bims-placeb 2026-04-19 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–04–19
ten papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

3D imaging of the pregnant uterus reveals an extensively invasive mouse placenta and early CXCL12-CXCR4 requirement.
New PPARG Exons: Cell-Specific Expression of Their RNAs in the Human Placenta.
cAMP signaling in the placenta: a pivotal determinant of trophoblast fate and pregnancy outcomes.
From Maternal Exposure to Fetal Risk: Unraveling the PFAS Exposure Pathway and Its Placental Toxicity Mechanism.
Chronic replication stress-mediated genomic instability disrupts placenta development in mice.
Cell migration and adhesion in autophagy-induced damage of human trophoblast cells.
Trophoblast aging driven by IL33 deficiency elevates recurrent pregnancy loss risk through SNAP29 lactylation-mediated autophagy impairment.
Quantitative human placental imaging: Concepts, technologies, and the persistent challenge of the villous tree.
High glucose exposure induces differential pathophysiologic changes in feto-maternal interface cells.
Mechanisms of reproductive toxicity and endocrine disruption of bisphenols and per- and polyfluoroalkyl substances (PFAS): Implications for women's reproductive health.

bioRxiv. 2026 Apr 09. pii: 2026.04.06.716785. [Epub ahead of print]

3D imaging of the pregnant uterus reveals an extensively invasive mouse placenta and early CXCL12-CXCR4 requirement.

James B Zwierzynski, Mira N Moufarrej, Kristy Red-Horse.

Successful pregnancy requires exquisite balance: the placenta must invade just enough to access maternal blood but not so deep it remains attached at birth. Disrupting this balance causes life-threatening pregnancy complications, for which treatments remain limited. Animal models are desperately needed to discover mechanisms underlying balanced uteroplacental development and how pregnancy complications arise, but this is hampered by the view that mouse placentation lacks human characteristics such as extensive trophoblast invasion and targeting of uterine spiral arteries. Here, we utilize 3D imaging, mouse genetics, and pharmacological perturbations to demonstrate that: (1) The mouse placenta invades more extensively than previously recognized with most spiral arteries heavily enveloped by fetal trophoblasts, (2) This process is disrupted without CXCL12-CXCR4 signaling specifically during early pregnancy, and (3) Disrupting early uteroplacental development ultimately results in excessively deep trophoblast invasion, closely mimicking the pregnancy complication placenta accreta. Mechanistically, uterine epithelium, stroma, and arteries activate CXCR4 signaling in early pregnancy, and inhibition causes decidualization failure, followed by dissolution of spiral artery development. Trophoblasts consequently migrate deep into uterine muscle and its arteries, reproducing hallmarks of human accreta. Thus, with 3D imaging, the mouse more effectively models human uteroplacental development and defines an early etiological window for intervention.

DOI: https://doi.org/10.64898/2026.04.06.716785
Cells. 2026 Apr 01. pii: 639. [Epub ahead of print]15(7):

New PPARG Exons: Cell-Specific Expression of Their RNAs in the Human Placenta.

Marie-Léone Vignaud, Nathalie Morin, Thierry Fournier.

  Peroxisome proliferator-activated receptor γ (PPARγ), encoded by the PPARG gene on chromosome 3p25.2 in humans, is a ligand-dependent transcription factor that belongs to the nuclear receptor family. In various tissues, PPARγ controls cell differentiation, proliferation, or fusion. Its essential role in the development and functions of the placenta is now well established. To date, the specific functions of its RNA isoforms, encoded by ten exons, in trophoblast biology, including cell fusion and invasion, remain unknown. As translation is mainly regulated by the 5'UTR sequences of mature mRNA, this region was analyzed, and four previously unreported exonic sequences were revealed. Their expressions were confirmed and quantified in villous cytotrophoblasts from term placenta and in chorionic villi from both first-trimester and term placenta. Distinct expression patterns were observed: one exon showed weak expression in placental and chorionic cells, another exhibited stable expression throughout pregnancy, while two exons specific to villous cytotrophoblasts displayed increased expression during the first trimester, suggesting a role in oxygen-responsive mechanisms. Among these, one may be involved in villous trophoblast differentiation. These findings demonstrate that the PPARG gene is composed of 14 exons and is highly regulated depending on cell type and the stage of cell differentiation.

