bims-placeb 2026-09-27 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–09–27
ten papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

HIF2α-Regulated Pathways Control Human Extravillous Trophoblast Functions by Modulating Cell-to-Cell Communication Through Extracellular Vesicles.
Placental trophoblasts exhibit iron dysregulation and ferroptosis signaling associated with SARS-CoV-2 restriction.
DNA methyltransferases in trophoblast differentiation: extant knowledge and emerging paradigms.
Cuproptosis: a novel mechanism linking placental metabolic stress to trophoblast injury in preeclampsia.
Placental endoglin protein expression across gestation in normal pregnancy and preeclampsia: Implications for anti-angiogenic therapeutic strategies.
Inhibition of SLC38A2 and loss of its N-glycosylation impair decidualization by promoting autophagy and apoptosis.
The curious case of the placental genome.
Maternal obesity programs offspring metabolic dysfunction via small extracellular vesicle-mediated epigenetic remodeling.
Influence of arteries, vein and placenta interactions on the blood flow in the human umbilical cord.
Olfactomedin 4 marks progenitor cells that give rise to the secretory cell lineage in the mouse cervix.

bioRxiv. 2026 Sep 16. pii: 2026.09.14.751396. [Epub ahead of print]

HIF2α-Regulated Pathways Control Human Extravillous Trophoblast Functions by Modulating Cell-to-Cell Communication Through Extracellular Vesicles.

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

Successful pregnancy in humans requires extravillous trophoblast (EVT) cells to invade the endometrium, remodel maternal tissue, and establish a functional placenta. How trophoblasts communicate with the endometrium to coordinate this remodeling remains poorly understood. We previously demonstrated that human endometrial stromal cells communicate through secreted extracellular vesicles (EVs) at the maternal-fetal interface, but whether trophoblasts engage in reciprocal EV-mediated communication remained unknown. Here, using an in vitro trophoblast stem cell differentiation model, we show that EVT cells secrete EVs carrying protein cargo that regulates endometrial stromal cell remodeling, revealing a previously unrecognized arm of maternal-fetal communication. Hypoxia, a defining feature of early placentation, enhanced EV secretion, EVT differentiation, and trophoblast invasion, and these responses required hypoxia-inducible factor 2α (HIF2α). Loss of HIF2α impaired EVT differentiation and significantly reduced EV production. Functionally, EVT-derived EVs altered endometrial stromal cell remodeling, in part through HIF2α-regulated cargo proteins including matrix metalloproteinase 2 (MMP2). MMP2 depletion reduced both EVT invasion and EV-mediated stromal remodeling, identifying MMP2 as an important mediator of trophoblast-maternal communication. Strikingly, MMP2 deficiency also redirected trophoblast cell fate toward the syncytiotrophoblast (ST) lineage, accompanied by morphological and molecular genetic hallmarks of syncytialization, revealing an unexpected role for a matrix-remodeling enzyme in trophoblast lineage specification. Together, these findings establish a hypoxia-regulated trophoblast EV signaling pathway that links oxygen sensing to trophoblast differentiation, invasion, and maternal tissue remodeling, and reveal an unexpected connection between extracellular matrix remodeling and trophoblast cell-fate decisions during early placental development.

DOI: https://doi.org/10.64898/2026.09.14.751396
Cell Rep. 2026 Sep 23. pii: S2211-1247(26)01118-6. [Epub ahead of print]45(10): 118040

Placental trophoblasts exhibit iron dysregulation and ferroptosis signaling associated with SARS-CoV-2 restriction.

Eliza R McColl, Deepak Kumar, Brittany R Jones, Nikole Marks, Emily Diveley, Rowan Karvas, Thorold W Theunissen, Jeannie C Kelly, Indira U Mysorekar.

