bims-placeb 2026-02-15 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–02–15
eighteen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Single-cell atlas of the equine placenta reveals cellular heterogeneity and gestational-stage-associated programs.
Fractalkine (Chemokine CX3CL1) Signaling During Placentation and Placental Function.
DHODH inhibition impairs mitochondrial function and extravillous trophoblast invasion: Protective roles of quercetin and riboflavin.
Estradiol promotes trophoblasts syncytization by upregulating ESR2/SP1 transcription factor-mediated poFUT2 expression.
Regulatory T cells and decidual vascular remodelling - A new piece in the preeclampsia puzzle.
Tim1 Deficiency Mediates Gestational Hyperglycemia-Related Syncytiotrophoblast Dysfunction and Fetal Growth Restriction.
Trophoblast ferroptosis restricts SARS-CoV-2 spread in the placenta.
Placental transfer characteristics and functional impact of SGLT2 inhibitors in human experimental models.
Placental mRNA and miRNA dynamics associated with lipid metabolism pathways in pregnancies affected by obesity.
Recreational Cannabis Use During Human Pregnancy: Its Effects on the Placenta and Endocannabinoid System.
Quantitative assessment of arterial remodeling from confocal microscopy image analysis of the mid-gestation mouse decidua.
Why reproduction has probably been very problematic in Neanderthals: The fabulous history of (pre)eclampsia.
scRNA-seq of preeclamptic trophoblasts identifies EBI3, COL17A1, miR-27a-5p, and miR-193b-5p as hypoxia markers: validation of neuradapt as a superior mimetic to cobalt chloride.
METTL3-regulated m6A modification modulates autophagy of placental mesenchymal stem/stromal cell by YTHDF3-mediated degradation of LncRNA GAS5 in preeclampsia.
IN-UTERO PROTEIN DEFICIENCY LEADS TO IMPAIRED HEPATIC LIPID METABOLISM IN ADULT MALE RATS.
FABP4 is highly expressed in preeclamptic placentas and regulates trophoblast lipid metabolism, mitochondrial function, and oxidative stress in vitro.
ELABELA targets the METTL3/PI3K/AKT axis to enhance trophoblast invasion in early-onset preeclampsia.
Maternal Obesity Decreases Offspring Lifespan.

Placenta. 2026 Feb 07. pii: S0143-4004(26)00051-2. [Epub ahead of print]176 13-21

Single-cell atlas of the equine placenta reveals cellular heterogeneity and gestational-stage-associated programs.

Margo H Verstraete, Jamie K Norris, Shavahn C Loux, Ward De Spiegelaere, Mariano Carossino, Peter Daels, Pouya Dini.

   INTRODUCTION: The placenta mediates critical interactions between mother and offspring that guide development and impact long-term health. Despite its importance, the cellular organization of the equine (Equus caballus) placenta remains poorly defined. The equine epitheliochorial placenta, characterized by the absence of trophoblast invasion and prominent endocrine activity, provides a unique comparative model for studying placental cellular composition and development.
METHODS: We applied single-cell RNA sequencing to chorioallantois tissue collected from first-trimester (n = 1) and term (n = 2) equine placentas to generate a comprehensive cellular atlas across gestation.
RESULTS: We identified four major fetal cell lineages: trophoblast, stromal, endothelial, and Hofbauer-like cells. Subclustering revealed ten transcriptionally distinct cell populations, highlighting previously unrecognized heterogeneity within trophoblast, stromal, and Hofbauer-like cells. Comparative analyses between first-trimester and term placentas demonstrated marked gestational-stage-associated differences in cellular composition and gene expression programs. The early-stage placenta was dominated by shared transcriptional signatures associated with growth, extracellular matrix organization, and cell cycle activity, whereas term placentas exhibited increased immune-related and tissue remodeling pathways and greater cell type-specific specialization.
DISCUSSION: Together, this study provides the first high-resolution single-cell transcriptomic atlas of the equine placenta, offering fundamental insights into placental cellular diversity and developmental dynamics. This resource establishes a foundation for comparative placental biology and for investigating equine gestational disorders.

Keywords:  Chorioallantois; Epitheliochorial placenta; Equine; First-trimester placenta; Term placenta; scRNAseq

DOI:  https://doi.org/10.1016/j.placenta.2026.02.004
Int J Mol Sci. 2026 Jan 23. pii: 1172. [Epub ahead of print]27(3):

Fractalkine (Chemokine CX3CL1) Signaling During Placentation and Placental Function.

Dariusz Szukiewicz.

