bims-placeb Biomed News
on Placental cell biology
Issue of 2026–11–01
fifteen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences
  1. Implantation begins with a conversation.
  2. Alcohol-induced placental vasculopathy reprograms the placental-fetal cardiovascular axis: angiogenic mechanisms linking maternal alcohol exposure to developmental cardiovascular programming.
  3. Lipidomes of placenta-derived extracellular vesicles reveal disrupted metabolic adaptation in type 1 diabetes.
  4. PFOS and PFHxS Disrupt Forskolin-Induced Syncytialization but Differentially Affect hCGβ Production in BeWo Cells.
  5. Syncytiotrophoblast differentiation defects drive ER stress and reprogram placental PSG1 glycosylation in preeclampsia.
  6. Genetic engineering in the Post Implantation Uterus using a 4-hydorxytamofen Regulated Cre Recombination.
  7. Preconception paternal PFAS exposure in mice reprograms the placental epigenome.
  8. OVOL1/2 regulate trophectoderm differentiation during the morula-to-blastocyst transition.
  9. A three-dimensional human co-culture system reveals reciprocal embryo-endometrial adaptation at implantation onset.
  10. mRNA encoding norovirus VP1 produces antigenically functional virus-like particles in vitro.
  11. Spatio-temporally regulated maternal RNA decay factor essential for zebrafish development.
  12. Mitochondrial amino acid export preserves mitochondrial volume at the egg-to-embryo transition.
  13. Proteomic and transcriptomic analysis reveals an intracellular role for zona pellucida protein 2 in mouse morula-blastocyst transition.
  14. miRNA-543 attenuates placental angiogenesis in female fetal growth restriction by targeting ANGPT2 and inhibiting the PI3K/AKT/mTOR pathway.
  15. Screening of Bioactive Compounds in the Tianma-Gouteng Pair and Its Protective Effects on an L-NAME-Induced Trophoblast Organoid Injury Model.
  1. Nat Cell Biol. 2026 Oct 27.
    Implantation begins with a conversation.
    Thomas M Rawlings.
      
    DOI:  https://doi.org/10.1038/s41556-026-02105-5
  2. Front Physiol. 2026 ;17 1917947
    Alcohol-induced placental vasculopathy reprograms the placental-fetal cardiovascular axis: angiogenic mechanisms linking maternal alcohol exposure to developmental cardiovascular programming.
    Elisa Cebral.
      Among prenatal insults, maternal alcohol consumption has emerged as an important determinant of fetal cardiovascular development and long-term cardiovascular disease susceptibility. Growing evidence indicates that the placenta is a central biological mediator linking maternal alcohol exposure with abnormal fetal cardiac development. This review integrates current experimental and clinical findings on the developmental relationship between placental vascularization and fetal cardiogenesis, highlighting the placental-embryofetal cardiovascular axis as a conceptual framework for alcohol-induced cardiopathy programming. We examine evidence that prenatal alcohol exposure disrupts placental vascular development through impaired decidual spiral artery angiogenesis and remodeling and altered trophoblast differentiation and invasion, and labyrinthine vascularization. Experimental studies suggest that oxidative stress and hypoxia perturb interconnected angiogenic vascular endothelial growth factor (VEGF)-nitric oxide synthases (NOS)-matrix metalloproteinases (MMPs) pathways, and related redox-sensitive mediators, ultimately compromising placental perfusion and fetoplacental hemodynamics. We further discuss that placental dysfunction may alter the molecular, metabolic, endocrine, oxygen-dependent, and hemodynamic signals regulating fetal cardiac development, potentially affecting myocardial morphogenesis, cardiac remodeling, coronary vascularization, septation, valvulogenesis, and cardiovascular maturation during critical developmental windows. Collectively, available evidence supports a model in which disruption of placental angiogenic homeostasis may represent a key intermediary linking maternal alcohol exposure with fetal cardiovascular programming. This perspective integrates direct embryofetal effects with indirect placental-mediated mechanisms and highlights the need to clarify their relative contributions across developmental windows. Improved understanding of the placental-embryofetal cardiovascular axis may facilitate identification of early biomarkers and preventive or therapeutic strategies to reduce the lifelong cardiovascular consequences of prenatal alcohol exposure.
