB formation.
    Keywords:  Placenta development; Purinergic signalling; Syncytiotrophoblast; Trophoblast fusion
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153142
  5. JCI Insight. 2025 Dec 23. pii: e195801. [Epub ahead of print]
    Distinct transcriptional and epigenomic programs define Hofbauer cells in term placenta.
    Benjámin R Baráth, Dóra Bojcsuk, Krisztian Bene, Noemí Caballero-Sánchez, Tímea Cseh, João Cr de Freitas, Petros Tzerpos, Marta Toth, Zhonghua Tang, Seth Guller, Zoárd Tibor Krasznai, Patrícia Neuperger, Gabor J Szebeni, Gergely Nagy, Tamás Deli, Laszlo Nagy.
      Hofbauer cells (HBC) are fetal-derived macrophages located in the placenta that contribute to antimicrobial defense, angiogenesis, tissue remodeling, and metabolic processes within the chorionic villi. Although their roles in placental biology are increasingly recognized, the mechanisms that regulate HBC identity and function are not yet fully defined. This study aimed to define the core transcriptomic and epigenomic features of HBCs in term placentas and to examine their capacity for transcriptional responsiveness and phenotypic variation. Using chromatin accessibility profiling and bulk RNA sequencing, we found that HBCs exhibit a unique gene expression and chromatin accessibility profile compared to other fetal and adult macrophages. We identified a coordinated transcriptional network involving nuclear receptors NR4A1-3, the glucocorticoid receptor (GR), and RFX family members (RFX1, RFX2, RFX5) that appears to shape HBC identity, particularly through pathways linked to lipid metabolism and angiogenesis. Although exploratory in nature, in vitro stimulation studies showed that HBCs exhibited increased transcriptional activity in response to combined IL-4 and RSG treatment, including induction of the lipid transporter CD36. Mass cytometry analysis revealed surface markers indicative of both immature and mature macrophage states. Together, these results indicated that HBCs represent a distinct and diverse macrophage population with specialized and adaptable regulatory program in the human placenta.
    Keywords:  Immunology; Macrophages; Reproductive biology
    DOI:  https://doi.org/10.1172/jci.insight.195801
  6. Placenta. 2025 Dec 15. pii: S0143-4004(25)00769-6. [Epub ahead of print]174 126-137
    HIF-2α / HILPDA promotes ferroptosis sensitivity in placenta trophoblast cells of early-onset preeclampsia.
    Qianghua Wang, Nana Yang, Huijuan Chen, Biao Ding, Chengli Dou, Xuegu Wang, Xingchen Pan, Xiaojing Wang, Xiang Li.
       BACKGROUND: Early-onset preeclampsia (EOPE) is a severe pregnancy disorder characterized by placental dysfunction. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key pathogenic mechanism in EOPE. This study investigated the role of the hypoxia-inducible factor-2α (HIF-2α) and its downstream target, Hypoxia-Inducible Lipid Droplet-Associated protein (HILPDA), in regulating ferroptosis in EOPE placentas.
    METHODS: Placental tissues from EOPE patients and normotensive controls were analyzed for ferroptosis markers (MDA, GSH, ACSL4, Ferroportin-1, GPX4) and HILPDA/HIF-2α expression. In vitro models employed HTR-8/SVneo trophoblasts and primary human trophoblasts. HILPDA was manipulated via siRNA knockdown or CRISPR-Cas9 knockout. HIF-2α was pharmacologically activated using agonists (HIF-2α agonist 2, AKB-6899). Erastin was used to induce ferroptosis. Assessments included CCK-8 assays for viability, C11-BODIPY581/591 staining and flow cytometry for lipid peroxidation, MDA/GSH quantification for ferroptosis levels, qRT-PCR and Western blotting for HILPDA/HIF-α expression.