Keywords:  5′UTR exon; PPARG gene; cell-type-specific expression; placenta; pregnancy; trophoblast differentiation

DOI:  https://doi.org/10.3390/cells15070639
Biol Reprod. 2026 Apr 16. pii: ioag081. [Epub ahead of print]

cAMP signaling in the placenta: a pivotal determinant of trophoblast fate and pregnancy outcomes.

Enoch Appiah Adu-Gyamfi, Daniel Neubauer.

  Cyclic adenosine monophosphate (cAMP) signaling is a crucial pathway which regulates a myriad of physiological processes. cAMP is synthesized by adenylyl cyclases and then degraded by phosphodiesterases (PDEs). This intricate interplay of synthesis and degradation, often localized to specific subcellular compartments, tightly regulates cAMP signaling in a context-dependent manner, ensuring that the normal levels of cAMP needed for specific cellular processes are maintained within cells. The downstream actions of cAMP are mediated by effectors such as protein kinase A (PKA) and exchange proteins activated by cAMP (EPAC). At the feto-maternal interface, these actions ensure a proper timing and spatial regulation of trophoblast proliferation, survival and differentiation along the villous and extravillous pathways, leading to successful placental development and pregnancy progression. Disruptions in cAMP signaling result in mal-formed and dysfunctional placentas, thus causing pregnancy complications such as preeclampsia and fetal growth restriction. This suggests that cAMP modulation in the uterine environment right after embryo implantation is a potential therapeutic strategy to prevent abnormal placentation and the associated pregnancy disorders.

Keywords:  Placenta; Pregnancy complication; Trophoblast; cAMP

DOI:  https://doi.org/10.1093/biolre/ioag081
Environ Sci Technol. 2026 Apr 17.

From Maternal Exposure to Fetal Risk: Unraveling the PFAS Exposure Pathway and Its Placental Toxicity Mechanism.

Yurou Gao, Zichen Kuang, Qian S Liu, Qunfang Zhou, Guibin Jiang.

  Per- and polyfluoroalkyl substances (PFAS) have triggered a global crisis due to their severe toxicities and widespread occurrence in human populations. Notably, PFAS is frequently detected in maternal blood, placental tissue, and umbilical cord blood, indicating direct fetal exposure to PFAS through the maternal-fetal interface. As the central organ regulating nutrient exchange, endocrine signaling, and immune balance, the placenta is particularly vulnerable to PFAS exposure, and its dysfunction is linked with various adverse pregnancy outcomes, including fetal growth restriction, low birth weight, preterm birth, preeclampsia, etc. However, existing knowledge on PFAS-induced placental dysfunction remains fragmented, typically addressing their occurrence, transplacental transfer, specific mechanistic targets, or epidemiological evidence in isolation. This review synthesizes evidence tracing the entire trajectory of PFAS exposure─from maternal uptake and distribution in the bloodstream to placental accumulation, transplacental passage, and fetal exposure. It further highlights how PFAS may interfere with key processes of placental development, including angiogenesis and vascular remodeling, trophoblast migration and invasion, lipid metabolism, hormone production, and establishment of the maternal-fetal immune microenvironment, which provides mechanistic explanations linking PFAS exposure to adverse pregnancy outcomes. By integrating transplacental behaviors, mechanistic insights, epidemiological findings, and methodological advances, this review offers a comprehensive perspective on PFAS-induced placental toxicity and presents new directions for assessing maternal-fetal health risks.

Keywords:  adverse pregnancy outcomes; dysregulation of placental development; per- and polyfluoroalkyl substances (PFAS); placenta; transplacental passage

DOI:  https://doi.org/10.1021/acs.est.5c18201
PLoS Genet. 2026 Apr 13. 22(4): e1012111

Chronic replication stress-mediated genomic instability disrupts placenta development in mice.

