bims-placeb 2026-07-26 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–07–26
eight papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

OVOL2 Reinforces Epithelial Identity and Promotes SynT-I Differentiation in the Mouse Placenta.
Preimplantation Exposure to Viral dsRNA Impairs Decidualization Leading to Altered Placental Development and Fetal Growth Restriction.
Transcriptomic Perturbations in Placental Gene Expression Following Developmental Exposure to Perfluorooctanoic Acid (PFOA) or Hexafluoropropylene Oxide-Dimer Acid (HFPO-DA or GenX) in CD‑1 Mice Are Consistent with Placental Insufficiency.
Thyroid antibodies in pregnancy: The placenta enters the conversation.
MiR-126-3p promotes the development and progression of preeclampsia through the inactivation of the PI3K/AKT pathway.
Long-read transcriptome sequencing reveals isoform signatures in preeclamptic placentas.
Differential transcript usage in the placenta in early onset preeclampsia.
A small GTPase, RHOH, is upregulated in the uterus during miscarriage in human and mouse model.

Biol Reprod. 2026 Jul 23. pii: ioag157. [Epub ahead of print]

OVOL2 Reinforces Epithelial Identity and Promotes SynT-I Differentiation in the Mouse Placenta.

Violet S Patterson, Mariyan J Jeyarajah, Amanda M Rampersaud, Gargi Jaju Bhattad, Stephen J Renaud.

  The placenta establishes the maternal-fetal interface during pregnancy, enabling the selective exchange of nutrients and gases between maternal and fetal circulations. In humans and mice, this exchange surface is lined by multinucleated epithelial layers called the syncytiotrophoblast (SynT), which in the mouse placenta is organized into two distinct layers, SynT-I and SynT-II. SynT formation from trophoblast precursors requires epithelial plasticity to permit cell differentiation, fusion, and morphogenesis, while preserving epithelial integrity to maintain the maternal-fetal exchange barrier. However, the mechanisms that safeguard epithelial features during SynT development remain unclear. OVO-like 2 (OVOL2), a transcriptional repressor of mesenchymal-associated programs and key regulator of epithelial identity, is highly expressed in the mouse placenta and essential for its development. We hypothesized that OVOL2 promotes SynT lineage formation by restraining mesenchymal-associated transcriptional programs during trophoblast differentiation. To test this, placental development was examined following Ovol2+/- matings, and wild-type and Ovol2-deficient trophoblast stem cells were analyzed under stem conditions or differentiated with CHIR99021 to enrich for SynT lineages. SynT-I lineage development was disrupted in both Ovol2-deficient placentas and differentiating trophoblast stem cells, whereas SynT-II-associated differentiation appeared less severely affected. Chromatin profiling identified OVOL2 binding near genes associated with epithelial-to-mesenchymal transition, including Id1, Zeb1, and Vim, which were upregulated in Ovol2-deficient trophoblasts. Consistent with these observations, Ovol2-deficient cells showed elevated levels of mesenchymal markers such as ZEB1 and Vimentin and reduced levels of epithelial markers including E-cadherin. These findings identify OVOL2 as a critical regulator of SynT-I lineage formation and epithelial identity in the mouse placenta.

Keywords:  Epithelium; Mesenchymal; OVOL2; Placenta; Syncytiotrophoblast; Trophoblast

DOI:  https://doi.org/10.1093/biolre/ioag157
Reprod Fertil. 2026 Jul 21. pii: RAF-26-0018. [Epub ahead of print]

Preimplantation Exposure to Viral dsRNA Impairs Decidualization Leading to Altered Placental Development and Fetal Growth Restriction.

Jacy N Scott, Thomas M Rawlings, Laiba Jamshed, Maria Tryfonos, Zhonghua Tang, Rolando Garcia-Milian, Eric Y Huang, Paul J Brighton, Jan J Brosens, Emma S Lucas, Mancy Tong.