    RESULTS: EOPE placentas exhibited significantly elevated ferroptosis, with increased MDA, ACSL4, Ferroportin-1; decreased GSH, GPX4, and upregulated expression of both HILPDA and HIF-2α (but not HIF-1α) compared to controls. In vitro, HIF-2α activation triggered HILPDA expression and robust ferroptosis (increased lipid peroxidation, MDA; decreased GSH; reduced viability) in trophoblasts. Crucially, HILPDA knockdown/knockout significantly attenuated ferroptosis sensitivity and protected trophoblast viability against both Erastin and HIF-2α agonist-induced ferroptotic stress. HIF-2α-induced ferroptosis was substantially rescued by HILPDA deficiency.
    CONCLUSION: Our findings identify the HIF-2α/HILPDA axis as a critical regulator of trophoblast ferroptosis in EOPE. HIF-2α, upregulated in EOPE placenta, transcriptionally induces HILPDA, which sensitizes trophoblasts to ferroptotic death. Targeting this signaling pathway represents a promising therapeutic strategy for mitigating placental dysfunction in EOPE.
    Keywords:  Ferroptosis; HILPDA; Hif-2α; Preeclampsia
    DOI:  https://doi.org/10.1016/j.placenta.2025.12.009
  7. Pediatr Investig. 2025 Dec;9(4): 372-382
    Sex-specific associations between hypertensive disorders in pregnancy and fetal and placental weight.
    Alexandra R Sitarik, Ganesa Wegienka, Christine C Johnson, Raminder Khangura, Jennifer K Straughen, Andrea E Cassidy-Bushrow.
       Importance: Hypertensive disorders in pregnancy (HDPs) are common and increase the risk of maternal and fetal morbidity and mortality. HDPs may impact fetal growth; however, sex-specific effects have been understudied.
    Objective: To examine whether sex-specific differences exist in the association between HDPs and birthweight and placental weight.
    Methods: A birth cohort based in Detroit, Michigan, was utilized (n = 1258). HDPs and birthweight were abstracted from medical records; placental weight was obtained from placental pathology reports. Linear regression was used to model sex-specific associations, after multiple imputation, confounder adjustment, and inverse probability weighting to account for selection bias.
    Results: The primary analysis included all pregnancies (n = 853), while the secondary analysis included those sent for placental pathology, reflective of complicated pregnancies (n = 165). In the primary analysis subset, males of mothers with gestational hypertension had birthweight Z-scores that were on average 0.90 standard deviations higher, but this association was not found among females (interaction P = 0.019; male β [95% confidence interval {CI}]: 0.90 [0.28, 1.52]; female β [95% CI]: -0.12 [-0.65, 0.41]). However, in the subset of complicated pregnancies, female mothers with gestational hypertension also had reduced birthweight (interaction P = 0.013; male β [95% CI]: 1.50 [0.15, 2.86]; female β [95% CI]: -1.14 [-2.13, -0.16]). For fetoplacental weight ratio, any HDP was associated with a lower ratio among females only (interaction P = 0.028; male β [95% CI]: -0.04 [-0.71, 0.64]; female β [95% CI]: -0.95 [-1.57, -0.33]).
    Interpretation: Male fetuses may prioritize growth, whereas females may prioritize placental development when exposed to HDPs.
    Keywords:  Birth cohort; Birthweight; Hypertension; Placenta; Pregnancy
    DOI:  https://doi.org/10.1002/ped4.70015
  8. Biol Sex Differ. 2025 Dec 24.
    Sex-specific placental transcriptome alterations in late-onset preeclampsia reveal male-biased immune and metabolic dysregulation.
    Melanie D Smith, Seema Plaisier, James Breen, K Justinian Bogias, Tanja Jankovic-Karasoulos, Dylan McCullough, Dale McAninch, Anya L Arthurs, Melissa A Wilson, Katherine A Pillman, Claire T Roberts.