  Precise postimplantation regulation of placental development with trophoblast invasion of uterine spiral arteries and the generation of low-resistance circulation within the utero-fetal unit are crucial for the further development of pregnancy. Cytokines, including chemokines, are crucial for ensuring placental function throughout pregnancy. The CX3CL1 chemokine (fractalkine), occurring in its membrane-bound form and as a soluble chemokine (sCX3CL1), acts on its sole receptor, namely, CX3CR1, creating a signaling axis that orchestrates the balance of cellular interactions, immune responses, and tissue remodeling needed at every stage of a healthy pregnancy. CX3CL1/CX3CR1 signaling is characterized by the activation of several downstream signaling cascades that interact with numerous pathways, coordinate with other receptors and modulate the expression of relevant genes. This review presents the current state of knowledge regarding the role of CX3CL1 and its interaction with CX3CR1 in establishing placental homeostasis during placentation, and it discusses the contribution of disturbances in this interaction to placental dysfunction. These disturbances are part of the pathomechanisms of specific pregnancy complications, including preeclampsia (PE) and diabetes. The potential to target the CX3CL1/CX3CR1 axis via therapeutic intervention at the level of the placenta in PE- and diabetes-complicated pregnancy is the subject of ongoing research.

Keywords:  CX3CR1; chemokine CX3CL1; fractalkine; fractalkine receptor; fractalkine signaling; placenta; placental function; pregnancy; pregnancy complications

DOI:  https://doi.org/10.3390/ijms27031172
J Pharmacol Sci. 2026 Mar;pii: S1347-8613(26)00001-0. [Epub ahead of print]160(3): 143-151

DHODH inhibition impairs mitochondrial function and extravillous trophoblast invasion: Protective roles of quercetin and riboflavin.

Kanoko Yoshida, Kazuya Kusama, Kana Kanazawa, Yu Kawaguchi, Atsuya Tsuru, Mikihiro Yoshie, Kazuhiro Tamura.

  Hypertensive disorders of pregnancy (HDPs) are serious complications that pose significant risks to both maternal and fetal health. In HDP, placental circulatory impairment is generally attributed to defective differentiation and invasion of the human extravillous trophoblasts (EVTs). Our previous RNA-seq analysis of placentas from early-onset HDP patients revealed decreased expression of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme involved in pyrimidine biosynthesis. DHODH inhibition is hypothesized to induce mitochondrial dysfunction. In this study, we investigated whether DHODH inhibition affects mitochondrial homeostasis and invasive capacity in EVT cell line. Selective DHODH inhibitors resulted in decreased mitochondrial membrane potential, upregulation of mitochondrial degradation factors, and mitochondrial fragmentation. Inhibition of DHODH or mitochondrial complexes I, II, and IV led to impaired cell invasion, accompanied by an increase in SA-β-gal-positive senescent cells. Treatment with quercetin or riboflavin, enhancers of mitochondrial ATP functions, partially restored invasive capacity and reduced senescent cell accumulation under mitochondrial stress conditions. Thus, DHODH inhibition in EVTs induces cellular senescence and diminished capacity for invasion. Mitochondrial activators such as quercetin and riboflavin may hold therapeutic promise for ameliorating the pathology of HDPs.

Keywords:  Cell invasion; Dihydroorotate dehydrogenase; Extravillous trophoblasts; Hypertensive disorder of pregnancy; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.jphs.2026.01.001
Mol Cell Endocrinol. 2026 Feb 09. pii: S0303-7207(26)00034-1. [Epub ahead of print] 112757

Estradiol promotes trophoblasts syncytization by upregulating ESR2/SP1 transcription factor-mediated poFUT2 expression.

Yaqi Li, Yuyu Lei, Yu Chen, Luyao Wang, Yanbo Wang, Wenbo Wang, Jiao Wang, Shuai Liu.

  The multinucleated syncytiotrophoblast (STB) at the maternal-fetal interface is formed through the continuous fusion of mononucleated cytotrophoblasts (CTBs). Estradiol and protein glycosylation are known to participate in trophoblast syncytialization. O-fucosyltransferase 2 (poFUT2), which catalyzes protein O-fucosylation, has been implicated in placental development. However, the exact role of poFUT2 in trophoblast syncytialization remains unclear. The aim of the present study is to investigate the function of the estradiol-poFUT2 axis in trophoblast syncytialization. Here, by applying immunohistochemistry, we found that poFUT2 expression was decreased in syncytiotrophoblast of placental tissues from preeclampsia patients. Employing a cell-model to induce trophoblast syncytialization in vitro, we demonstrated that poFUT2 promotes trophoblast cell fusion. Mechanistically, during pregnancy, elevated estradiol upregulated the expression of poFUT2 and enhanced syncytium formation. Chromatin immunoprecipitation and co-immunoprecipitation assays indicated that the regulation depends on the participation of SP1 in the estrogen receptor 2 (ESR2)-mediated regulation of the poFUT2 gene. Conclusively, our findings demonstrated that estradiol upregulated poFUT2 expression via the ESR2/SP1 complex, increasing trophoblast cell differentiation and fusion.

