bims-placeb 2026-10-04 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–10–04
nine papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Spatial Logic and Evolutionary Innovation in Human Placentation.
Gestational Changes in Placental Iron Homeostasis are Associated With Ferroptosis-Associated Redox Signaling and Trophoblast Behavior.
Gestational cadmium exposure is associated with dysregulated HIF-1α/Parkin-mediated mitophagy: implications for fetal growth restriction.
Impaired syncytin-1-CXCR4 crosstalk contributes to trophoblast migration defects in preeclampsia.
SMURF1 alleviates preeclampsia by suppressing ferroptosis in trophoblast cells via mediating ubiquitination of FLT1.
Prolactin receptor signalling contributes to the attenuation of stress-induced hyperthermia during pregnancy.
Excess glutamine in embryo culture media alters mitochondrial and autophagy-related dynamics associated with impaired postnatal development.
A genetically encoded redox bottleneck constrains human developmental rate.
High-throughput functional characterization of enhancers in totipotent-like cells.

bioRxiv. 2026 Sep 09. pii: 2026.09.04.749511. [Epub ahead of print]

Spatial Logic and Evolutionary Innovation in Human Placentation.

Zhida Luo, Cheng Wang, Yan Zhou, Tuhin Kumar Guha, Purnima Narasimhan Iyer, Selina Lao Mason, Areca Smit, Xiaofei Sun, Michael P Snyder, Gary M Shaw, David K Stevenson, Antonina Frolova, Sarah K England, Virginia D Winn, Susan J Fisher, Jingjing Li.

Human pregnancy unfolds in a unique mosaic tissue context. Embryonic/fetal placental and maternal uterine cells (decidua basalis) coalesce, forming the basal plate where immune tolerance is coordinated and the utero-placental circulation is initiated. The remaining approximately 70% of the maternal-fetal interface is comprised of the chorionic membranes, an epithelial-like layer of placental cells that lies adjacent to but does not coalesce with the overlying decidua capsularis and parietalis. It is unknown how these two regions of the maternal-fetal interface, which are comprised of seemingly similar cell types, diverge anatomically and functionally. Likewise, it is unknown whether the molecular characteristics of the maternal-fetal interface vary across human populations, potentially contributing to population disparities in pregnancy complications. Here, we generated large-scale paired single-nucleus RNA-seq and chromatin-accessibility profiles of the basal plate and chorionic membranes-associated decidual compartments from diverse-ancestry pregnancies, integrated with spatial transcriptomics and multiplexed protein imaging. We show that the two interfaces share a conserved cytotrophoblast differentiation hierarchy, which is deployed differently resulting in the observed distinct architectures. In the chorionic membranes, progenitor, early, and mature extravillous cytotrophoblast (EVT) states form an epithelial-like laminar shell. In the basal plate, this hierarchy is elaborated upon to enable deep placentation: EVTs that arise early in pregnancy invade the farthest into the uterus, while mature EVTs accumulate superficially to sculpt the local maternal immune microenvironment. Comparative analysis identified DSC4, a decidual stromal cell subtype, as an anti-invasive barrier that is densely enriched adjacent to the chorionic membranes but substantially reduced at the basal plate. Population-resolved analysis further identified the DSC4 marker NID2 , which encodes the basement-membrane glycoprotein nidogen-2, as an ancestry-associated rheostat of EVT invasion. A specific NID2 promoter haplotype arose on the modern-human lineage, is absent from available archaic-human genomes, and shows evidence of positive selection in Eurasian populations. This haplotype is associated with reduced local chromatin accessibility and lower NID2 expression in DSC4 cells. Consistent with this genetic association, extracellular NID2 directly suppressed the invasion of primary human cytotrophoblasts in vitro . Together, these findings reveal how a shared developmental program is spatially reconfigured across distinct regions of the maternal-fetal interface and identify a recent modern-human regulatory innovation that modulates maternal decidual restraint of fetal trophoblast invasion across populations.

DOI: https://doi.org/10.64898/2026.09.04.749511
FASEB J. 2026 Oct 15. 40(19): e72310

Gestational Changes in Placental Iron Homeostasis are Associated With Ferroptosis-Associated Redox Signaling and Trophoblast Behavior.

Wenxin Jiang, Yike Yang, Xiao Yuan, Wei Deng, Mark D Kilby, Philip N Baker, Chao Tong, Yi Yang.