Mumingjiang Munisha, Rui Huang, Jordan Khan, John C Schimenti.

Abnormal placentation drives many pregnancy-related pathologies and poor fetal outcomes, but the underlying molecular causes are understudied. Here, we show that persistent replication stress due to mutations in the MCM2-7 replicative helicase disrupts placentation and reduces embryo viability in mice. MCM-deficient embryos exhibited normal morphology, but their placentae had a drastically diminished junctional zone (JZ). Whereas cell proliferation in the labyrinth zone (LZ) remained unaffected, it was reduced in the JZ during development. MCM2-7 deficient trophoblast stem cells (TSCs) failed to maintain stemness, suggesting that replication stress affects the initial trophoblast progenitor pool in a manner that preferentially impacts the developing JZ. In contrast, pluripotency of mouse embryonic stem cells (ESCs) with MCM2-7 deficiency were not affected. Developing female mice deficient for FANCM, a protein involved in replication-associated DNA repair, also had placentae with a diminished JZ. These findings indicate that replication stress-induced genomic instability compromises embryo outcomes by impairing placentation.

DOI: https://doi.org/10.1371/journal.pgen.1012111
Placenta. 2026 Apr 07. pii: S0143-4004(26)00110-4. [Epub ahead of print]179 87-94

Cell migration and adhesion in autophagy-induced damage of human trophoblast cells.

Jia Liu, Yiyuan Zhou, Ruyi Zhang, Taiwei Zhang, Dongyang Deng, Xuanyin Zhao, Qian Chen.

   INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) is a common pregnancy complication. It has relatively minor impacts on the mother, but elevated bile acid levels pose severe risks to the fetus, potentially causing adverse pregnancy outcomes such as preterm birth, intrauterine distress, and fetal death. Autophagy plays a pivotal role in embryonic development, implantation, and pregnancy maintenance. Emerging evidence indicates autophagy is involved in ICP, yet its underlying mechanism remains unclear.
METHODS: An ICP-associated autophagy-impaired cell model was established. This was achieved by treating human HTR-8/SVneo trophoblast cells with high-concentration bile acids and culturing the cells under starvation conditions.
RESULTS: The induced autophagic impairment significantly reduced placental cell migration, adhesion, and proliferation. This effect was mediated by inhibiting the extracellular matrix (ECM) and focal adhesion (FA) pathways, while also promoting cell apoptosis. Gene expression analysis revealed a regulatory connection between the autophagic pathway and key molecules-including ECM, integrins, and actin-which are critical for placental development and functional maintenance.
DISCUSSION: This study provides novel theoretical insights into the pathogenesis of ICP. It proposes that the dysregulation of FAs and ECM by autophagy is a key mechanism underlying ICP-associated adverse pregnancy outcomes.

Keywords:  Autophagy; Extracellular matrix (ECM); Focal adhesions (FAs); Intrahepatic cholestasis of pregnancy (ICP)

DOI:  https://doi.org/10.1016/j.placenta.2026.04.002
Autophagy. 2026 Apr 13.

Trophoblast aging driven by IL33 deficiency elevates recurrent pregnancy loss risk through SNAP29 lactylation-mediated autophagy impairment.

Jia-Jing Lu, Yan-Ran Sheng, Wen-Ting Hu, Yu-Kai Liu, Feng Xie, Ming-Qing Li, Xiao-Yong Zhu.