    Keywords:  angiogenesis; cardiovascular programming; early gestation; feto-maternal remodeling; heart disease; maternal alcohol; placenta; placentopathy
    DOI:  https://doi.org/10.3389/fphys.2026.1917947
  3. J Clin Endocrinol Metab. 2026 Oct 30. pii: dgag411. [Epub ahead of print]
    Lipidomes of placenta-derived extracellular vesicles reveal disrupted metabolic adaptation in type 1 diabetes.
    Miira M Klemetti, Jiayi Li, Sruthi Alahari, Ante B V Pettersson, Denice Feig, Helen R Murphy, Martin Post, Hannes Röst, Isabella Caniggia.
       CONTEXT: Placental metabolic adaptation is dynamically orchestrated across gestation to support fetal development, yet how this process is disrupted in type 1 diabetes (T1D) and contributes to altered fetal metabolic outcomes remains unclear. Small extracellular vesicles (sEVs) may provide a minimally invasive window into placental metabolic state during pregnancy.
    OBJECTIVE: To determine whether lipidomic profiling of placental sEVs (P-sEVs) in maternal circulation captures dynamic placental metabolic adaptation and its dysregulation in T1D pregnancy.
    DESIGN AND SETTING: Prospective longitudinal cohort study conducted within the Ontario Birth Study and the Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes (CONCEPTT) study.
    PARTICIPANTS: Maternal plasma samples were collected across gestation (10-14, 24-32, and 34-40 weeks of gestation) from 200 normoglycemic pregnancies and 151 pregnancies from individuals with preexisting T1D.
    METHODS: Placental sEVs were isolated and characterized, and lipid composition was quantified using shotgun mass spectrometry-based lipidomics. Multivariate and machine learning approaches were applied to define gestational lipid trajectories and assess associations with fetal metabolic outcomes.
    MAIN OUTCOME MEASURES: Gestational lipid trajectories in P-sEVs from normoglycemic and T1D, and their association with maternal and fetal risk factors and clinical outcomes.
    RESULTS: Placental sEVs from T1D pregnancies exhibited increased vesicle size and reduced abundance. Lipidomic profiling revealed divergence in the magnitude, direction, and timing of gestational lipid trajectories compared with controls. Lipid species involved in membrane remodeling and bioactive signaling distinguished pregnancies with high vs low cord blood C-peptide, a marker of fetal endogenous insulin secretion, with strong discrimination (area under the characteristic curve = 0.85).
    CONCLUSION: Circulating P-sEV lipid profiles reflect disrupted placental metabolic adaptation in T1D pregnancy and are associated with fetal hyperinsulinemia at birth, supporting their potential for minimally invasive assessment of placental function.
    Keywords:  fetal hyperinsulinemia; lipidomics; placenta; pregnancy; small extracellular vesicles; type 1 diabetes
    DOI:  https://doi.org/10.1210/clinem/dgag411
  4. Biol Pharm Bull. 2026 ;49(10): 1738-1745
    PFOS and PFHxS Disrupt Forskolin-Induced Syncytialization but Differentially Affect hCGβ Production in BeWo Cells.
    Minaho Yamauchi, Kazuma Higashisaka, Wakako Okuno, Momoe Serizawa, Yuzuki Inaishi, Mikihiro Yoshie, Kazuhiro Tamura, Yuya Haga, Yasuo Tsutsumi.
      Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been used in a wide range of consumer products and industrial applications. However, because of their long persistence in the environment and the human body, there is growing concern about their effects on health. The detection of PFAS in the blood of pregnant women and the placenta has highlighted the urgent need to evaluate their effects on reproduction and development. In this study, we used perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS), which are PFAS already regulated by the Stockholm Convention, and investigated their effects on placental syncytialization, a key process in placental development. First, we assessed the effect of PFOS and PFHxS on BeWo cell fusion and showed that both PFAS significantly suppressed fusion at noncytotoxic concentrations. Real-time RT-PCR analysis showed that mRNA levels of syncytialization markers were reduced in both PFOS- and PFHxS-treated cells. The production of hCGβ, normally upregulated during syncytialization, was significantly reduced in PFOS-treated groups but not in PFHxS-treated groups. These results, showing that PFOS and PFHxS both disrupt BeWo cell fusion while only PFOS suppresses hCGβ production, highlight the need for further investigation into the effects of PFAS on placental and fetal development.
    Keywords:  developmental toxicity; hormone; per- and polyfluoroalkyl substance; placentation; pregnancy outcome; reproductive toxicity
    DOI:  https://doi.org/10.1248/bpb.b26-00379
  5. Mol Biomed. 2026 Oct 30. pii: 235. [Epub ahead of print]7(1):
    Syncytiotrophoblast differentiation defects drive ER stress and reprogram placental PSG1 glycosylation in preeclampsia.
    Charlotte Harms, Yiru Wang, James Warren, Julia Baumeister, Fabian Higel, Cristina Antich, Marc Ferrer, Jennifer J Hill, Mariana G Garcia, Alexandra Gellhaus, Nándor Gábor Than, Florian Herse, Stefan Verlohren, Gabriela S Dveksler, Sandra M Blois.
      During pregnancy, placenta-derived proteins such as pregnancy-specific glycoprotein 1 (PSG1) enter the maternal circulation, providing a window into placental health and enabling liquid biopsy strategies for monitoring pregnancy disorders. PSG1, a highly glycosylated protein secreted by syncytiotrophoblast (STB) cells, reflects trophoblast differentiation status. Circulating PSG1 levels are reduced in early-onset preeclampsia (PE), but how PSG1 glycosylation is altered in this condition remains unclear. Here, we show by liquid chromatography-tandem mass spectrometry that native PSG1 purified from healthy and early-onset PE pregnancies carries an O-linked glycan in its N domain in addition to diverse N-linked glycans. In PE, PSG1 N-glycans displayed a shift toward increased oligomannose structures and reduced sialylation. Induction of endoplasmic reticulum (ER) stress in primary STBs altered the glycosylation enzyme machinery, and single-nucleus transcriptomic data indicated a reduced contribution of mature STB populations in PE, consistent with an immature STB-like glycoprotein signature. Altered N-glycosylation increased binding to mannose and asialoglycoprotein receptors and cellular uptake, suggesting enhanced hepatic clearance as a possible explanation for reduced circulating PSG1 levels in PE. Our data link ER stress during STB differentiation to altered glycoprotein maturation and identify PSG1 glycosylation as a readout of a stress-impaired STB in PE. Glycan features of circulating placental proteins could therefore provide information beyond protein levels alone and complement liquid biopsy approaches.
    Keywords:   N-glycosylation; ER stress; PSG1; Preeclampsia; STB differentiation
    DOI:  https://doi.org/10.1186/s43556-026-00634-x
  6. Biol Reprod. 2026 Oct 24. pii: ioag239. [Epub ahead of print]
    Genetic engineering in the Post Implantation Uterus using a 4-hydorxytamofen Regulated Cre Recombination.
    Shuyun Li, Francesco J DeMayo.
      The tamoxifen-inducible PgriCreERT2 mouse model enables temporal Cre recombination in progesterone receptor (Pgr)-expressing reproductive tissues. However, it remains unclear whether the PgriCreERT2 model can be safely activated during pregnancy, as tamoxifen exposure in pregnant mice can adversely affect pregnancy outcomes. Here, we established a 4-hydroxytamoxifen (4-OHT) dosing strategy for inducing Cre recombination after implantation using the PgriCreERT2 model. Pregnant females carrying PgriCreERT2 and a Cre-dependent Rosa26Sun1 reporter were administered a single dose of 4-OHT at gestational day (GD) 8.5. Dose-dependent effects on pregnancy and reporter recombination were evaluated using gross morphology, immunofluorescence, histology, placental and fetal measurements, gestation length, litter size, and resorption rate. A dose of 37.5 mg/kg produced robust SUN1 reporter activation in post-implantation uterine tissues while avoiding the overt adverse effects observed at the higher dose tested. Reporter-positive cells were detected predominantly in the uterus. Placental morphology, steroid hormone receptor (PGR and estrogen receptor alpha (ERα/ESR1)), placental development, and vascularization were preserved following treatment. These findings establish a practical 4-OHT induction regimen for temporally controlled recombination in the PgriCreERT2 model during post-implantation pregnancy and provide a methodological framework for studying uterine cell function during decidualization, placentation, and maternal-fetal development while reducing pregnancy-related confounding effects.