Keywords:  ESR2/SP1 complex; Estradiol; Glycosylation; Preeclampsia; Syncytiotrophblast

DOI:  https://doi.org/10.1016/j.mce.2026.112757
J Reprod Immunol. 2026 Jan 30. pii: S0165-0378(26)00016-1. [Epub ahead of print]174 104847

Regulatory T cells and decidual vascular remodelling - A new piece in the preeclampsia puzzle.

Sarah A Robertson, Alison S Care.

  Improperly constrained inflammation at the placental-uterine interface is strongly implicated as a causal factor in preeclampsia. Inflammatory mediators and leukocytes in the decidua are key features of the underlying pathophysiology, with potential to cause uterine vascular anomalies that give rise to compromised placental function, particularly in the severe, early onet form of the disease. While uterine natural killer (uNK) cells are clearly involved, a critical question has been whether and how T cells might also contribute. Regulatory T (Treg) cells, immune-regulatory T cells that counteract inflammation and promote robust placentation, are commonly perturbed in preeclampsia, and systemic Treg cell insufficiency often precedes symptom onset. This review summarizes recent evidence from preclinical studies that collectively point to Treg cells as critical regulators of decidual spiral artery adaptation in early pregnancy, in part through modulating uNK cells. Transient depletion of Treg cells during early placental morphogenesis in mice causes fetal growth restriction and fetal loss associated with impaired remodeling of decidual spiral arteries, compromised uterine artery function, and uNK cell defects. Together with RNA sequencing data to evaluate the effects of Treg cell depletion on decidual biology, the findings provide compelling evidence to implicate Treg cells as essential upstream drivers of uterine vascular adaptation to pregnancy, through a mechanism involving regulation of uNK cells and trophoblast invasion. This new insight provides an important link between adaptive immune tolerance and spiral artery remodeling to better understand the origins of preeclampsia.

Keywords:  Decidual vascular remodelling; Immune tolerance; Placental development; Treg cells; UNK cells

DOI:  https://doi.org/10.1016/j.jri.2026.104847
Adv Sci (Weinh). 2026 Feb 11. e08686

Tim1 Deficiency Mediates Gestational Hyperglycemia-Related Syncytiotrophoblast Dysfunction and Fetal Growth Restriction.

Junsen She, Rui Liu, Chen Fang, Shuyu Zhang, Yizhi Hu, Fei Guo, Yuhang Long, Mengzhen Ding, Haiyan Wu, Bokang Zhou, Zexin Yang, Ying Jiang, Jianzhong Sheng, Ling Gao, Hefeng Huang.

  Gestational hyperglycemia (GHG) causes fetal growth restriction (FGR), while its mechanism remains incompletely understood. Defects in the syncytiotrophoblast, which is pivotal for maternal-fetal substance exchange, adversely affect fetal development. Whether dysfunction in syncytiotrophoblast is involved in GHG-related FGR remains unclear. In this study, we used an STZ-induced GHG mouse model and found that GHG-induced FGR (44.5% reduction in fetal weight) was associated with a 28.3% decrease in placental efficiency. Immunofluorescence and transmission electron microscopy examinations revealed defective formation of the syncytiotrophoblast layer in GHG placenta, resulting from impaired fusion of trophoblast cells. Gene expression profiling and staining analysis of the placenta revealed that Tim1, a phosphatidylserine-binding protein, was 43.5% downregulated in GHG placenta. In vitro studies confirmed that hyperglycemia decreased Tim1 and led to trophoblast fusion defects. Tim1 silence alone recapitulated the effects of hyperglycemia on trophoblast fusion, while Tim1 overexpression rescued the anti-fusion effects of hyperglycemia. Moreover, we generated a Tim1 knockout mouse strain, and observed that Tim1 deficiency alone induced defective formation of syncytiotrophoblast and FGR during pregnancy. Further analysis revealed that Tim1 was downregulated by hyperglycemia-related oxidative stress. Antioxidant treatment during pregnancy reversed Tim1 downregulation, promoted syncytiotrophoblast formation and improved FGR. Finally, the reduction of TIM1 expression was confirmed in human placenta with pre-gestational diabetes and FGR. These findings suggest that Tim1 downregulation in GHG inhibits placental syncytiotrophoblast formation and contributes to FGR.