  Prenatal SARS-CoV-2 infection is associated with adverse pregnancy outcomes, but mechanisms shaping placental viral spread and injury remain unclear. We show that SARS-CoV-2 induces ferroptosis-linked iron dysregulation in the placenta as a potential attempt to limit trophoblast infection. Placentas from early gestation infection exhibit persistent viral protein expression, iron accumulation, disrupted iron transport protein localization, and reduced expression of the ferroptosis inhibitor glutathione peroxidase 4 (GPX4) at term. In trophoblast cells and stem cell-derived trophoblast organoids with apical-out polarity, SARS-CoV-2 Delta infection suppresses the iron efflux transporter ferroportin and ferroptosis inhibitors GPX4 and phospholipase A2 group VI (PLA2G6), promoting ferroptotic signaling. Pharmacological activation of ferroptosis reduces viral titers in trophoblasts, supporting a potential antiviral role during infection. Together, these findings identify a possible mechanism through which the placenta restricts SARS-CoV-2 levels. However, this response is accompanied by placental iron sequestration that may compromise maternal-fetal iron transfer, highlighting a delicate balance between iron and ferroptosis-mediated protection and damage.

Keywords:  COVID-19; CP: immunology; FSP1; GPX4; SLC40A1; ferroportin; iron homeostasis; lipid peroxidation; maternal-fetal interface; nutritional immunity; programmed cell death

DOI:  https://doi.org/10.1016/j.celrep.2026.118040
Biol Reprod. 2026 Sep 21. pii: ioag203. [Epub ahead of print]

DNA methyltransferases in trophoblast differentiation: extant knowledge and emerging paradigms.

Enoch Appiah Adu-Gyamfi.

  Successful human pregnancy depends on the precise spatio-temporal orchestration of trophoblast lineages to establish a functional feto-maternal interface. While DNA methyltransferases (DNMTs) are recognized as core drivers of epigenetic programming, emerging evidence reveals that they are not merely passive transcriptional silencers, but also dynamic architectural coordinators of placental morphogenesis. This work presents the roles of maintenance (DNMT1) and de novo (DNMT3A, DNMT3B) methyltransferases in dictating the precise timing of trophoblast fate transitions. During trophoblast fusion, a coordinated downregulation of the DNMT machinery permits the localized demethylation and activation of vital fusogenic networks. Conversely, extravillous trophoblast invasion requires active DNMT-mediated hypermethylation to silence anti-invasive genes. Disruptions in these tightly synchronized epigenetic pulses trigger lineage-specific malfunctions that are associated with the pathogenesis of gestational disorders such as preeclampsia and fetal growth restriction. Despite these insights, fundamental knowledge gaps remain unaddressed. For instance, how DNMT expression and enzymatic assembly adapt to localized physical forces at the feto-maternal interface remains unknown. It is also unclear whether DNMTs exhibit non-canonical and non-enzymatic structural scaffolding properties during early implantation, and whether functional DNMT machinery is actively encapsulated within placenta-derived extracellular vesicles to cross the fetal blood-brain barrier and alter distant fetal neurodevelopment. Resolving these profound mechano-chemical, structural, and systemic knowledge gaps is essential to deciphering early human development and identifying novel therapeutic targets in feto-maternal medicine.

Keywords:  DNA Methyltransferase; Fetal Growth Restriction; Placenta; Preeclampsia; Trophoblast

DOI:  https://doi.org/10.1093/biolre/ioag203
Front Endocrinol (Lausanne). 2026 ;17 1926486

Cuproptosis: a novel mechanism linking placental metabolic stress to trophoblast injury in preeclampsia.

Ling Liu, Baoxiang Xing, Yan Zhang.