    Keywords:  4-hydroxytamoxifen; CreERT2; decidua; pregnancy; progesterone receptor; uterus
    DOI:  https://doi.org/10.1093/biolre/ioag239
  7. Mol Hum Reprod. 2026 Oct 06. pii: gaag056. [Epub ahead of print]32(4):
    Preconception paternal PFAS exposure in mice reprograms the placental epigenome.
    DruAnne L Maxwell, Anthony Maxwell, Karolina Nowak, Katherine Gurdziel, Jiahui Ding, Gil Mor, Michael C Petriello, J Richard Pilsner.
      The placenta plays a vital role in supporting fetal growth and development by facilitating nutrient exchange, hormone signaling, and immune regulation. Environmental toxicants such as perfluoroalkyl and polyfluoroalkyl substances (PFAS) can disrupt placental homeostasis, leading to increased risk of disease later in life. Paternal environmental exposures may influence offspring health by inducing epigenetic changes in sperm, which may affect sex-dependent placental programming. Here, male mice were exposed to a PFAS mixture (PFOS, PFOA, PFNA, PFHxS, GenX; 20 μg/l each) for 10 weeks and mated with unexposed females. We identified 6656 and 3242 differentially methylated regions (DMRs) in E12.5 placentas of female and male offspring, respectively. Female placentas showed predominantly hypermethylation (78.5%), whereas male placentas were mostly hypomethylated (62%). Gene ontology analyses linked female placental DMRs to cell and embryonic morphogenesis, and male DMRs to anatomical size regulation and hemostasis. Bulk RNA sequencing revealed 168 and 148 differentially expressed genes (DEGs) in female and male placentas, respectively. Female DEGs were related to immune regulation, while male DEGs were involved in muscle and mesenchyme development. Sex-by-PFAS interaction models identified distinct methylation and transcription biological pathways. Overlap analysis between F0 sperm and F1 placentas identified 265 shared genes, including 289 female-specific and 124 male-specific genes. Paternal exposure to the PFAS mixture increased glycogen concentrations in male, but not female, placentas. No effects were observed at imprinted loci. These findings demonstrate that paternal preconception exposure to a PFAS mixture alter placental epigenomic and transcriptomic landscapes, which may contribute to sex-dependent trajectories of fetal health and development and offspring phenotypes.
    Keywords:  environmental toxicology; paternal effects; paternal exposure; perfluoroalkyl and polyfluoroalkyl substances; placental epigenome; reproductive health
    DOI:  https://doi.org/10.1093/molehr/gaag056
  8. Commun Biol. 2026 Oct 29. pii: 1386. [Epub ahead of print]9(1):
    OVOL1/2 regulate trophectoderm differentiation during the morula-to-blastocyst transition.
    Yi Zhu, Xueqin Chen, Xin Deng, Shuoping Zhang, Jue Zhang, Fei Meng, Qinwei Zhou, Yifan Gu, Fei Gong, Guangxiu Lu, Ge Lin, Lizhi Leng.