   ABSTRACT: Viral infections are associated with early pregnancy loss as well as later gestational complications including preeclampsia and fetal growth restriction. While viral components, including viral double-stranded RNA (dsRNA), have been shown to affect placental trophoblast function; how these components may affect maternal endometrial function is less understood. Endometrial stromal cells make up the bulk of the human endometrium and they undergo a specialized hormone-driven differentiation process termed decidualization monthly in preparation for pregnancy. We have previously shown that these stromal cells exhibit robust inflammatory responses to bacterial LPS and viral dsRNA. The goals of this study are to determine the effects of prior viral dsRNA exposure on endometrial decidualization and whether this affects subsequent placentation and pregnancy outcomes. Using a combination of 2D endometrial stromal cell cultures, 3D human endometrial assembloids, as well as mouse models of decidualization and pregnancy, we demonstrate that exposure to viral dsRNA [Poly(I:C)] 48 hours prior to hormonal stimulation impaired decidualization in vitro and in vivo. Similarly, preimplantation exposure to Poly(I:C) on GD0.5 in timed-mated dams inhibited decidualization as well as reduced implantation success and induced fetal growth restriction. This was associated with altered placentation, in particular, formation of the Syn-TII cells in the labyrinth zone, and dysregulated expression of glucose and amino acid transporters in the placenta. This work emphasizes the importance of preconception endometrial health for successful pregnancy and identifies a novel mechanism by which prior viral infection can lead to implantation failure as well as later pregnancy complications.
LAY SUMMARY: Viral infections increase the risk of early pregnancy loss and later complications such as poor fetal growth. While viruses are known to affect the placenta, less is understood about their impact on the uterine lining, which must be healthy for pregnancy to begin. The uterine lining is made up of cells that go through changes each month called decidualization which is driven by hormones to help with implantation. In this study, we examined how early exposure to viral infection affects decidualization and pregnancy outcomes. Using cell cultures, 3D uterine models, and mouse studies, we found that exposure to viral factors impaired decidualization, reduced embryo implantation, and disrupted fetal growth. These effects were linked to abnormal placental development and altered nutrient transport to the fetus. Overall, our findings show that uterine health before conception is critical for successful pregnancy and identify a mechanism by which early maternal viral infections may lead to pregnancy complications. This provides exciting opportunities to screen and prevent complications much earlier on in pregnancy.

Keywords:  Infection; SGA; Toll-like receptor; decidua; endometrium; inflammation; placentation; resorption; trophoblast

DOI:  https://doi.org/10.1530/RAF-26-0018
Environ Health (Wash). 2026 Jul 17. 4(7): 1417-1432

Transcriptomic Perturbations in Placental Gene Expression Following Developmental Exposure to Perfluorooctanoic Acid (PFOA) or Hexafluoropropylene Oxide-Dimer Acid (HFPO-DA or GenX) in CD‑1 Mice Are Consistent with Placental Insufficiency.

Bevin E Blake, Vesna A Chappell, Colette N Miller, Helen Nguyen, Trina P Phan, Dhiral P Phadke, Michele R Balik-Meisner, Ignacio J Tripodi, Deepak Mav, Ruchir R Shah, Suzanne E Fenton.

  Per- and polyfluoroalkyl substances (PFAS) comprise a group of synthetic chemicals that are ubiquitous global contaminants. Exposure to certain PFAS has been associated with adverse pregnancy outcomes in humans and animal models including preeclampsia and low birth weight. The placenta is critical for a healthy pregnancy, and evidence suggests adverse pregnancy outcomes associated with exposure to certain PFAS may arise from aberrant placental development and/or function. To investigate the effects of two different PFAS on the placenta, samples collected from a prior study of pregnant CD-1 mice exposed to perfluorooctanoic acid (PFOA; 1 or 5 mg/kg) or hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX; 2 or 10 mg/kg) via oral gavage from embryonic day (E) 1.5 to E 11.5 or E 17.5 were used. Placentas were evaluated for morphometric, transcriptomic, and pathway-level effects. Although relatively few genes were significantly differentially expressed, multiple significantly enriched pathways were identified and were involved in biological processes related to hemostasis (e.g., coagulation and angiogenesis), the innate immune response (e.g., acute phase response signaling), and metabolism, synthesis, and transport of cholesterol, lipids, and bile acids (e.g., FXR/RXR activation and fatty acid metabolism). These pathway-level observations provide a mechanistic basis for observed morphometric changes, fetal:placental weight changes, and previously reported histopathological changes. Overall, these findings confirm proposed Adverse Outcome Pathways consistent with placental insufficiency and fetal nutrient restriction and PFAS-induced maternal vascular malperfusion of the placenta.

