bims-placeb 2026-09-06 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–09–06
seven papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Isthmin-2 is a first-trimester predictor of preeclampsia and fetal growth restriction.
Functional expression of TRPV6 in human syncytiotrophoblasts from trophoblast stem cells - possible role in maternal-fetal calcium transport.
Insulin receptor substrate 2 regulates placental syncytiotrophoblast differentiation at the maternal-fetal interface.
Sex-Dependent Placental Neuroendocrine Disruption by Maternal Arsenic Exposure: From Neurotransmitter Dysregulation to Neurobehavioral Outcomes.
Transcriptomic Profiling of SLC and ABC Transporters in the Human Term Placenta.
Bridging cotyledon histopathology and perfusion in healthy primate pregnancy.
Polystyrene nanoparticles impair endometrial decidualization in early pregnant mice via oxidative stress-driven autophagy suppression and ferroptosis induction.

Nat Med. 2026 Sep 01.

Isthmin-2 is a first-trimester predictor of preeclampsia and fetal growth restriction.

IMPACT Consortium

Preeclampsia and fetal growth restriction (FGR) are major causes of global morbidity and mortality. Both conditions are associated with impaired invasion of the uterus by extravillous trophoblast (EVT). We performed proteomics in maternal serum obtained at ~12 weeks of gestational age in a prospective pregnancy cohort (Pregnancy Outcome Prediction Study). Here we show that low maternal serum isthmin-2 (ISM2) was the strongest protein signal (out of 2,904) in the first trimester of pregnancy for preeclampsia or FGR. We validated the association in two independent cohorts (Pregnancy Outcome Prediction Study 2 and Improving Maternal Pregnancy And Child ouTcomes study). ISM2 protein and mRNA are almost exclusively produced in the placenta, and, within the placenta, ISM2 mRNA is highly enriched in EVT. Knocking down ISM2 in cultured human trophoblast stem cells profoundly inhibited EVT invasion. Conversely, expressing ISM2 in a cell line lacking endogenous ISM2 (HEK293 cells) promoted migration. We conclude that ISM2 may be causally involved in the early pathophysiology of failed trophoblast invasion and that the protein and its associated pathways are potential targets for the prediction and prevention of preeclampsia and FGR.

DOI: https://doi.org/10.1038/s41591-026-04573-6
J Physiol Sci. 2026 Aug 31. pii: S1880-6546(26)00045-4. [Epub ahead of print]76(3): 100099

Functional expression of TRPV6 in human syncytiotrophoblasts from trophoblast stem cells - possible role in maternal-fetal calcium transport.

Yoshiro Suzuki, Soshi Otani, Shouichi Shibasaki, Keishi Otsu, Katsumi Nakajima.

  Maternal-fetal calcium (Ca2 +) transport through the placenta is crucial for the development of fetal organs including bones. Although we have reported that the transient receptor potential cation channel, subfamily V, member 6 (TRPV6) was responsible for the maternal-fetal Ca2+ transport, there has been no direct evidence for its channel activity in placental trophoblasts. By using human trophoblast stem cells, we observed biphasic higher intracellular Ca2+ levels compared with undifferentiated cells during the differentiation of syncytiotrophoblasts. Second Ca2+ peak, when the syncytiotrophoblasts might mature with transport function, was found to be a Ca2+ flux through TRPV6. Unexpectedly we observed the first peak, when trophoblasts fuse to form syncytiotrophoblast. We found that it was derived through TRPV4, and blocking TRPV4 suppressed trophoblast cell fusion. Our results might provide the first evidence for TRPV6 channel activities in syncytiotrophoblasts involved in the maternal-fetal Ca2+ transport.

Keywords:  Cell fusion; Maternal-fetal calcium transport; Placenta; TRPV4; TRPV6

DOI:  https://doi.org/10.1016/j.jphyss.2026.100099
Stem Cell Reports. 2026 Sep 03. pii: S2213-6711(26)00272-9. [Epub ahead of print] 103061

Insulin receptor substrate 2 regulates placental syncytiotrophoblast differentiation at the maternal-fetal interface.

Johanna Grinat, María Moya-Navamuel, Paula Blanco-Cueto, Claudia Alemán-Juanes, Nathaly Hernández-Díaz, Maravillas Mellado-López, Amparo Galán, Luke A Noon, Deborah J Burks, Katrien De Clercq, Jorge López-Tello, Vicente Pérez-García.