      The blastocyst formation rate of human embryos cultured in vitro for assisted reproduction is approximately 50%, with most embryos arresting at the cleavage stage; however, the underlying mechanisms remain poorly understood. Here, we performed single-cell RNA sequencing of biopsied blastomeres from morphologically high-quality 8-cell embryos and tracked the developmental progression of the remaining embryos to the blastocyst stage. Embryos that failed to form blastocysts exhibited impaired zygotic genome activation (ZGA). We identified OVOL1/2 as critical ZGA genes that were markedly underactivated in these embryos. Functional analyses in both mouse and human embryos demonstrate that depletion of OVOL1/2 disrupts trophectoderm differentiation via ARPC1B-dependent mechanisms, thereby impairing the morula-to-blastocyst transition. Collectively, these findings provide mechanistic insights into preimplantation embryonic development and reveal potential causes of blastocyst formation failure.
    DOI:  https://doi.org/10.1038/s42003-026-11168-x
  9. Nat Cell Biol. 2026 Oct 27.
    A three-dimensional human co-culture system reveals reciprocal embryo-endometrial adaptation at implantation onset.
    Yan Bi, Zhifen Tu, Xinbao Zhang, Jindian Hu, Che Chen, Yiliang Xu, Yaqi Zheng, Yujiao Song, Yiwen Chen, Tan Lin, Hong Wang, Xuan Che, Jingyu Li, Guoning Huang, Shaorong Gao, Yixuan Wang.
      Human embryo implantation begins with dynamic, tightly coordinated interactions between embryonic and endometrial compartments, yet the earliest trophoblast-endometrial interface dynamics remain poorly resolved in vivo. Here, using an endometrial assembloid-based three-dimensional co-culture system with human blastoids and natural blastocysts, we analyse implantation-like progression by time-series single-cell transcriptomics and functional perturbation. Importantly, we identify co-culture-induced trophoblast subsets marked by SDC1+MMP7+ and enriched for transcriptional features associated with extracellular matrix remodelling and cell migration. These subsets are reproducibly detected across independent implantation-like systems, emerge specifically within a decidualized stromal co-culture context, and are further linked to stromal-derived CSF3 signalling by intercellular communication analysis and targeted perturbation. In parallel, the endometrium displays transcriptional changes associated with enhanced decidualization and a glandular hypersecretory transition. Together, our study provides a tractable framework for dissecting reciprocal embryo-endometrial adaptation at the onset of implantation.
    DOI:  https://doi.org/10.1038/s41556-026-02106-4
  10. Vaccine. 2026 Oct 26. pii: S0264-410X(26)01081-9. [Epub ahead of print]95 129272
    mRNA encoding norovirus VP1 produces antigenically functional virus-like particles in vitro.
    Judith M Reyes Ballista, Courtney David, Amanda Pirrone, Estibaliz Gonzalez-Fernandez, Jiajie Wei, Zhiyun Wen.
      Human norovirus is a leading cause of acute gastroenteritis worldwide across all age groups, yet no licensed vaccine is available. The major capsid protein, VP1, self-assembles into highly immunogenic virus-like particles (VLPs) that have shown promise in clinical studies. Recently, mRNA has emerged as a compelling platform for norovirus vaccination. However, whether VP1-encoding mRNA can drive authentic VLP formation in human cells relevant to the vaccination environment has remained unknown. In this study, we used multiple human cell lines, including THP-1-derived macrophage-like cells, to model the post-vaccination environment. Transfection with norovirus GII.4 VP1 mRNA or lipid nanoparticle-formulated VP1 mRNA induced both intracellular and extracellular VP1 expression. Sucrose gradient purification and electron microscopy confirmed VLP assembly. These particles retained key antigenic and functional properties, including recognition by norovirus-specific antibodies in human serum and binding to histo-blood group antigens. Collectively, our findings provide direct evidence that VP1-encoding mRNA can generate structurally and functionally relevant norovirus VLPs in physiologically relevant human cell systems. These results strengthen the mechanistic rationale for mRNA-based norovirus vaccines and support their continued development.
    Keywords:  Norovirus VP1; Virus-like particle formation; mRNA vaccine
    DOI:  https://doi.org/10.1016/j.vaccine.2026.129272
  11. bioRxiv. 2026 Aug 31. pii: 2026.08.20.745964. [Epub ahead of print]
    Spatio-temporally regulated maternal RNA decay factor essential for zebrafish development.