Keywords:  fetal growth restriction; gestational hyperglycemia; oxidative stress; syncytiotrophoblast

DOI:  https://doi.org/10.1002/advs.202508686
bioRxiv. 2026 Jan 26. pii: 2026.01.26.701742. [Epub ahead of print]

Trophoblast ferroptosis restricts SARS-CoV-2 spread in the placenta.

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

Prenatal SARS CoV 2 infection is associated with adverse pregnancy outcomes, but placental mechanisms that restrict viral spread remain unclear. Here we show that SARS CoV2 exposure induces ferroptosis-linked iron dysregulation in the placenta as a host defense. Human placentas from early gestation SARS CoV 2 exposed pregnancies exhibited persistent viral protein expression at term, iron accumulation, disrupted localization of iron transport proteins, and reduced expression of the ferroptosis inhibitor, GPX4. In trophoblast cells and newly generated stem cell-derived trophoblast organoids (SCTOs) with physiological apical-out polarity, infection with live SARS CoV 2 Delta variant suppressed expression of iron efflux transporter, ferroportin and ferroptosis inhibitors, GPX4 and PLA2G6, promoting lipid peroxidation and ferroptotic signaling. Sub-lethal pharmacological activation of ferroptosis reduced viral titers in trophoblasts, indicating an antiviral function. Together, these results uncover a new mechanism through which the placenta attempts to restrict SARS CoV 2 replication. However, this protective response is accompanied by placental iron sequestration, which may compromise maternal-fetal iron transfer and help explain iron deficiency and anemia reported in infants born after prenatal SARS CoV 2 exposure, highlighting a delicate balance between iron and ferroptosis-mediated protection and damage with implications for pregnancy outcomes.

DOI: https://doi.org/10.64898/2026.01.26.701742
Biomed Pharmacother. 2026 Feb 12. pii: S0753-3322(26)00129-0. [Epub ahead of print]196 119097

Placental transfer characteristics and functional impact of SGLT2 inhibitors in human experimental models.

Sabrina Kuoni, Alexandra Dolder, Roger Lehmann, Regula Steiner, Nicole Ochsenbein-Kölble, Ana Paula Simões-Wüst.

  Understanding the mechanisms of drug transfer across the human placenta is critical for evaluating foetal exposure and developmental safety. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), a novel class of antidiabetics, remain poorly characterized with respect to their placental transfer and potential effect on placental function. Here, we address this knowledge gap. We investigated placental transfer mechanisms of dapagliflozin (DAPA), empagliflozin (EMPA), ertugliflozin (ERTU) and canagliflozin (CANA) using term placentas and complementary in vitro assays. All SGLT2i crossed the barrier within four hours of perfusion at clinically relevant concentrations. DAPA, the smallest compound, showed the fastest transfer, whereas EMPA, the largest, was the slowest. The more lipophilic compounds, CANA and ERTU, accumulated strongly in placental tissue. Transport of all SGLT2i - especially EMPA and ERTU - increased with the addition of an ATP-synthesis inhibitor, indicating the influence of active efflux transporters. Additionally, transport was significantly enhanced under low-bovine serum albumin conditions, implicating protein binding as a key rate-limiting factor. During Transwell® permeability assays, all SGLT2i crossed the BeWo b30 cell layer that mimics early gestational cytotrophoblasts. BeWo cells exposed to SGLT2i showed no impairment in forskolin-induced differentiation, viability, or secretion of pregnancy-related hormones, but revealed increased glycolytic activity. Our findings indicate that at clinically relevant concentrations, SGLT2i cross the placenta by passive diffusion, modulated by efflux transporters and protein binding, and might alter placental glycolytic activity without impairing viability, differentiation, or hormone secretion. Their use during pregnancy should remain contraindicated, but if attempted, monitoring unbound drug concentrations is advised.

Keywords:  BeWo cells; Diabetes; Ex vivo placenta perfusion; Pregnancy; SGLT2 inhibitors; Transwell

DOI:  https://doi.org/10.1016/j.biopha.2026.119097
Front Endocrinol (Lausanne). 2025 ;16 1736033

Placental mRNA and miRNA dynamics associated with lipid metabolism pathways in pregnancies affected by obesity.

Ruggero Spadafora, Jiayi Zhang, N R Nirmala, Xue Li, Perrie O'Tierney-Ginn.