  Preeclampsia (PE) is characterized by placental hypoxia, metabolic stress, trophoblast dysfunction, and impaired spiral artery remodeling, but the mechanisms linking these abnormalities remain incompletely understood. Cuproptosis, a recently identified form of regulated cell death driven by copper-dependent aggregation of lipoylated tricarboxylic acid cycle proteins, may provide a mechanistic link between placental metabolic stress and trophoblast injury. Here, we propose a hypothesis in which hypoxia-induced glycolytic reprogramming and lactate accumulation promote histone H3K18 lactylation, activate GRHL2, and increase SLC31A1/CTR1-mediated copper uptake. Subsequent FDX1-dependent copper reduction, DLAT aggregation, Fe-S cluster loss, and mitochondrial proteotoxic stress may preferentially affect mitochondria-rich villous syncytiotrophoblasts, while also impairing EVT function. Cuproptosis may interact with ferroptosis and oxidative stress through shared metal-redox and mitochondrial vulnerabilities. Although current evidence does not establish cuproptosis as an initiating cause of PE, it may amplify placental dysfunction. Targeting copper transport, mitochondrial stress, or pathway-specific biomarkers warrants further investigation.

Keywords:  copper homeostasis; cuproptosis; placental hypoxia; preeclampsia; trophoblast injury

DOI:  https://doi.org/10.3389/fendo.2026.1926486
Placenta. 2026 Sep 10. pii: S0143-4004(26)00677-6. [Epub ahead of print]183 177-185

Placental endoglin protein expression across gestation in normal pregnancy and preeclampsia: Implications for anti-angiogenic therapeutic strategies.

Jayasri Basu, Ashley Armstrong, Liaisan Uzianbaeva, Alireza Mehdizadeh, Magdy Mikhail.

   INTRODUCTION: Preeclampsia is a human-specific hypertensive disorder of pregnancy characterized by new-onset hypertension and proteinuria after 20 weeks of gestation. Placental dysfunction and angiogenic imbalance are central to its pathophysiology. Endoglin, a membrane-bound glycoprotein and precursor of soluble endoglin (sEng), contributes to impaired placentation. This study examined placental endoglin protein expression across normal gestation and compared it with expression in preeclampsia.
METHODS: Placentas from normotensive pregnancies across all three trimesters and from women with preeclampsia were collected under IRB-approved protocols. Chorionic villi were isolated, and endoglin protein expression was quantified using a monoclonal anti-human Endoglin/CD105 ELISA kit, DY1097. Of a total of 333 placentas, 324 with gestational age ≥37-weeks comprised the primary dataset, and 9 preeclamptic placentas delivered before 37 weeks were analyzed separately. Group differences were assessed using ANOVA, with significance set at p < 0.05.
RESULTS: Endoglin protein expression varied significantly across gestation (p < 0.001). Mean levels (ng/100 mg tissue) were: first trimester 40.94 (n = 116), second trimester 29.24 (n = 79), and third trimester 30.93 (n = 100). Preeclamptic placentas exhibited markedly higher levels (50.77; n = 29). Expression patterns were comparable between Black American and Hispanic women.
DISCUSSION: Placental endoglin protein expression peaks in early gestation and is significantly upregulated in preeclampsia. These findings support the role of angiogenic imbalance in disease pathogenesis and provide a biological marker distinguishing normal from pathological placentation. The data also offer a foundation for estimating early pregnancy sEng levels, which may inform dosing strategies for future monoclonal antibody therapies targeting sEng.

Keywords:  Biomarker; ELISA; Endoglin protein; Normal pregnancy; Placenta; Preeclampsia; Trimesters; sEng

DOI:  https://doi.org/10.1016/j.placenta.2026.09.003
Life Sci. 2026 Sep 21. pii: S0024-3205(26)00507-2. [Epub ahead of print]405 124698

Inhibition of SLC38A2 and loss of its N-glycosylation impair decidualization by promoting autophagy and apoptosis.

Hongshuo Zhang, Xiaolan Zeng, Xinyi Gao, Zishuo Wu, Zirong Wang, Xiaotong Li, Jingxuan Wei, Youfei Guan, Ying Kong.