    Gopal Kushawah, Victor Daniel Aldas Bulos, Danielson Baia Amaral, Huzaifa Hassan, Stephanie H Nowotarski, Ariel A Bazzini.
      Maternal mRNA decay is essential for the Maternal-to-Zygotic Transition (MZT), yet its impact on spatial regulation has remained largely unexplored. We identify Cth1 as the first maternally encoded RNA-decay factor regulated in a spatiotemporal manner outside the germline in zebrafish, driven by conserved 3'UTR cis-elements. RfxCas13d-mediated depletion of maternal cth1 revealed early developmental defects that could not be assessed with SpyCas9 mutants due to infertility from impaired gametogenesis. Mechanistically, Cth1 acts independently of zygotic genome activation, recognizing AU-rich motifs in maternal 3'UTRs to promote deadenylation and decay in a spatio-temporal manner; deletion of these motifs or depletion of Cth1 stabilizes both reporter and endogenous transcripts. These findings establish Cth1 as a key component of the maternal program and provide the first direct evidence that spatio-temporally regulated mRNA decay, outside the germline, contributes to early vertebrate development.
    Keywords:  CRISPR-Cas13d; CRISPR-Cas9; Cth1; Embryonic lethal; Gametogenesis; MZT; RNA decay; RNA-decay factor; Spatio-temporal maternal RNAs; Zebrafish
    DOI:  https://doi.org/10.64898/2026.08.20.745964
  12. bioRxiv. 2026 Oct 09. pii: 2026.10.08.757432. [Epub ahead of print]
    Mitochondrial amino acid export preserves mitochondrial volume at the egg-to-embryo transition.
    Melissa C Pamula, Lauren Clamon, Samuel Block, Suzanne Savage, Christoph Gaebelein, Ashid Amarsanaa, Margaret E Bisher, David Mankus, Abigail Kr Lytton-Jean, Nora Kory, Ruth Lehmann.
      In animals, the transition from egg to embryo marks a rapid shift in cellular physiology, yet how mitochondria adapt to support this conversion remains poorly understood. We performed a targeted RNAi screen of conserved, nuclear-encoded mitochondrial proteins in Drosophila melanogaster to identify maternal effects. We identified distinct phenotypic classes affecting mitochondrial distribution or morphology in early embryos. We focused on Sideroflexin-1/3 (Sfxn1-3), a conserved mitochondrial inner membrane transporter, because it uniquely affects embryonic mitochondrial morphology. Maternal loss of Sfxn1-3 causes striking mitochondrial enlargement in embryos but not in oocytes, placing the trigger at the egg-to-embryo transition. Combining mitochondrial immunopurification with LC/MS-based metabolomic profiling, we show that amino acids are markedly enriched in Sfxn1-3-deficient mitochondria in both oocytes and embryos. This accumulation developmentally uncouples the metabolic and morphological phenotypes. By selectively disrupting discrete steps of egg activation, including translational activation, cell cycle re-entry, and fertilization, we demonstrate that mitochondrial swelling is independent of each, prompted instead by egg hydration. Beyond its reported role in proliferating cells as a serine importer, our data support a role for germline Sfxn1-3 in regulating inner mitochondrial membrane permeability to osmotically active amino acids. This activity is crucial for preserving organelle volume during the osmotic challenge of oocyte hydration. When this export fails, amino acid accumulation amplifies osmotic stress and drives rapid mitochondrial swelling. Together, these findings identify mitochondrial inner membrane permeability to amino acids as a key regulatory step that couples pre-established metabolite compartmentalization to osmotic adaptation at egg activation, and reveal how mitochondrial metabolic integrity and volume control are coordinated at this critical developmental transition.
    DOI:  https://doi.org/10.64898/2026.10.08.757432
  13. BMC Genomics. 2026 Oct 22. pii: 885. [Epub ahead of print]27(1):
    Proteomic and transcriptomic analysis reveals an intracellular role for zona pellucida protein 2 in mouse morula-blastocyst transition.