   Introduction: Maternal obesity (pregravid body mass index >30 kg/m2), which has reached epidemic levels in the US, increases the incidence of cardiovascular disease and all cause premature death in the offspring. The placenta modulates fetal access to lipids and other nutrients and is considered a key player in fetal growth and maturation. However, the complex interplay between dysregulated metabolism in mothers with obesity and placental pathways mediating impacts on fetal development that predispose offspring to morbidities later in life, is poorly understood.
Methods: We used unbiased Whole Genome Correlation Network Analysis (WGCNA) in 39 full-term unlabored placentas from mothers affected by obesity to explore relationships between coding and non-coding placental transcripts with maternal and fetal metabolic variables.
Results: We identified positive correlations between members of the Rho network, a key inflammation regulator, with maternal leptin and cord blood free fatty acids (cbFFA). Furthermore, we identified negative correlations between epigenetic regulators and the lipid metabolism drivers SMUG1 and CDS1, with cbFFA. A set of placental miRNAs showed positive correlations with cbFFA. Using mirTarRnaSeq, an R/Bioconductor package, we predicted interactions between placental coding genes and miRNA, which correlated negatively and positively with cbFFA, respectively. Several FFA-associated miRNAs (miR-23b cluster, -168, -138, -6825, -6845) have been previously associated with obesity in animal models and human cohorts.
Discussion: Further studies are required to investigate the role that the Rho network plays in placental inflammation and the link between miRNAs and the predisposition towards cardiovascular diseases in the offspring of obese mothers.

Keywords:  free fatty acids; maternal obesity; microRNA; placenta; transcriptome

DOI:  https://doi.org/10.3389/fendo.2025.1736033
Int J Mol Sci. 2026 Jan 30. pii: 1398. [Epub ahead of print]27(3):

Recreational Cannabis Use During Human Pregnancy: Its Effects on the Placenta and Endocannabinoid System.

Madhavi S Harhangi, Lisa Höfert, A H Jan Danser, Hilmar H Bijma, Sinno H P Simons, Irwin K M Reiss, Sven Baumann, Michelle Broekhuizen.

  The use of cannabis during pregnancy is increasing, in line with its growing societal acceptance and legalization. Cannabis use mainly concerns its active components Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). While cannabis has therapeutic effects on pain, nausea, and vomiting, its impact on fetal development remains a significant public health concern. Given the existence of a local endocannabinoid system (ECS) in the placenta, with proven effects on placental development and blood flow, it is likely that THC and CBD exert effects via interference with the placental ECS. This review summarizes how cannabis use affects the placental ECS and describes the consequences of such use on placental function and fetal development. It starts with discussing the placental ECS, the effects of THC and CBD on placental function, and the pharmacokinetics of cannabinoids during pregnancy. It then describes the effects of both paternal and maternal cannabis use and provides epidemiological data linking placental insufficiency, impaired fetal growth, and preeclampsia to cannabis use. It also raises awareness for the possibility that cannabis use, by altering DNA methylation, might result in transgenerational effects. It is concluded that current evidence supports abstaining from cannabis use during preconception, pregnancy, and lactation to optimize maternal, fetal, and intergenerational health outcomes.

Keywords:  cannabidiol; cannabis; endocannabinoid system; fetal development; maternal health; placental function; pregnancy; Δ9-tetrahydrocannabinol

DOI:  https://doi.org/10.3390/ijms27031398
Methods Cell Biol. 2026 ;pii: S0091-679X(25)00209-2. [Epub ahead of print]202 187-204

Quantitative assessment of arterial remodeling from confocal microscopy image analysis of the mid-gestation mouse decidua.

Dema Alghabban, Alexander J Muller.

  The pathophysiological process of tumorigenesis involves numerous parallels with the physiological process of placentation. One critical feature that both tumors and embryos share is the need to access the host blood supply. During gestation, the uterine spiral arteries, from which maternal blood is accessed, undergo a remodeling process to become enlarged, dilated, low-resistance vessels capable of delivering an increased volume of blood through placental circulatory connections made by invasive, extravillous trophoblasts. Decidual immune cells are associated with the initial stages of this remodeling prior to the arrival of trophoblasts, and mouse studies have demonstrated that, in the absence of IFNγ produced by uterine natural killer cells, spiral artery remodeling is impaired. To better understand the role of inflammatory decidual immune cells in spiral artery remodeling, it is important to have an assay that quantifiably assesses the remodeling process. Here we describe a confocal microcopy-based methodology for digitally evaluating individual vessels within the decidua basalis of mid-gestation mouse concepti by immunofluorescence staining using DAPI for general cellularity and antibodies to CAV1 (caveolin 1) and SMA (smooth muscle alpha actin) for ECs (endothelial cells) and VSMCs (vascular smooth muscle cells), respectively. Reflecting the loss of VSMCs during normal remodeling, SMA within the vascular media is markedly reduced between gd 7.5 and 9.5, while retention of SMA is a characteristic feature of impaired remodeling. Through quantitative analysis of the relative percentage of SMA within vessel walls, the methodology described here provides an objective means to assess impairment of the spiral artery remodeling process.