  Decidualization plays a crucial role in embryo implantation and successful pregnancy. Dysregulation and dysfunction of decidualization caused by any factor may lead to a variety of pregnancy related disorders. However, many underlying molecular pathways regulating decidualization remain unknown, especially the impact of glycosylation. Protein glycosylation is vital for maternal fetal crosstalk, and its aberrance may result in adverse pregnancy outcomes. This study focused on SLC38A2, a member of the solute carrier family (neutral amino acid transporter), to investigate its function in endometrial decidualization and the effect of its N-glycosylation modification. Our results demonstrated that SLC38A2 was highly expressed in mouse endometrial stromal cells during the peri implantation period and in in vitro decidualized endometrial stromal cells (ESCs), and inhibition of SLC38A2 impeded the decidualization process. N-glycosylation of SLC38A2 was essential for its function by affecting protein stability and membrane localization, as well as its glutamine transport activity. Mechanistically, downregulation of SLC38A2 or loss of its N-glycosylation suppressed the mTOR pathway and promoted autophagy and apoptosis in decidualized ESCs. These findings suggest that SLC38A2 and its glycosylation modification may serve as potential therapeutic targets for decidual abnormalities and implantation failure, providing novel insights into how amino acid metabolic dysregulation contributes to embryo implantation failure caused by decidualization defects.

Keywords:  Apoptosis; Autophagy; Decidualization; N-glycosylation; SLC38A2

DOI:  https://doi.org/10.1016/j.lfs.2026.124698
Development. 2026 Sep 15. pii: dev205800. [Epub ahead of print]153(18):

The curious case of the placental genome.

Zoé Ducarne, Agathe Chaigne, My Anh Truong.

  The human placenta is among the few, if not the only, healthy mammalian tissues that may exploit a cancer-like somatic genome for its function. Acting simultaneously as the lungs, kidneys, liver and gastrointestinal tract, the placenta mediates nutrient and gas exchange, blocks out toxins and pathogens, removes fetal waste, and secretes hormones essential for pregnancy. Recent research has revealed that the placenta is a genomically distinctive organ with an unusually high mutational load, abundant structural variations, prevalent aneuploidy and genome amplification, as well as a tissue-sized multinucleated syncytium. These features may underlie its invasiveness and high levels of cell proliferation, as well as its dual role as both exchange platform and barrier between mother and fetus. Here, we review our current understanding of the unique genomic features of the human placenta and their potential functions. We identify prevalent gaps in current literature and suggest new research directions to address the need for a better understanding of placental genomics. Such understanding has the potential to inform clinical diagnostic and management strategies for pregnancy complications, thereby improving pregnancy outcomes.

Keywords:  Aneuploidy; Genome amplification; Genomics; Mutation; Placenta; Structural variant

DOI:  https://doi.org/10.1242/dev.205800
Nat Commun. 2026 Aug 25. pii: 10139. [Epub ahead of print]17(1):

Maternal obesity programs offspring metabolic dysfunction via small extracellular vesicle-mediated epigenetic remodeling.

Huichen Song, Dameng Li, Lina Ma, Jin Wang, Nina Zhang, Chao Yan, Ke Zen, Xi Chen, Qipeng Zhang, Xiaohong Jiang, Jing Li, Zhijuan Ge, Yujing Zhang, Chen-Yu Zhang, Liang Li.

Maternal obesity is linked to heightened metabolic disease risk in offspring, but the mediators of this intergenerational effect remain unclear. Using a diet-induced obesity (DIO) mouse model, we showed that maternal circulating small extracellular vesicles (sEVs) crossed the placenta and delivered obesity-associated miRNAs to the fetal liver, with lasting consequences for insulin sensitivity in male offspring. Among these miRNAs, miR-29a-3p was pathologically elevated and targeted both DNA methyltransferases and demethylases, thereby reshaping the DNA methylation landscape. This included hypomethylation of the Pgc-1α locus, a key regulator of gluconeogenesis, which resulted in premature activation of hepatic gluconeogenesis that contributed to the persistent metabolic dysfunction in adulthood in male offspring. These findings identify a transplacental sEV-miRNA-epigenetic axis that perturbs fetal metabolic programming and may represent a conserved mechanism underlying the developmental origins of metabolic disease.