    Thomas Nolte, Steffen Israel, Hannes C A Drexler, Georg Fuellen, Julina Wiese, Michele Boiani.
       BACKGROUND: Since the first description in 1827, the zona pellucida (ZP) has been viewed as an extracellular structure surrounding mammalian oocytes, with three canonical roles: encasement of the oocyte in the follicle, sperm binding at fertilization, and physical protection of the early embryo. However, over the past 10 years, mass spectrometry analyses in this laboratory have repeatedly and consistently detected abundant ZP proteins inside mouse embryos. Therefore, this study investigated whether ZP2, the most abundant of the ZP proteins, might also serve non-canonical functions that operate from inside the embryo rather than from the outside.
    RESULTS: Using mass spectrometry and monoclonal immunofluorescence, an intracellular fraction of ZP2 was found to persist throughout preimplantation mouse development, being among the most abundant proteins of the embryo. Intracellular ZP2 underwent an apparent increase at the 8-cell to morula stage rather than the monotonic decline expected of a passive maternal legacy. Basic colocalization analysis showed that part of this intracellular pool overlapped neither the cis-Golgi marker GM130 nor the endoplasmic reticulum marker Calreticulin, identifying a non-Golgi, non-ER intracellular ZP2 fraction. Consistent with this, ZP2 was susceptible to Trim-Away mediated depletion, which typically can act on a protein only if this is cytosolically accessible. Although ZP2 depletion stalled at approximately 50% due to the enormous abundance of ZP2, this partial knockdown delayed the morula-to-blastocyst transition and produced blastocysts with reduced trophectoderm and primitive endoderm and impaired postimplantation development in vitro and in vivo. These effects were specific to ZP2, as they did not occur when Trim-Away was redirected to an irrelevant target. Proteome and transcriptome analyses of ZP2 knockdown embryos returned overrepresented gene ontology terms related to cytoplasmic translation in the proteome, which was confirmed by an O-propargyl-puromycin incorporation assay; and to endoderm development and gastrulation in the transcriptome, which provide a coherent molecular correlate of the morula retardation phenotype.
    CONCLUSIONS: These results confer ZP2 with hitherto unsuspected intracellular roles during embryogenesis in the mouse model of human reproduction. ZP2 can therefore no longer be referred to as a solely extracellular-operating, oocyte-specific gene product.
    Keywords:   Trim-Away ; Animal model; Embryo development; Morpholino; Oocyte; Proteomics; RNA-seq; ZP2; Zona pellucida
    DOI:  https://doi.org/10.1186/s12864-026-13487-z
  14. Front Cell Dev Biol. 2026 ;14 1912518
    miRNA-543 attenuates placental angiogenesis in female fetal growth restriction by targeting ANGPT2 and inhibiting the PI3K/AKT/mTOR pathway.
    Wenhui Song, Xuemei Yang, Chunyan Yang, Yuanyuan Zhao, Xinxian Zhang, Qing Guo.
       Background: Insufficient placental angiogenesis is a predominant pathological cause of fetal growth restriction (FGR). Placental capillary development is regulated in a sex-dependent manner, with female placentas exhibiting greater susceptibility to angiogenic dysfunction than male placentas. However, the sex-specific interplay between microRNAs (miRNAs) and human placental angiogenesis in FGR pathogenesis remains poorly defined. Emerging transcriptomic sequencing evidence has implicated miR-543 as a pivotal regulator of impaired angiogenesis in female FGR placentas. This study aimed to elucidate the sex-dependent mechanistic role of miR-543 in modulating placental angiogenesis in a cell-specific manner.
    Method: FGR pregnancies were recruited, and placental tissues were collected after delivery. The dual-luciferase reporter assay was used to detect the direct binding site of miR-543 to ANGPT2. Next, immunohistochemistry (IHC) and immunofluorescence (IF) staining were used to detect the expression and localization of ANGPT2. To verify the cell-specific gene expression of miR-543 and ANGPT2, laser capture microdissection (LCM) was employed to isolate endothelial cells from human placentas. The gene expression levels of miR-543 and ANGPT2 were quantified by qRT-PCR. CCK8, wound healing, Transwell, and tube formation assays and flow cytometry were performed to assess the functional effects of miR-543 and ANGPT2 on the biological function of human umbilical vein endothelial cells (HUVECs). The PI3K/AKT/mTOR signaling pathway was predicted and verified by Western blotting.