  The placental labyrinth is the primary site of maternal-fetal exchange, and its disruption contributes to placental insufficiency and fetal growth restriction (FGR). Here, we identify insulin receptor substrate 2 (IRS2) as a key regulator of mouse placental labyrinth development. Irs2 is expressed in the syncytiotrophoblast (SynT) layers of the labyrinth, where it integrates growth factor signaling during placental morphogenesis. Loss of IRS2 disrupts labyrinth organization, causing defective SynT-II differentiation, impaired trophoblast fusion, and reduced fetal vascularization. Using CRISPR-Cas9-engineered Irs2-/- trophoblast stem cells, we show that IRS2 deficiency impairs upregulation of the SynT-II regulators Pparγ and Gcm1, disrupting SynT-II differentiation and sinusoidal trophoblast giant cell specification. Mechanistically, IRS2 relays insulin-like growth factor (IGF) signals through phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways to coordinate trophoblast proliferation, differentiation, and vascular morphogenesis. Human trophoblast stem cell differentiation and organoid analyses reveal IRS2 enrichment in the human syncytiotrophoblast (STB), indicating conserved expression at the human maternal-fetal interface.

Keywords:  CRISPR-Cas9 technology; IGF; fetal growth restriction; fetal vasculature; insulin-like growth factor signaling; maternal-fetal interface; placental labyrinth; syncytiotrophoblast; trophoblast stem cells

DOI:  https://doi.org/10.1016/j.stemcr.2026.103061
Environ Sci Technol. 2026 Sep 01. 60(34): 23722-23735

Sex-Dependent Placental Neuroendocrine Disruption by Maternal Arsenic Exposure: From Neurotransmitter Dysregulation to Neurobehavioral Outcomes.

Fang Chen, Xie He, Hui Qin, Jun Wang, Changsong Tian, Wenjuan Wang, Aihua Zhang.

  Epidemiological evidence suggests that developmental arsenic (As) exposure increases behavioral abnormalities in offspring. However, how placental neuroendocrine function and sex-specific responses contribute to these effects remains poorly understood. Here, we demonstrate that maternal As exposure induces trophoblastic damage, vascular disruption, and placental labyrinth thinning, leading to placental dysplasia, fetal growth restriction, and sex-specific behavioral outcomes in offspring. Integrated transcriptomic and neurobehavioral analyses revealed sex-dependent alterations primarily involving neurodevelopmental pathways and transporter dysfunction. Concurrently, neurotransmitter metabolomic profiling identified profound disturbances in tryptophan, tyrosine, and amino acid metabolism in the placenta and fetal brain. Bayesian benchmark dose (BMD) modeling revealed that points of departure (PoDs) followed the rank order, such that metabolomic (mPoDs) < neurobehavioral (nPoDs) < apical (aPoDs). Notably, alterations in the tryptophan pathway were the most sensitive early perturbations observed, with BMDL10 values for 5-hydroxy-l-tryptophan of 3.73 μg/L in females and 4.17 μg/L in males, respectively. Overall, this exploratory framework provides evidence for placental neuroendocrine toxicity of As and highlights its potential relevance for refined environmental risk assessment.

Keywords:  arsenic; neurotransmitters; placenta; points of departure; sex-specific

DOI:  https://doi.org/10.1021/acs.est.6c02167
Clin Pharmacol Ther. 2026 Sep 01.

Transcriptomic Profiling of SLC and ABC Transporters in the Human Term Placenta.

Elijah Marsh Jung, Nicholas Ieronimakis, Bothaina Mousa, Emily D Sheikh, Sarah E Ligon, Joshua W Monson, Jennifer R Damicis, Hillary J Kinsman, Lydia E Bettridge, Samuel L M Arnold, Edward J Kelly, Jashvant D Unadkat, Joanne Wang.