  Well-regulated trophoblast proliferation, migration, invasion, and cell turnover are essential for normal placental development in humans and rodents. Given the established role of oxidative stress in placentation and the redox activity of iron, we investigated whether ferroptosis-associated redox signaling contributes to trophoblast function and placental development. Placental iron profiling revealed significantly elevated total and ferrous iron levels in first-trimester human villi compared with term placentas, accompanied by the transcript levels of several iron uptake- and reduction-related genes, including TFRC, DMT1, ZIP8, STEAP3, and STEAP4, which were elevated in first-trimester villi. Murine placentas also exhibited gestational changes in iron abundance and iron-homeostasis-related gene expression. HO-1 protein abundance was highest during early gestation and declined thereafter, suggesting a potential association between heme degradation and gestational iron homeostasis. In contrast, placental labile iron pool (LIP) levels showed only modest, statistically nonsignificant changes across gestation, suggesting a relatively stable redox-active iron pool. Immunofluorescence analyses demonstrated spatially distinct expression of ferroptosis-associated regulators, with ACSL4 enriched in invasive trophoblast populations and GPX4 predominantly localized in surrounding decidual tissues, suggesting regional heterogeneity in ferroptosis-associated molecular features during placentation. Functional studies in HTR-8/SVneo trophoblast cells further demonstrated that mild ferroptosis-associated redox perturbation induced by low-dose erastin or ferrous iron enhanced trophoblast migration and invasion without overt cytotoxicity. These effects were attenuated by ferrostatin-1, deferoxamine mesylate (DFOM), or the mitochondria-targeted antioxidant MitoQ and were blunted following FTH1 and TFRC knockdown, indicating that trophoblast responsiveness depends on iron availability and ferroptosis-associated redox signaling. Importantly, these pro-invasive effects were preserved under physiologically relevant hypoxic conditions. Together, our findings support a model in which gestational changes in placental iron homeostasis are associated with ferroptosis-related molecular features, while experimentally induced iron-dependent redox signaling modulates trophoblast behavior. Rather than inducing overt ferroptotic cell death, sublethal iron-dependent redox perturbation may act as a signaling mechanism influencing trophoblast function during placental development.

Keywords:  ferroptosis‐associated redox signaling; iron metabolism; lipid peroxidation; placental iron homeostasis; placentation; trophoblast invasion

DOI:  https://doi.org/10.1096/fj.202504881RR
Placenta. 2026 Sep 24. pii: S0143-4004(26)00692-2. [Epub ahead of print]186 82-90

Gestational cadmium exposure is associated with dysregulated HIF-1α/Parkin-mediated mitophagy: implications for fetal growth restriction.

Zheyu Lu, Na Chen, Run Luo, Keqi Xu, Cengqi Xu, Fan Wang.

   INTRODUCTION: Cadmium (Cd) is an environmental toxicant associated with fetal growth restriction (FGR). However, the molecular mechanism underlying Cd-associated placental dysfunction remains incompletely understood. This study investigated whether altered mitochondrial quality control involving HIF-1α and Parkin contributes to Cd-induced trophoblast injury and impaired fetal growth.
METHODS: We integrated a gestational Cd-exposed rat model, human JEG-3 trophoblast cells, and human placenta samples. Interventions included the mitophagy-modulating compound Mdivi-1 (M - 1), the HIF-1α inhibitor PX-478, and Parkin-siRNA, in combination with Western blotting, TUNEL staining, and transmission electron microscopy.
RESULTS: Cd exposure reduced the level of mitochondrial proteins HSP60 and COX IV while upregulating PGC-1α in rat placenta and JEG-3 cells, consistent with enhanced mitochondrial clearance. Pretreatment with M - 1 attenuated these mitochondrial alterations and reduced Cd-induced apoptosis. Mechanistically, Cd exposure increased mitochondrial Parkin accumulation and HIF-1α expression, accompanied by mitophagy-related mitochondrial alterations. Parkin-siRNA suppressed Parkin expression and attenuated Cd-induced mitochondrial loss, whereas the HIF-1α inhibitor PX-478 reversed Cd-associated reductions in HSP60 and COX IV and blunted the upregulation of PGC-1α and Parkin. Functionally, Cd altered the balance of apoptosis-related proteins (upregulating Bax and Cleaved Caspase-3 while downregulating Bcl-2 and total caspase-3), and these changes were partially rescued by M-1. Human FGR placentas exhibited alterations broadly consistent with the mitochondrial changes observed in the experimental models; however, the absence of placental Cd quantification limits these findings to correlative evidence.
DISCUSSION: These findings support the involvement of HIF-1α/Parkin-associated mitochondrial quality-control dysregulation in Cd-induced trophoblast injury and suggest that altered mitochondrial clearance and apoptosis may contribute to Cd-associated FGR.