       BACKGROUND: Preeclampsia is a hypertensive disorder of pregnancy with major maternal and fetal consequences. While the molecular basis of early-onset preeclampsia is well studied, the mechanisms underlying late-onset disease-and how they differ by fetal sex-remain poorly understood. Placental transcriptomic profiling at term can reveal persistent molecular alterations reflecting cumulative disease processes.
    METHODS: We conducted a cross-sectional observational analysis of placental gene expression using RNA sequencing in a subset of 58 term placentas (21 male-bearing and 37 female-bearing pregnancies) drawn from two large prospective birth cohorts. Pregnancies were classified based on a clinical diagnosis of late-onset preeclampsia (diagnosed ≥ 20 weeks' gestation according to ISSHP criteria) or as uncomplicated pregnancies. We then assessed for differential gene expression. Cell type proportions were estimated using CIBERSORTx from a placenta-specific reference single-cell dataset. Weighted gene co-expression network analysis identified modules of co-expressed genes associated with late-onset preeclampsia and fetal sex.
    RESULTS: Differential gene expression analysis identified 150 genes with altered expression in male-bearing placentas from pregnancies with late-onset preeclampsia compared to those from uncomplicated pregnancies. No differentially expressed genes were identified in female-bearing placentas. Cell type deconvolution revealed increased abundance of CD14 + monocytes and CD8 + activated T cells (log odds of 1.42 and 1.44 respectively) and reduced fetal GZMK natural killer cells (log odds of 0.60) in male-bearing placentas from affected pregnancies. In female-bearing placentas, late-onset preeclampsia was associated with increased fetal nucleated red blood cells and maternal plasma cells (log odds of 1.33 and 1.40 respectively). Male-specific co-expression analysis identified gene modules enriched for biological processes including RNA processing, immune regulation, and metabolism.
    CONCLUSIONS: Placental transcription and cellular responses to late-onset preeclampsia differ by fetal sex. Evidence of altered immune cell composition and gene co-expression in male-bearing placentas suggests a sex-specific vulnerability. These findings highlight the importance of considering fetal sex in molecular investigation and clinical management of preeclampsia. Preeclampsia is a common pregnancy complication marked by high blood pressure, but how it affects the placenta, especially in later pregnancy and depending on the baby's sex, is not well understood. In this study, we analysed placental tissue from pregnancies with and without late-onset preeclampsia using RNA sequencing. By separating the data based on whether the neonate was male or female, we found striking differences in gene expression. Only placentas from male-bearing pregnancies showed significant changes in gene expression linked to preeclampsia. These changes involved genes related to immune response, metabolism and vascular function. We also used computational tools to estimate what types of cells were present in each placental sample. In male-bearing pregnancies affected by late-onset preeclampsia, there was a notable increase in certain immune cells, suggesting an altered immune response and increased inflammation. In contrast, female-bearing pregnancies affected by late-onset preeclampsia showed an increase in cell composition for two blood related cell types, but no significant gene expression differences. By grouping genes that worked together into networks, we identified several groups, especially in placentas from male-bearing pregnancies, that were strongly associated with biological processes known to be disrupted in preeclampsia, such as blood vessel formation, extracellular matrix remodelling, and hormone regulation. These findings emphasise the importance of considering fetal sex in pregnancy research and could help guide future sex-specific diagnostic or treatment strategies.
    Keywords:  Cell type deconvolution; Extra-cellular matrix; Late-onset preeclampsia; Placenta; Pregnancy; Transcriptomics
    DOI:  https://doi.org/10.1186/s13293-025-00781-w
  9. Front Mol Biosci. 2025 ;12 1731126
    Comparative analysis of lipid metabolism in trophoblast subpopulations in preeclampsia and in vitro hypoxia model.
    Ivan Antipenko, Evgeny Knyazev, Timur Kulagin, Alexander Tonevitsky.