Keywords:  confocal microscopy; decidua basalis; immunofluorescence; placenta; pregnancy; smooth muscle alpha actin; spiral artery remodeling

DOI:  https://doi.org/10.1016/bs.mcb.2025.10.009
J Reprod Immunol. 2026 Jan 30. pii: S0165-0378(26)00021-5. [Epub ahead of print]174 104852

Why reproduction has probably been very problematic in Neanderthals: The fabulous history of (pre)eclampsia.

Pierre-Yves Robillard, Shigeru Saito, Gustaaf Dekker.

  Preeclampsia and eclampsia, unique to human reproduction, represent the first disease documented in written history over 5000 years ago, yet their etiology remains elusive in 2026. These disorders, exclusive to Homo sapiens among 4300 mammal species, may have posed an even greater reproductive challenge to Neanderthals, potentially contributing to their poor fecundity. Arising from incomplete deep trophoblast invasion into maternal spiral arteries, essential for nourishing the energy-demanding fetal brain, they lead to placental insufficiency and fetal growth restriction (FGR). In humans, eclampsia (grand mal seizures) occurs naturally in ∼1 % of pregnancies, while preeclampsia affects 2-8 %, with untreated cases carrying high maternal and fetal mortality. Predominantly affecting primiparas and multiparas with a new partner ("primipaternity"), early-onset preeclampsia (EOP; delivery <34 weeks) results from failed maternal immune tolerance to paternal antigens, causing partial fetal rejection and inadequate artery remodeling. This manifests as FGR with or without maternal syndrome. Critically, humans evolved a protective mechanism decoupling maternal preeclampsia from ∼75 % of placental FGR cases, averting life-threatening complications. Without this safeguard, preeclampsia rates could soar to 10-20 %, with eclampsia at 4-5 %, severely impeding reproductive success. Neanderthals, sharing deep hemochorial placentation but possibly lacking this adaptation due to genetic divergences (e.g., imprinted genes, KIR-HLA interactions, PIEZO1 variants), likely suffered higher incidences, exacerbating demographic vulnerabilities like small populations and inbreeding. This hypothesis bridges a gap in paleoanthropology: preeclampsia, the principal human reproductive complication, is never cited by anthropologists as possible explanation of the well-known low fecundity rates in Neanderthals communities.

Keywords:  Anthropology; Eclampsia; Foetal growth restriction (FGR); Neanderthals; Preeclampsia; Reproduction

DOI:  https://doi.org/10.1016/j.jri.2026.104852
Placenta. 2026 Feb 07. pii: S0143-4004(26)00052-4. [Epub ahead of print]176 1-12

scRNA-seq of preeclamptic trophoblasts identifies EBI3, COL17A1, miR-27a-5p, and miR-193b-5p as hypoxia markers: validation of neuradapt as a superior mimetic to cobalt chloride.

Evgeny Knyazev, Timur Kulagin, Ivan Antipenko, Alexander Tonevitsky.