    Results: Significantly downregulated miR-543 expression was observed in the placentas of female FGR fetuses relative to matched normal controls. According to target gene prediction and the dual-luciferase reporter assay, ANGTP2 was identified as a target candidate of miR-543. Moreover, immunofluorescence staining and LCM analysis verified the cell-specific distribution of ANGPT2 in female FGR placentas, partly indicating its key involvement in placental capillary angiogenesis. Furthermore, dysregulated expression of miR-543 and ANGPT2 was closely correlated with aberrant proliferation, migration, and apoptosis of HUVECs. KEGG analysis revealed that the candidate targets of miR-543 were mainly enriched in the PI3K/AKT/mTOR pathway. Western blot analysis demonstrated that the PI3K/AKT/mTOR signaling pathway mediated the ANGPT2-induced attenuation of placental angiogenesis in female FGR.
    Conclusion: miR-543 negatively regulated ANGPT2 expression, leading to impaired endothelial cell function via inactivation of the PI3K/AKT/mTOR signaling pathway. This, in turn, contributed to sex-specific inhibition of capillary angiogenesis in the placenta of female fetuses. These findings reveal a novel miRNA-mediated, sex-dependent regulatory mechanism underlying the pathogenesis of impaired placental angiogenesis.
    Keywords:  angiopoietin 2; apoptosis; endothelial cell; fetal growth retardation; microRNA; placenta
    DOI:  https://doi.org/10.3389/fcell.2026.1912518
  15. Pharmaceuticals (Basel). 2026 Sep 28. pii: 1540. [Epub ahead of print]19(10):
    Screening of Bioactive Compounds in the Tianma-Gouteng Pair and Its Protective Effects on an L-NAME-Induced Trophoblast Organoid Injury Model.
    Aolin Zhang, Baofeng Rao, Yu Lu, Ying Liu, Anqi Zheng, Ruipeng Liu, Xinyue Liu, Tao He, Chi Chiu Wang, Lu Li.
      Background: Preeclampsia (PE) is a hypertensive, high incidence disorder occurring only during pregnancy and has high incidence. The Tianma-Gouteng pair (TGP) is used in traditional Chinese medicine for cardiovascular indications, but its candidate bioactive constituents and relevance to PE remain unclear. Objectives: This study aimed to identify candidate TGP compounds relevant to PE and elucidate their effects in experimental trophoblast models. Methods: Placental transcriptomes and network pharmacology analysis were used as an exploratory discovery stage. Candidate compounds of TGP were then evaluated using ADRA1A-overexpression cells and trophoblast organoids, molecular docking, surface plasmon resonance (SPR), and an L-NAME-induced trophoblast organoid injury model. Results: Placental injury and dysfunction were observed in PE mice. Integrated analyses prioritized α1A-adrenergic receptor (ADRA1A) as a candidate TGP-associated target. Five database-derived compounds of TGP were evaluated experimentally. Isorhynchophylline (SRH) showed direct binding to ADRA1A by SPR (equilibrium KD = 4.67 μM). In trophoblast organoids, 15 μM SRH did not significantly reduce viability and was associated with partial restoration of Ki67 and HLA-G expression after L-NAME injury. Conclusions: The data supported ADRA1A as a prioritized candidate target and SRH as a candidate compound with ADRA1A binding and activity in the experimental models. However, the current study did not establish that the biological effects of SRH depend on ADRA1A or demonstrate clinical efficacy of TGP or SRH in PE.
    Keywords:  Tianma–Gouteng pair; bioactive compound; preeclampsia; transcriptome sequencing; trophoblast organoids
    DOI:  https://doi.org/10.3390/ph19101540
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