  Emerging evidence implicates premature placental senescence as a central driver of pregnancy complications, though its underlying mechanisms remain elusive. Here, we report marked downregulation of IL33 (interleukin 33) in villi from unexplained recurrent pregnancy loss (URPL) patients, concomitant with elevated trophoblast senescence. More importantly, il33 knockout mice exhibited placental senescence and impaired trophoblast invasion. Mechanistically, senescent trophoblasts displayed metabolic dysregulation - including enhanced glycolysis and lactate accumulation - which disrupted macroautophagic/autophagic flux and mitochondrial function. Lactate-induced lysine lactylation at residue K169 of SNAP29 (synaptosome associated protein 29) promoted its degradation, impairing macroautophagy/autophagy and trophoblast function, ultimately driving pregnancy loss. In interventional studies, senotherapies with metformin or dasatinib plus quercetin restored placental development and improved pregnancy outcomes in both IL33-deficient and inflammation-induced miscarriage models. Our findings establish the IL33-senescence-lactate axis as a critical pathway in URPL pathogenesis and support senomodulation as a therapeutic strategy.Abbreviations: 2-DG: 2-deoxy-D-glucose; BafA1: bafilomycin A1; CHX: cycloheximide; CTB: cytotrophoblasts; D-gal: D-galactose; EVT: extravillous trophoblasts; HDAC: histone deacetylase; H2O2: hydrogen peroxide; IL33: Interleukin 33; LPS: lipopolysaccharide; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; SNAP29: synaptosome associated protein 29; STB: syncytiotrophoblasts; UMAP: uniform manifold approximation and projection; URPL: unexplained recurrent pregnancy loss; VP: etoposide.

Keywords:  Autophagy; SNAP29; cell senescence; interleukin 33; lactylation; trophoblast

DOI:  https://doi.org/10.1080/15548627.2026.2659946
Placenta. 2026 Apr 17. pii: S0143-4004(26)00119-0. [Epub ahead of print]

Quantitative human placental imaging: Concepts, technologies, and the persistent challenge of the villous tree.

Nirav Barapatre, Hans-Georg Frank.

  The human placenta is a transient yet highly complex organ whose structural organisation underpins materno-fetal exchange and pregnancy outcome. Despite more than a century of anatomical investigation and rapid advances in imaging technology, quantitative linking of placental structure to function remains challenging. This review surveys the evolution of placental imaging from classical histology and stereology to contemporary microscopic, mesoscopic, and functional imaging approaches, with a particular emphasis on the extraction and interpretation of quantitative information. Microscopic techniques, including stereology and immunohistochemistry-guided villous typing, have enabled robust quantification of cellular and subcellular features, but remain constrained by their reliance on two-dimensional sections. Three-dimensional microscopy and optical tissue clearing provide richer spatial information, yet are still largely experimental for human placentas and limited in scalability and standardisation. Mesoscopic modalities such as micro-computed tomography and magnetic resonance imaging have expanded access to villous architecture, fetal vasculature, and flow-related proxies, but a pronounced gap persists at the intermediate scale where the hierarchical branching of the villous tree resides. Across imaging modalities, heterogeneity of protocols and analytical frameworks hampers reproducibility and cross-study comparability, impeding translation to clinically actionable biomarkers. We argue that future progress in quantitative placental imaging depends on closing the mesoscopic gap, harmonising imaging and analysis workflows, and integrating structural imaging with quantitative models of placental function. Only through coordinated methodological development and conceptual clarity can the full diagnostic and prognostic potential of placental imaging be realised.

Keywords:  Magnetic resonance imaging; Microcomputed tomography; Placental blood flow; Quantitative imaging; Stereology; Villous tree

DOI:  https://doi.org/10.1016/j.placenta.2026.04.011
J Endocrinol. 2026 Apr 15. pii: JOE-25-0411. [Epub ahead of print]

High glucose exposure induces differential pathophysiologic changes in feto-maternal interface cells.

Glenmarie Angelica S Perias, Ana Paula Pereira Guimaraes, Ourlad Alzeus G Tantengco, Leslie Michelle M Dalmacio, Lauren S Richardson, Ananth Kumar Kammala, Ramkumar Menon.