   BACKGROUND: Preeclampsia (PE) complicates 2-8% of pregnancies and involves placental hypoxia and HIF-pathway activation, especially in early-onset PE (eoPE). Chemical mimetics like cobalt (II) chloride (CoCl2) and oxyquinoline derivatives model trophoblast hypoxia in vitro, yet their fidelity in recapitulating PE gene profiles remains unclear. Integrating patient tissue analyses with experimental models may reveal common markers and validate physiologically relevant paradigms.
METHODS: We analyzed scRNA-seq data from 10 eoPE, 7 late-onset PE, and matched control placentas, identifying villous cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast (EVT). BeWo b30 cells were treated for 24 h with CoCl2 (300 μM) or the oxyquinoline derivative neuradapt (5 μM) to induce hypoxia. RNA-seq with qPCR validation and small RNA-seq quantified mRNA and microRNA changes; PROGENy inferred pathway activities.
RESULTS: scRNA-seq revealed highest hypoxia activation in eoPE, with EVT showing maximum activity. Nine genes were upregulated across all trophoblast types (EBI3, CST6, FN1, RFK, COL17A1, LDHA, PKP2, RPS4Y1, RPS26). In vitro, neuradapt induced more specific hypoxia responses than CoCl2 (1284 vs. 3032 differentially expressed genes). Critically, EBI3, FN1, and COL17A1 showed concordant upregulation in tissue and neuradapt-treated cells, whereas CoCl2 produced opposite patterns. MicroRNAs hsa-miR-27a-5p and hsa-miR-193b-5p were consistently elevated in both models; 3'-isoforms of hsa-miR-9-5p and hsa-miR-92b-3p were identified as hypoxia-associated.
CONCLUSIONS: EBI3, COL17A1, miR-27a-5p, and miR-193b-5p emerge as trophoblast hypoxia markers. Neuradapt (a selective HIF-prolyl hydroxylase inhibitor) provides a more physiologically relevant in vitro model than CoCl2, recapitulating transcriptomic signatures observed in PE placentas. This integrated approach advances understanding of PE pathophysiology and therapeutic targeting.

Keywords:  Hypoxia; MicroRNA; Preeclampsia; Single-cell RNA sequencing; Trophoblast

DOI:  https://doi.org/10.1016/j.placenta.2026.02.005
Placenta. 2026 Jan 29. pii: S0143-4004(26)00029-9. [Epub ahead of print]176 31-42

METTL3-regulated m6A modification modulates autophagy of placental mesenchymal stem/stromal cell by YTHDF3-mediated degradation of LncRNA GAS5 in preeclampsia.

Yang Zhang, Di Wu, Li Zou, Xiangwei Cheng, Xiaoxia Liu.

   BACKGROUND: Preeclampsia (PE) causes maternal and perinatal morbidity through defective placental vascularization. Autophagy enhances placental mesenchymal stem/stromal cells (PMSC) proangiogenic properties while autophagy is reduced in PE. Long non-coding RNA GAS5, elevated in PE placenta, suppresses endothelial angiogenesis. N6-methyladenosine (m6A) modification through METTL3 regulates RNA stability and autophagy. However, regulatory mechanisms governing PMSC autophagy in PE remain unclear.
METHOD: Placenta specimens and PMSC from the normal and PE were compared. Molecular analyses included qRT-PCR, Western blotting, and m6A level evaluation. Transfections used siRNA knockdown and plasmid overexpression with rescue experiments. Autophagy was evaluated through LC3-II/LC3-I ratios and p62. Cellular functional assessments comprised CKK8 assays, ELISA for VEGF secretion, and tube formation for angiogenesis. MeRIP-PCR, RNA pull-down assay and RNA immunoprecipitation PCR identified m6A-modified transcripts.
RESULT: PE placenta and PMSC demonstrated significantly reduced METTL3 expression and global m6A modification levels, accompanied by elevated GAS5 expression. METTL3 overexpression enhanced PMSC autophagy, cell proliferation, VEGF secretion, and angiogenic capacity, while GAS5 exhibited opposing effects. GAS5 knockdown rescued PMSC autophagy and dysfunction caused by METTL3 deficiency. Mechanistically, METTL3 catalyzed m6A modification of GAS5 transcripts, facilitating YTHDF3-mediated recognition and degradation. YTHDF3 depletion reversed METTL3-induced autophagy improvements, confirming the regulatory cascade.
CONCLUSION: Our findings establish a novel epigenetic regulatory network wherein METTL3/YTHDF3-mediated GAS5 degradation controls PMSC autophagy in PE. This pathway represents a potential therapeutic target for ameliorating placental vascularization defects in PE.

Keywords:  Angiogenesis; GAS5; METTL3; Preeclampsia; YTHDF3

DOI:  https://doi.org/10.1016/j.placenta.2026.01.017
J Nutr. 2026 Feb 11. pii: S0022-3166(26)00054-4. [Epub ahead of print] 101405

IN-UTERO PROTEIN DEFICIENCY LEADS TO IMPAIRED HEPATIC LIPID METABOLISM IN ADULT MALE RATS.

Vipin A Vidyadharan, Chandrasekhar Yallampalli, Chellakkan S Blesson.