Keywords:  Cadmium; Fetal growth restriction; HIF-1α; Mitophagy; Parkin; Placenta

DOI:  https://doi.org/10.1016/j.placenta.2026.09.018
Placenta. 2026 Sep 25. pii: S0143-4004(26)00693-4. [Epub ahead of print]186 110-118

Impaired syncytin-1-CXCR4 crosstalk contributes to trophoblast migration defects in preeclampsia.

Ya-Nan Wang, Hai-Feng Zhang, Xue-Ling Chen, Ju Yang, Yun-Shan Xue, Pei-Shan Chen, Hai-Bin Chen.

   BACKGROUND: Preeclampsia is a pregnancy-specific disorder characterized by de novo hypertension and proteinuria after 20 weeks of gestation, affecting 3-8% of pregnant women globally. Current management relies primarily on preventive strategies and symptomatic relief, with urgent delivery remaining the only definitive intervention. Syncytin-1, a human endogenous retroviral envelope protein, is implicated in preeclampsia pathogenesis via modulating trophoblast function and uterine spiral artery remodeling, though its precise molecular mechanisms remain unclear.
METHODS: This study utilized transcriptome sequencing of syncytin-a conditional knockout mice, alongside String database analysis, ClusPro/GRAMM/HDOCK molecular docking, immunofluorescence co-localization, and co-immunoprecipitation to predict and validate Syncytin-1 interacting partners. Bioinformatics, western blotting, and RT-qPCR were applied to screen and confirm differentially expressed genes in preeclamptic cell models and placental tissues. HTR-8/SVneo cells were treated with si-ERVW-1, the CXCR4 inhibitor AMD3100, or the CXCR4 agonist NUCC390, followed by functional analyses.
RESULTS: We identified direct co-localization and interaction between Syncytin-1 and CXCR4 in HTR-8/SVneo cells. Downregulated expression of Syncytin-1 and key components of the CXCR4/GNAQ/CALM2/NFATC1 pathway was observed in preeclamptic cell models and placental tissues. In HTR-8/SVneo cells, si-ERVW-1 or AMD3100 treatment markedly reduced Syncytin-1 and CXCR4 signaling molecule expression (CXCR4, GNAQ, CALM2, NFATC1) and significantly suppressed cell migration and invasion effects reversed by NUCC390.
CONCLUSION: These findings suggest that Syncytin-1 downregulation may drive preeclampsia by targeting CXCR4 to inhibit the GNAQ/CALM2/NFATC1 pathway and reduce trophoblast migratory and invasive capacities.

Keywords:  CXCR4; GNAQ/CALM2/NFATC1 pathway; Preeclampsia; Syncytin-1; Trophoblasts

DOI:  https://doi.org/10.1016/j.placenta.2026.09.019
Cell Signal. 2026 Oct 02. pii: S0898-6568(26)00583-8. [Epub ahead of print] 112924

SMURF1 alleviates preeclampsia by suppressing ferroptosis in trophoblast cells via mediating ubiquitination of FLT1.

Yanting Nie, Yali Deng, Mei Peng, Jingfei Chen, Hongyu Liu.