  Gestational diabetes mellitus (GDM), a hyperglycemic condition during pregnancy, increases the risk of macrosomia and preterm birth (PTB). Nutrient-sensing pathways, particularly mTOR in placental trophoblasts (PTC), promote fetal overgrowth. NF-κB, oxidative stress, and p38 MAPK pathways in fetal membranes and decidua (DEC) contribute to PTB. However, the impact of hyperglycemia on these compartments remain unclear. We hypothesized that hyperglycemia differentially affects these maternal, placental, and fetal membrane interface cells, inducing macrosomia-associated pathways and perturbing homeostasis through different pathophysiologic signals. Human PTC, DEC, and amnion epithelial (AEC) cells were exposed to 50 mM glucose for up to 48 hr. Cell markers (ICC), cell cycle (flow cytometry), cytotoxicity (LDH assay), GLUT expression (RT-qPCR), signaling (mTOR, p38 MAPK, NF-κB by western blot), cytokines (ELISA), and oxidative stress (glutathione assay) were measured. PTC showed increased mTOR and p38 MAPK activation (p≤0.05), reduced GSH levels and GSH/GSSG balance (p≤0.05), but maintained GLUT expression. DEC reduced GLUT1/3 expression (p≤0.01, p≤0.05) with minimal stress and nutrient signaling. Neither cell type showed NF-κB activation. AEC downregulated GLUT1/3/11 (p≤0.05-0.0001), activated NF-κB (p≤0.01), produced IL-8 (p≤0.01), increased GSH production (p≤0.05), but maintained mTOR signaling and GSH/GSSG balance. Hyperglycemia induces compartment-specific adaptations across the feto-maternal interface. Placental trophoblasts preserve nutrient transport capacity and nutrient-signaling despite redox imbalanc.e Fetal membranes exhibit inflammatory response, while decidua reduce transport capacity with minimal stress activation. Together, these findings suggest that hyperglycemia may preferentially support fetal growth through trophoblasts while sensitizing decidua and membrane to secondary stressors.

Keywords:  amnion; diabetes; gestational diabetes; placenta; pregnancy

DOI:  https://doi.org/10.1530/JOE-25-0411
Reprod Toxicol. 2026 Apr 09. pii: S0890-6238(26)00082-1. [Epub ahead of print]143 109239

Mechanisms of reproductive toxicity and endocrine disruption of bisphenols and per- and polyfluoroalkyl substances (PFAS): Implications for women's reproductive health.

Alexandra M Stone, Gloria H Fung, Alwin Joseph, Mia M Biernat, Olivia G Camp, Husam M Abu-Soud.

  Bisphenols and per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental endocrine-disrupting chemicals with widespread human exposure and growing concern regarding their reproductive toxicity. This review integrates current experimental and epidemiologic evidence to evaluate the potential endocrine-disrupting mechanisms and reproductive toxicity of bisphenols, particularly bisphenol A (BPA), and PFAS on female reproductive health. Available data demonstrate that these chemicals disrupt key hormonal and cellular processes regulating female reproduction, including hypothalamic-pituitary-ovarian axis signaling, ovarian steroidogenesis and folliculogenesis, oocyte quality and maturation, uterine structure and function, and oxidative stress. Across in vitro and animal models, BPA and PFAS consistently induce hormonal dysregulation, oxidative stress, mitochondrial dysfunction, and epigenetic alterations that impair coordinated ovarian-uterine signaling. Importantly, these mechanistic findings align with epidemiologic studies reporting associations between BPA and PFAS exposure and increased risk of adverse reproductive outcomes, including endometriosis, polycystic ovary syndrome, diminished ovarian reserve, premature ovarian insufficiency, infertility, and adverse pregnancy outcomes. Collectively, this review underscores the relevance of environmental chemical exposure as a modifiable risk factor for female reproductive health and emphasizes the need for further integration of mechanistic and population-based research to inform exposure assessment, risk evaluation, and regulatory strategies to reduce exposure to endocrine-disrupting chemicals and protect female reproductive health.

Keywords:  Bisphenol A; Endocrine-disrupting chemicals; Infertility; Ovarian function; Per- and polyfluoroalkyl substances (PFAS); Reproductive health

DOI:  https://doi.org/10.1016/j.reprotox.2026.109239