      Preeclampsia is a leading cause of maternal and perinatal morbidity associated with systemic lipid metabolism disturbances, yet the underlying molecular mechanisms remain incompletely understood. In this study, we integrated single-cell RNA-seq data from preeclamptic placentas with an in vitro hypoxia model to analyze gene expression changes across distinct trophoblast subpopulations. While all trophoblast lineages exhibited hypoxia-driven metabolic reprogramming, the response was highly cell-type specific. In the syncytiotrophoblast (SCT), the primary maternal-fetal barrier, preeclampsia was associated with a significant downregulation of LDLR and cholesterol biosynthesis genes (OR = 4.991, p = 6.30e-04). Concurrently, we observed increased expression of genes governing transcytosis (SCARB1, CAV1). In contrast, the extravillous trophoblast (EVT) displayed a divergent adaptive response, characterized by elevated LDLR expression and downregulated cholesterol biosynthesis. In vitro hypoxia modeling in BeWo b30 cells recapitulated the SCT-specific phenotype and identified a potential regulatory mechanism: a fivefold increase in PCSK9 expression (padj = 3.53e-10) and a 1.5-fold decrease in SNX17 (padj = 1.76e-04)-key regulators that limit lipoprotein receptor recycling. This was accompanied by the suppression of lipid biosynthesis genes and the transcriptional activation of pathways associated with transcytosis and cholesterol efflux. Collectively, these results confirm the pivotal role of hypoxic stress in disrupting placental lipid metabolism and reveal a subpopulation-specific transcriptional program in preeclampsia-a shift from endocytosis to transcytosis-that likely serves as a compensatory mechanism to ensure fetal lipid supply under conditions of limited availability.
    Keywords:  PCSK9; SCARB1; hypoxia; lipid metabolism; preeclampsia; single-cell RNA-seq; trophoblast
    DOI:  https://doi.org/10.3389/fmolb.2025.1731126
  10. Biol Reprod. 2025 Dec 23. pii: ioaf285. [Epub ahead of print]
    Research Progress on RNA m6A Methylation Modification Mediating Placental Disorders Induced by Maternal Stress.
    Lingtong Gao, Yinan Han, Yuhong Li, Xin Guan, Lu Gao.
      Maternal stress caused by the environmental factors varied in intrauterine and extrauterine during pregnancy may significantly affect placental and fetal development, as well as offspring health in adulthood. Epigenetic mechanisms are frequently invoked to elucidate these effects. RNA N6-methyladenosine (m6A) modification, one of the most prevalent and abundant post-transcriptional epigenetic modifications in eukaryotic mRNA, has recently garnered widespread attention in life sciences. RNA m6A modification plays critical roles in RNA splicing, translation, localization, stability, and has been implicated in various biological processes, including embryonic development, sex determination, and disease pathogenesis. In studies of placental developmental abnormalities induced by maternal stress during pregnancy, m6A modification has emerged as a key mechanism. This article initially introduces the impact of RNA m6A methylation modification on placental development, subsequently elaborates on recent advances in understanding how maternal stress induces placental abnormalities via m6A modification, and finally summarizes unresolved key questions in this field. This review aims to propose strategies for preventing and treating placental developmental abnormalities caused by maternal stress.
    Keywords:  epigenetic modification; maternal stress; placenta development; rna m6a methylation
    DOI:  https://doi.org/10.1093/biolre/ioaf285
  11. Cell. 2025 Dec 23. pii: S0092-8674(25)01230-9. [Epub ahead of print]
    A 3D in vitro model for studying human implantation and implantation failure.
    Qian Li, Yang Yuan, Wentao Zhao, Yuanjun Li, Juanzi Shi, Yu Xiu, Mi Han, Yan Han, Junmei Zhang, Shuhan Cheng, Xin Qi, Xizhuang Sun, Tan Jia, Jiaqi Xing, Siwei Deng, Xiaodi Yan, Seiya Oura, Hongfei Li, Ying Sun, Huiyao Yuan, Xiaohong Ma, Miaomiao Xin, Jianchao Zhao, Xili Zhu, Cong Wang, Qin Wang, Ge Lin, Xiaokui Yang, Yulei Wei, Jun Wu, Hongmei Wang, Leqian Yu.