   BACKGROUND: Ferroptosis, an emerging form of regulated cell death, and ubiquitination have not been fully clarified in preeclampsia (PE). Aberrant overexpression of Fms-like tyrosine kinase 1 (FLT1) is closely associated with PE development, yet the association between FLT1 and ferroptosis in PE, as well as the involvement of ubiquitination in this process, remains unexplored.
METHODS: To recapitulate PE pathophysiology, rat models were generated via N(G)-Nitro-L-arginine methyl ester (L-NAME) administration, and HTR-8/Svneo cells were subjected to hypoxic stress. The expression patterns of SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) and FLT1, as well as their regulatory relationship in trophoblast ferroptosis, were examined. Furthermore, the molecular mechanism by which SMURF1 regulates FLT1 and ferroptosis in PE was clarified via FLT1 knockdown, SMURF1 overexpression, Ferrostatin-1 treatment, and rescue experiments.
RESULTS: We successfully established a PE rat model through L-NAME administration, with marked ferroptosis activation in placental tissues. FLT1 was notably upregulated and positively correlated with Fe2+ levels. Knockdown of FLT1 markedly attenuated ferroptosis, improved placental pathological damage, pregnancy outcomes, and clinical manifestations of PE. In vitro, FLT1 was highly expressed in PE-stimulated trophoblasts, and silencing FLT1 inhibited ferroptosis with an effect similar to that of the ferroptosis inhibitor Ferrostatin-1. Bioinformatics prediction and experimental validation revealed that SMURF1, a downregulated E3 ubiquitin ligase in PE models, associates with FLT1 and promoted its ubiquitin-dependent degradation. Moreover, overexpression of SMURF1 suppressed ferroptosis in PE-stimulated trophoblasts, an effect that was reversed by FLT1 restoration.
CONCLUSIONS: Downregulated SMURF1 in PE degrades FLT1 through ubiquitination, thereby suppressing ferroptosis in trophoblast cells, and alleviating placental pathological injury and PE-related symptoms. This study reveals the central regulatory function of the SMURF1-FLT1-ferroptosis pathway in PE progression, providing fresh perspectives on the link between placental damage and ferroptosis.

Keywords:  FLT1; Ferroptosis; Preeclampsia; SMURF1; Trophoblast cells; Ubiquitination

DOI:  https://doi.org/10.1016/j.cellsig.2026.112924
J Neuroendocrinol. 2026 Oct;38(10): e70261

Prolactin receptor signalling contributes to the attenuation of stress-induced hyperthermia during pregnancy.

Andrew M Stewart, David R Grattan, Teodora R Georgescu.

  During pregnancy, thermoregulation is tightly controlled to protect the foetus from harmful elevated temperatures. Stress-induced hyperthermia is a component of the stress response that increases alertness to a perceived threat. Previous literature has shown that like other aspects of the stress response, stress-induced hyperthermia is attenuated in late pregnancy. We sought to investigate how stress-induced hyperthermia is attenuated in pregnancy of mice. The lactogenic hormones, prolactin and placental lactogen, have been previously shown to act through the prolactin receptor (Prlr) to keep maternal temperature in pregnancy low to ensure successful reproductive outcomes. We hypothesised that Prlr signalling in the brain would attenuate stress-induced hyperthermia during pregnancy. To investigate this, we specifically knocked out Prlr from glutamatergic (Vglut2) neurons in mice (Prlrlox/lox/Vglut2Cre). These neurons have been implicated in maternal adaptations and in stress-induced hyperthermia. Using radiotelemetry to record core temperature (Tcore) and activity levels, non-pregnant and pregnant mice were handled daily by scruffing the skin on the back of the neck to elicit a stress-induced hyperthermic response. In pregnant control mice (Prlrlox/lox), stress-induced hyperthermia became attenuated from day 12 of pregnancy. This was not due to habituation to the stressor, as non-pregnant mice did not show any attenuation of the stress-induced Tcore response following repeated handling for up to 20 days. In the Prlrlox/lox/Vglut2Cre mice, the pregnancy-induced attenuation of stress-induced Tcore was markedly delayed, only appearing at day 14 of pregnancy. The changes were specific to the temperature response to stress, as both genotypes displayed similar levels of stress-induced activity following handling. Together, these data demonstrate that stress-induced hyperthermia is attenuated during pregnancy in mice and that this effect is at least partially mediated by Prlr signalling in glutamate neurons. However, as the stress-induced Tcore response of the knockout mice was eventually attenuated in late pregnancy (gestation day 15-17), comparable to controls, other factors may also be involved.

Keywords:  lactogenic hormones; pregnancy; prolactin receptor; stress‐induced hyperthermia; thermoregulation

DOI:  https://doi.org/10.1111/jne.70261
Front Cell Dev Biol. 2026 ;14 1920196

Excess glutamine in embryo culture media alters mitochondrial and autophagy-related dynamics associated with impaired postnatal development.

Norermi Firzana Alfian, Yui Maruhashi, Masahiro Horizoe, Wasim Bari, Shiori Ishiyama, Kazuki Mochizuki, Satoshi Kishigami.