Keywords:  PFAS; hypertensive disorders of pregnancy; maternal vascular malperfusion; placental morphometry; preeclampsia

DOI:  https://doi.org/10.1021/envhealth.5c00350
J Physiol. 2026 Jul 20.

Thyroid antibodies in pregnancy: The placenta enters the conversation.

Sarah A Marshall.



Keywords:  placenta; pregnancy; thyroid hormone

DOI:  https://doi.org/10.1113/JP291999
Mol Biol Rep. 2026 Jul 22. pii: 1231. [Epub ahead of print]53(1):

MiR-126-3p promotes the development and progression of preeclampsia through the inactivation of the PI3K/AKT pathway.

Pingping Zhu, Yanjun Hu, Jiaying Shen, Jianqiong Zheng, Tingting Liao, Yeping Wang.

  Preeclampsia (PE) is a severe pregnancy complication that endangers maternal and fetal health. Accumulating evidence indicates that miR-126-3p is aberrantly expressed in PE placentas, yet its specific regulatory mechanism remains poorly defined. In the present study, we confirmed that miR-126-3p was significantly upregulated in placental tissues from PE patients. Functional assays demonstrated that overexpression of miR-126-3p suppressed proliferation, migration and invasion of HTR-8/SVneo trophoblast cells, and induced cell apoptosis, while miR-126-3p knockdown exerted opposite effects. Dual-luciferase reporter assay verified that miR-126-3p directly targeted PIK3R. Further mechanism experiments revealed that miR-126-3p inactivated the PI3K/AKT signaling pathway. Intervention with PI3K agonist and inhibitor further validated that miR-126-3p modulated trophoblast biological behaviors dependent on the PI3K/AKT pathway. In conclusion, elevated miR-126-3p contributes to the development and progression of PE via inhibiting the PI3K/AKT pathway through targeting PIK3R2. This work provides a novel molecular mechanism and potential therapeutic target for PE.

Keywords:  Preeclampsia; miR-126-3p༛PI3K༛proliferation༛invasion ༛migration

DOI:  https://doi.org/10.1007/s11033-026-12290-z
BMC Genomics. 2026 Jul 21.

Long-read transcriptome sequencing reveals isoform signatures in preeclamptic placentas.

Yancheng Song, YuTing Guo, Jie Wu, Debang Li, Xiaohua Wang, Yongchun Zuo, Yongqiang Xing.

   BACKGROUND: Preeclampsia is a major pregnancy-specific multisystem disorder that affects a substantial proportion of pregnancies globally and is a significant contributor to maternal and neonatal mortality. The molecular pathogenesis of this complex disease, however, remains elusive. Long-read sequencing technologies, with their ability to produce long, continuous reads, offer enhanced resolution for genomic studies. This study utilizes this technology to reveal novel insights at the isoform level in preeclamptic placentas.
RESULT: In this study, we enrolled six participants, including three with normotensive pregnancies and three with preeclamptic pregnancies. By integrating Oxford Nanopore Technologies (ONT) long-read sequencing, Illumina short-read RNA-Seq, ATAC-seq, and Whole-Genome Bisulfite Sequencing (WGBS) of placental tissues, we generated an isoform-resolved transcriptome. We identified a total of 48,175 isoforms, encompassing 19,584 previously unannotated splice variants from known genes and 2,744 novel isoforms from the newly identified loci. Furthermore, we found that epigenetic modifications in promoter regions trigger alternative first exon usage, leading to additional novel isoforms of key preeclampsia regulators (e.g., ADARG1).
CONCLUSION: This study expands the known transcriptomic landscape of the human placenta, revealing tens of thousands of previously unannotated isoforms. Integration of cross-platform validation and multi-omics datasets not only confirmed the robustness of these findings but also provided insights into their potential biological functions. The resources generated here establish a valuable foundation for future investigations into placental development and the molecular mechanisms of preeclampsia.

Keywords:  Alternative splicing; Long-read sequence; Preeclampsia

DOI:  https://doi.org/10.1186/s12864-026-13207-7
Placenta. 2026 Jul 17. pii: S0143-4004(26)00320-6. [Epub ahead of print]182 376-387

Differential transcript usage in the placenta in early onset preeclampsia.