   BACKGROUND: In-utero exposure to a low-protein (LP) diet is a well-established model of developmental programming linked to increased risk of chronic metabolic diseases, including lean Type 2 Diabetes (T2D).
OBJECTIVE: In this study, we investigated the long-term effects of maternal LP diet on hepatic lipid metabolism and mitochondrial dynamics in adult lean T2D male rat offspring.
METHODS: Pregnant Wistar rats were fed either a control (20% protein) or isocaloric low-protein (6% protein) diet during gestation, and male offspring were examined in adulthood. Hepatic lipid accumulation, mitochondrial function, and related signaling pathways were analyzed using integrated histological, metabolomic, and molecular methods. Student's t-test and two-way ANOVA were used for statistical analyses.
RESULTS: In LP-programmed livers, Oil Red O staining and TEM revealed increased lipid accumulation, with a 55% increase in lipid droplet area compared with controls. Further, relative levels of carnitine and acylcarnitines were elevated (carnitine 66%, deoxycarnitine 33%, glutarylcarnitine 37%, malonylcarnitine 44%, methylglutarylcarnitine 83%; p ≤ 0.05), consistent with disrupted fatty-acid handling. Transcriptionally, β-oxidation genes (Acadm, Acads, Cact) were ∼2-fold downregulated, and the lipogenic gene Acaca was ∼1.5-fold upregulated (p ≤ 0.05), indicating a shift toward lipid synthesis and reduced mitochondrial fatty-acid oxidation. TCA-cycle intermediates were lower (p ≤ 0.05) in LP, with citrate (∼2.5-fold), succinate (∼1.5-fold), and malate (∼1.2-fold), suggesting impaired oxidative metabolism. Mitochondrial remodeling was evident with increased OPA1 (115%) and decreased FIS1 (35%), alongside reduced mitophagy regulators LC3B (45%) and BNIP3L (41%) (all, p ≤ 0.05), suggesting compromised mitochondrial quality control. mtDNA copy number was unchanged, but multiple PKC isoforms were increased (p ≤ 0.05), consistent with altered intracellular insulin signaling.
CONCLUSION: Our findings collectively demonstrate that in-utero protein restriction induces persistent impairments in hepatic mitochondrial function and lipid metabolism, contributing to the developmental origins of insulin resistance and metabolic dysfunction.

Keywords:  Developmental Origins of Health and Disease; Lipid Accumulation; Metabolically Dysfunctional-Associated Steatotic Liver Disease; Mitochondrial dysfunction; Mitophagy; β-oxidation

DOI:  https://doi.org/10.1016/j.tjnut.2026.101405
BMC Pregnancy Childbirth. 2026 Feb 10.

FABP4 is highly expressed in preeclamptic placentas and regulates trophoblast lipid metabolism, mitochondrial function, and oxidative stress in vitro.

Hui Sun, Qiaozhen Wang, Lipei Wu, Rongrong Jing, Shihai Xuan, Wenming Zhuang.



Keywords:  FABP4; Lipid metabolism; Mitochondrial oxidative stress; Preeclampsia; Trophoblast

DOI:  https://doi.org/10.1186/s12884-026-08789-9
BMC Pregnancy Childbirth. 2026 Feb 10.

ELABELA targets the METTL3/PI3K/AKT axis to enhance trophoblast invasion in early-onset preeclampsia.

Lijing Wang, Xiaokun Wang, Xue Wang, Mingsheng Wu, Minghui Ou, Ningning He.



Keywords:  AKT; Invasion; METTL3; PI3K; Preeclampsia

DOI:  https://doi.org/10.1186/s12884-026-08792-0
bioRxiv. 2026 Feb 07. pii: 2026.02.04.703858. [Epub ahead of print]

Maternal Obesity Decreases Offspring Lifespan.

Eric Moore, Ramasamy Selvarani, Kavitha Kurup, Michael Chan, Mani Saminathan, Natesan Pazhanivel, Kai Ding, Alexandra Ford, Brianne M Taylor, Karen Jonscher, Arlan Richardson, Jacob E Friedman, Archana Unnikrishnan.

Data in mice, nonhuman primates, and in humans demonstrate that exposure to maternal obesity increases the risk of multiple diseases in offspring. However, little is known about the aging effects of maternal obesity on the offspring. This study shows that maternal obesity significantly reduced the lifespan of both male and female mice born to obese dams despite being weaned onto a healthy diet at three weeks of age. This reduction in longevity was linked to an increase in age-related fibrotic pathology across multiple organs, e.g., liver, heart, and kidney. Gompertz analysis of the lifespan data showed that maternal obesity offspring have reduced lifespan due to detrimental changes established early during development rather than factors that modify aging later-in-life. These findings are translationally significant as they demonstrate that the growing prevalence of MO may lead to a decrease in overall lifespan and increase in age-related diseases in the next generation.

DOI: https://doi.org/10.64898/2026.02.04.703858