  The preimplantation period is a critical nutrient-sensing window influencing metabolic disease risk, as established by the developmental origins of health and disease theory (DOHaD). In this study, we examined the postnatal consequences of increased glutamine concentration, an important energy source, by altering embryonic metabolic development. In vivo-fertilised ICR mouse embryos were cultured in modified Chatot-Ziomek-Bavister medium with 1 mM L-glutamine (Gln) and bovine serum albumin (BSA) as the control and compared with elevated Gln media (2 mM) with bovine serum albumin (+Gln) or without BSA (+Gln-BSA). Early embryonic developmental analysis showed that both +Gln and +Gln-BSA presented reduced blastocyst cell number, primarily in trophectoderm cells, associated with increased apoptosis. Embryos showed altered metabolic homeostasis, including reduced mitochondrial membrane potential and mitochondrial morphology, altered autophagy-related activity (indicated by discrepancies between the DAPGreen assay and LC3-positive autophagosomes), and reduced heterochromatin methylation signals (H3K27me3). Offspring derived from these embryos subsequently exhibited irregular body weight trajectories, reduced survival, and impaired glucose tolerance. These findings indicate that in vitro exposure to elevated glutamine during early development is associated with altered mitochondrial dynamics and autophagy-related responses, interrupting intracellular mechanisms with lifelong metabolic consequences.

Keywords:  DOHaD; autophagy; embryo culture; embryogenesis; glutamine; mitochondria

DOI:  https://doi.org/10.3389/fcell.2026.1920196
bioRxiv. 2026 Sep 13. pii: 2026.09.10.750701. [Epub ahead of print]

A genetically encoded redox bottleneck constrains human developmental rate.

Gabriel E Valdebenito, Jack P Madden, Carolina Mendez, Leslie M Azurdia, Xintao Zhu, Siyu Chen, Diana Atlas, Katherine Introcaso, Hao Zhang, Yahui Wang, Fangcong Dong, Rohit Sharma, Vamsi K Mootha, Gary J Patti, Margarete Diaz-Cuadros.

The intrinsically slow pace of human development poses challenges for regenerative medicine and disease modeling. This trait is attributed to low metabolic rates, yet the endogenous mechanisms determining species-specific metabolic flux remain unknown. Here, we identify coupling between glycolytic NADH production and mitochondrial oxidation through the glycerol-3-phosphate (G3P) shuttle as a genetic bottleneck constraining human developmental tempo. Using stem cell-derived models of the segmentation clock, an oscillator whose period reflects developmental rate, we show that low expression of the G3P shuttle enzyme GPD1L limits NADH oxidation in human progenitors compared to mouse. Overexpressing GPD1L boosts metabolic flux, accelerating the segmentation clock, cell cycle, and differentiation across germ layers. G3P-mediated redox coupling is thus a genetically encoded, rate-limiting mechanism that sets the tempo of human development.

DOI: https://doi.org/10.64898/2026.09.10.750701
Nat Commun. 2026 09 01. pii: 10399. [Epub ahead of print]17(1):

High-throughput functional characterization of enhancers in totipotent-like cells.

Lingyue Yang, Tianran Peng, Yating Zhu, Xuzhao Zhai, Boyan Huang, Hai Zhou, Dafeng Tao, Ling Li, Tao Zhang, Yunxia Cao, Jiekai Chen, Dan Liang, Jiangping He, Man Zhang.

Zygotic genome activation (ZGA) marks the initial transcription event in embryogenesis, yet the cis-regulatory mechanism remains unclear. Here, utilizing massively parallel reporter assays, we functionally dissect enhancers across mouse genome in DUX-induced 2C-like cells (2CLCs). Through integrated analysis with epigenomic and transcriptomic data from 2CLCs and 2C embryos, active enhancers in totipotent cells are depicted. Among them, a notable proportion of promoters exhibit enhancer activities, showing elevated active chromatin features and correlating with enhanced gene expression during ZGA. Transcription factors preferentially enriched at enhancer-promoter regions play critical roles in regulating ZGA and early embryonic development. Furthermore, only half of the MT2_Mm exhibit enhancer activities in 2CLCs. Notably, 2CLC enhancers augment transcription in 2C embryos. Finally, deleting enhancer regions in both 2CLCs and 2C embryos, together with dCas9-KRAB-MeCP2-mediated CRISPRi in vitro, collectively underscores their crucial role in facilitating transcription of ZGA genes. These findings advance our comprehension of the cis-regulatory mechanism governing ZGA process.

DOI: https://doi.org/10.1038/s41467-026-77311-8