Nufar Grinshpan, Tehila Mizrachi, Sapir Lianski, Raz Zarivach, Debra Goldman-Wohl, Ofer Beharier, Tal Shay.

   INTRODUCTION: Early onset preeclampsia (EOPE), a complex complication of pregnancy, is a major contributor to maternal and fetal morbidity and mortality. The only symptom consistently observed in EOPE is new maternal hypertension. Other symptoms vary among patients, posing challenges for early detection. There are currently no clinically accepted molecular markers other than FLT1, which is highly upregulated and displays a small change in its splicing ratio in EOPE placentas. However, an exhaustive search for changes in transcript use in EOPE has not been performed.
METHODS: Differential transcript usage (DTU) analysis was conducted between placental samples of women with and without EOPE for four public RNA sequencing datasets. To identify changes due to placental age, DTU events were compared to preterm placentas. Selected DTUs were experimentally validated in an independent cohort.
RESULTS: We identified 43 DTU events between term-birth and EOPE placentas in more than one dataset, and attributed 3 of the 43 to placental age. The genes that carry those DTUs were enriched for cell junction and cell membrane-associated pathways, which were previously suggested to be altered in preeclampsia at the gene expression level, although the alteration was mediated by other genes.
DISCUSSION: Alterations in transcript usage are part of the EOPE molecular mechanism. The validated DTUs in FLT4, ADGRG6, MXI1, and LCP1 may contribute to the development of EOPE. Surprisingly, the splicing change in FLT4 takes place in the intracellular domain, whereas the preeclampsia-associated changes in its paralog FLT1 are in the extracellular domain.

Keywords:  ADGRG6; Differential splicing; Differential transcript use; Early onset preeclampsia; FLT1; FLT4

DOI:  https://doi.org/10.1016/j.placenta.2026.07.006
Placenta. 2026 Jul 06. pii: S0143-4004(26)00315-2. [Epub ahead of print]182 354-367

A small GTPase, RHOH, is upregulated in the uterus during miscarriage in human and mouse model.

Raj Kumar Verma, Sudarsan Sarkar, Pushp Lata Sankhwar, Snigdha Tripathi, Prachi Chaubey, Rajesh Kumar Jha.

   INTRODUCTION: The small GTPase RAC1 is crucial for blastocyst attachment to the endometrium during embryo implantation. RAC1 is regulated by RHOH, whose role in pregnancy establishment we investigated.
METHODS: We analyzed uterine RHOH expression by immunoblotting during the endometrial receptivity window for embryo attachment and miscarriage (LPS-, and IFN-γ-induced), and abortion (RU-486-, and ormeloxifene-induced), using a mouse model, human-origin placenta and decidua-placenta, and human endometrial epithelial cells. Additionally, we determined the cellular localization of RHOH by immunohistochemistry.
RESULTS: RHOH levels were elevated in placentas from human miscarriage cases (n = 7) and in decidua-placenta tissues (n = 13) from these cases. In the mouse model, RHOH expression was downregulated at the implantation site during both receptive and post-receptive stages. Conversely, during pseudopregnancy, uterine RHOH expression was higher in the pre-receptive stage. RHOH was primarily localized in stromal and epithelial cells at all stages examined. In the decidualized uterus, RHOH expression was reduced and predominantly detected in stromal cells. Additionally, upregulation of RHOH was observed in the uterus from miscarriage/abortion cases and inter-implantation sites in non-miscarriage/abortion mouse models. Furthermore, the downstream effector RAC1 was also increased in the miscarriage/abortion mouse models.
DISCUSSION: RHOH was upregulated in the placenta and decidua-placenta tissues of human miscarriage cases. Similarly, in mouse models, RHOH expression increased in the endometrium during miscarriage/abortion. In contrast, RHOH expression decreased at implantation sites and in the decidualized endometrium. These findings suggest that RHOH functions as a regulator of endometrial receptivity, potentially involving RAC1, and that their upregulation is associated with miscarriage/abortion.

Keywords:  Abortion by d/l-ormeloxifene; Decidualization; Endometrial receptivity for embryo implantation; Human miscarriage; Interferon-gamma (γ); Miscarriage/abortion mouse model by lipopolysaccharide; Pseudopregnancy; RAC1; RHOH; RU-486

DOI:  https://doi.org/10.1016/j.placenta.2026.07.002