      A better understanding of human implantation is essential for improving assisted reproduction outcomes and addressing recurrent implantation failure (RIF). However, ethical constraints and limited access to human embryos make direct studies challenging. To overcome this, we developed a 3D in-chip implantation model using human blastoids or blastocysts co-cultured with a bioengineered human endometrial tissue, termed endometrioid. This system successfully recapitulates key events of human implantation and early post-implantation development. Importantly, when modeling implantation using samples derived from RIF patients, we observed significantly reduced blastoid implantation capability compared with endometrioids from fertile controls. Furthermore, a targeted screen of U.S. Food and Drug Administration (FDA)-approved compounds identified candidates that markedly enhanced implantation efficiency in RIF-derived endometrioids. Together, this 3D platform enables mechanistic investigation of human implantation and implantation failure and offers a scalable approach to evaluate therapeutic strategies for improving embryo-endometrium interaction in a clinical setting.
    Keywords:  endometrioid; human blastoid; human early development; human implantation; recurrent implantation failure; stem cell-derived embryo model
    DOI:  https://doi.org/10.1016/j.cell.2025.10.026
  12. Cell Stem Cell. 2025 Dec 23. pii: S1934-5909(25)00436-9. [Epub ahead of print]
    3D post-implantation co-culture of human embryo and endometrium.
    Jinzhu Song, Rusong Zhao, Yu Zhang, Minghui Lu, Peishu Liu, Tao Li, Cheng Li, Ruijie Yu, Xueyao Chen, Huajian Yang, Xinwen Zhang, Yining Su, Yanli Han, Duanchen Sun, Qingbin Zhou, Zhenzhen Hou, Weijing Liu, Xiaoyuan Gao, Wenrong Tao, Jingye Zhang, Jingwen Wang, Yingying Qin, Hongmei Wang, Keliang Wu, Jun Wu, Zi-Jiang Chen, Han Zhao.
      Embryo-maternal interaction is essential for post-implantation human development. While endometrial organoids have enabled in vitro modeling of the uterine environment, a fully integrated 3D co-culture system with human embryos has not been established. Here, we develop a physiologically relevant 3D platform that supports the co-culture of human embryos with endometrial organoids, enabling reciprocal embryo-maternal communication. This system sustains development to day 14 post-fertilization with structural and molecular fidelity to Carnegie stage landmarks, including yolk sac formation, primordial germ cell specification, and trophoblast maturation. Single-cell transcriptomics and functional assays reveal that the endometrial niche accelerates extravillous trophoblast emergence at day 9 post-fertilization and primes their invasive programs. Disruption of maternal signals, including human chorionic gonadotropin signaling blockade, markedly impairs embryonic progression. This co-culture system provides a powerful and tractable model to dissect human peri- and post-implantation development, with broad relevance to early pregnancy loss, placental biology, and reproductive medicine.
    Keywords:  Carnegie stage; embryo-endometrium interactions; endometrial organoids; extravillous trophoblast; fetal-maternal crosstalk; human blastocysts; human chorionic gonadotropin; human post-implantation development; primordial germ cell; syncytiotrophoblast
    DOI:  https://doi.org/10.1016/j.stem.2025.12.002
  13. bioRxiv. 2025 Dec 20. pii: 2025.12.17.695051. [Epub ahead of print]
    Fetoplacental circadian rhythms develop and then synchronize to the mother in utero.
    K L Nikhil, Keenan Bates, Elizabeth Sapiro, Jacob L Amme, Ronald McCarthy, Sarah Speck, Varun Vasireddy, Ethan Roberts, Carmel A Martin-Fairey, Miguel-E Dominguez-Romero, Sandra Paola Garcia Cardenas, Sarah K England, Erik Herzog.