DOI: https://doi.org/10.1038/s41467-026-77161-4
PLoS One. 2026 ;21(9): e0358954

Influence of arteries, vein and placenta interactions on the blood flow in the human umbilical cord.

Hatim Machrafi, Xavier Capelle, Sébastien Grandfils, Christine Vanlinthout, Frédéric Kridelka, Pierre C Dauby.

The mechanisms governing umbilical venous return in early pregnancy remain incompletely understood, particularly the roles and interactions of arterial pulsatility, umbilical cord mechanics, and placental compliance. In this study, we combine numerical modelling and in vivo measurements to investigate hemodynamic and mechanical interactions within the feto-placental circulation. A fully coupled three-dimensional fluid-structure interaction model of the umbilical cord-comprising two pulsatile arteries, a compliant vein, and Wharton's jelly-was developed and connected to a zero-dimensional compliant placental model. The model incorporates arterial pressure pulsations, vessel wall deformation, and mechanical coupling within the closed arteries-placenta-vein system. In parallel, Doppler ultrasound measurements were performed in singleton pregnancies to assess umbilical venous flow at the placental insertion and in a free loop of the cord. Numerical results show that venous flow is dynamically modulated by arterial pulsations transmitted through both the cord and placenta, producing phase-shifted venous deformation and low-amplitude oscillations. Despite strong placental damping, the model predicts measurable venous flow oscillations with increasing amplitude toward the fetus. This behaviour depends on cord elasticity and placental compliance. The numerical model also points out that mechanical interactions between arteries, vein, and Wharton's jelly contribute positively to the mean flow rate, demonstrating a pulsometer-like effect. Doppler measurements confirm that venous flow is not strictly steady and that oscillation amplitude increases toward the fetus, which is consistent with simulations. Overall, our combined computational and in vivo approach reveals that the interplay between arterial pulsations and placental compliance is a key driver of umbilical venous return. Finally, beyond their physiological significance, our findings may contribute to the design and optimization of future artificial placenta and extracorporeal fetal support systems.

DOI: https://doi.org/10.1371/journal.pone.0358954
Development. 2026 Sep 22. pii: dev.205710. [Epub ahead of print]

Olfactomedin 4 marks progenitor cells that give rise to the secretory cell lineage in the mouse cervix.

ShanmugaPriyaa Madhukaran, Yevgenia Fomina, Govindkumar Balagannavar, Elizabeth Payne, Jason Wilson, Lei Wang, Gary Hon, Maria Florian Rodriguez, Mala Mahendroo.

  Goblet cells, a specialized secretory cell type of mucosal epithelia, provide barrier function to the female lower reproductive tract. Current understanding proposes that squamous and secretory cells of the mouse cervicovaginal epithelium arise from a common Trp63+ progenitor. By contrast, in humans, a Krt8+ progenitor gives rise to endocervical secretory cells, whereas a Trp63+ progenitor gives rise to squamous cells in the ectocervix and vagina. We identify a population of Krt8+Trp63- epithelia that is retained in the mouse cervicovaginal epithelium during postnatal development and adulthood, with Olfactomedin 4 as a specific marker of this lineage. Adult lineage tracing and marker assessment during postnatal development support a revised model in which two epithelial progenitors are delineated by postnatal day 15. Olfactomedin4+ progenitors give rise to goblet cells, while Trp63+ progenitors give rise to keratinocytes in the cervicovaginal canal. Consistent with goblet cell expansion in pregnancy, Olfm4+ progenitors proliferate in early gestation and progesterone promotes their differentiation. These findings reveal a previously unrecognized similarity between mice and humans in which goblet and keratinized cell subtypes are derived from two independent progenitor populations.

Keywords:  Cervix; Epithelia; Female reproductive tract development; Goblet cells; Non-pregnant and pregnant cervix; Olfactomedin 4

DOI:  https://doi.org/10.1242/dev.205710