      Circadian rhythms in gene expression and hormones are ubiquitous across species and differentiated cell types, yet their developmental origins remain poorly understood. This study aimed to determine if daily rhythms can be detected in utero and if they synchronize to the mother. We developed methods to longitudinally monitor PERIOD2 (PER2), a core circadian clock protein, from embryonic day (E)8.5 to E17.5 by restricting PER2::LUCIFERASE (PER2::LUC) expression to the mouse fetoplacental unit (fetus and fetal-derived tissues). In utero fetoplacental bioluminescence imaging showed that PER2 levels rose exponentially during pregnancy, with variable daily peak times that stabilized to dusk by E15.5. Interestingly, pregnancies that did not exhibit daily in utero PER2 variation were more likely to fail. Because maternal glucocorticoids have been implicated in fetal development and synchronizing other circadian tissues, we tested its capability to shift fetoplacental PER2 rhythms in utero. Daily subcutaneous glucocorticoid injections over five days of late pregnancy phase-dependently shifted the fetoplacental PER2 rhythms in utero. Blocking glucocorticoid signaling in vitro reduced synchrony between maternal and fetal placenta by ~40%. We conclude that in utero daily rhythms gradually develop and synchronize with the mother prior to birth, potentially through glucocorticoid signaling.
    DOI:  https://doi.org/10.64898/2025.12.17.695051
  14. J Extracell Biol. 2025 Dec;4(12): e70100
    Isolation Strategy Matters: How Tissue Processing Shapes the Composition of Placental Extracellular Vesicles.
    Parinaz Kazemi, Elaine Lee, Daniel Dufort.
      The placenta is a vital mediator of maternal-foetal communication, and extracellular vesicles (EVs) derived from placental tissue have gained attention as promising biomarkers of pregnancy health. Accurate molecular profiling of placental EVs is critical for advancing their diagnostic and mechanistic applications. However, how different EV isolation methods influence their composition remains poorly understood. This study directly compared EVs isolated from mouse placental tissue using two common approaches, enzymatic digestion and explant culture, evaluating their structural features, size distribution and proteomic content. Both methods successfully isolated small EVs (sEVs) with canonical markers (CD63, TSG101 and HSC70) and characteristic EV morphology. The digestion method produced a higher yield of larger EVs with a broader size range. Proteomic profiling showed substantial overlap but also revealed method-specific enrichment. Explant-derived EVs were enriched in RNA-binding proteins, translation factors and proteins related to post-transcriptional regulation and stress responses. In contrast, digestion-derived EVs were enriched for extracellular matrix (ECM) proteins and ER- and mitochondrial-associated proteins. These EVs also demonstrated stronger enrichment for placental-specific proteins. Density gradient purification confirmed that canonical EV markers localized to expected fractions. However, the ER protein GRP94 was also present, indicating possible vesicle association, although its intracellular versus extracellular origin remains unclear. Together, our findings show that the tissue dissociation strategy significantly shapes placental EV composition. Enzymatic digestion may improve the recovery of matrix-embedded EVs, but it increases the likelihood of capturing intracellular components. An explant culture approach yields a more selective EV population, potentially influenced by prolonged ex vivo conditions. These results underscore the importance of aligning EV isolation methods with specific experimental objectives and highlight key considerations for placental EV biomarker discovery and translational applications.
    Keywords:  EVs; enzymatic digestion; explant culture; placenta; proteomics; tissue dissociation
    DOI:  https://doi.org/10.1002/jex2.70100
  15. Lancet. 2025 Dec 23. pii: S0140-6736(25)02599-1. [Epub ahead of print]
    Announcing the Lancet Commission on Maternal and Newborn Health.
    Lancet Commission on Maternal and Newborn Health
      
    DOI:  https://doi.org/10.1016/S0140-6736(25)02599-1
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