Solute carriers (SLC) and ATP-binding cassette (ABC) transporters are essential for placental solute exchange and fetal protection, yet their transcriptomic profiles in the human placenta remain poorly characterized. Although fetal sex influences placental development and function, its impact on transporter expression is unclear. Using RNA sequencing, we profiled SLC and ABC transporter expression in two anatomical regions of term human placentas (N = 10) with balanced fetal sex distribution and controlled clinical features. In the intervillous region, 276 SLCs were detected, with 60% expressed at low levels (CPM < 25) and 110 (40%) expressed at higher levels (CPM 25-1650). Four transporters-SLC2A1 (GLUT1), SLC44A2 (CTL2), SLC38A2 (SNAT2), and SLC38A1 (SNAT1)-showed the highest expression (CPM > 500). Functional annotation of 110 SLCs revealed transporters for amino acids, metals, and inorganic ions each accounted for ~9%. Other well-represented SLCs included xenobiotic and vitamin transporters. Mitochondrial, lysosomal, and endoplasmic reticulum and Golgi transporters together accounted for ~37%, while 11% were orphan transporters. Thirty-seven ABC transporter transcripts were detected, primarily associated with xenobiotic and lipid transport. Compared with the intervillous region, 1676 genes-including 32 SLC and 2 ABC transporters-were differentially expressed in the decidual region. Although 117 genes in the intervillous region and 79 genes in the decidual region exhibited sexually dimorphic expression, none were SLCs. Notably, male placentas showed higher expression of ABCB1 (P-gp), confirmed by qPCR and western blot. Our findings provide a transcriptomic map of placental transporters and highlight a potential sex-specific difference on ABCB1 expression and xenobiotic protection.

DOI: https://doi.org/10.1002/cpt.70463
Placenta. 2026 Aug 29. pii: S0143-4004(26)00673-9. [Epub ahead of print]183 103-112

Bridging cotyledon histopathology and perfusion in healthy primate pregnancy.

Logan T Keding, Ruo-Yu Liu, Taylor J Keding, Jessica Vazquez, Crystal G Bockoven, Dinesh M Shah, Thaddeus G Golos, Oliver Wieben, Aleksandar K Stanic.

   INTRODUCTION: Healthy and diseased placentae alike often display some degree of histopathology. However, quantitative techniques to characterize common placental lesions and their relationship to local maternal hemodynamics in healthy pregnancy are currently limited.
METHODS: Seven pregnant macaques with healthy fetoplacental biometrics were recruited for study. Placentae were imaged by MRI at three time points across mid-to late-gestation to quantify volume, blood flow, and perfusion of maternal blood across pregnancy. Near term, we collected placental cotyledons, imaged hematoxylin/eosin-stained slides, then annotated major histopathological features (sub-tissues, intervillous gaps, fibrin deposition, villous agglutination, inflammatory agglutination, and stromal mineralization) within each cotyledon. Histopathological lesions were assessed in relation to each other and MRI-based perfusion metrics, in a cotyledon-specific manner. Parallel analyses were performed to investigate both basic (Spearman correlation) and animal variance-conditioned (dimensionality-reduction) relationships.
RESULTS: Dimensionality reduction analysis revealed maternal vascular malperfusion-associated histopathology as the main contributor to dataset variance and was positively associated with increased maternal blood perfusion across gestation. Cotyledons with increased stromal mineralization demonstrated low blood perfusion across pregnancy, alongside changes potentially indicative of maternal compensation. Additionally, histopathology associated with healthy placental function demonstrated low cotyledon blood flow at all timepoints.
CONCLUSIONS: We revealed several relationships connecting histopathology and perfusion in the healthy pregnancy, such as maternal vascular malperfusion-associated lesions increasing with increased maternal blood perfusion - all accomplished at the smallest functional unit of the placenta. This methodological framework embeds pathologist-refined morphological expertise into a quantitative, spatially resolved format that can better ground unsupervised computational approaches to placental analysis.

Keywords:  Blood perfusion; Cotyledon; Histopathological annotation; Histopathology; Maternal compensation; Rhesus macaque

DOI:  https://doi.org/10.1016/j.placenta.2026.08.340
Food Chem Toxicol. 2026 Aug 31. pii: S0278-6915(26)00434-5. [Epub ahead of print]218 116359

Polystyrene nanoparticles impair endometrial decidualization in early pregnant mice via oxidative stress-driven autophagy suppression and ferroptosis induction.

Li-Qing Wang, Qian-Feng Qiao, Huang-Nian You, Yi-Bin Zheng, Xiao-Mei Wu, Wen-Jie Yu, Zeng Liu, Wen-Juan Song, Lin-Hong Zhang, Jia-Rui Hu, Xin-Yu Mao, Yong-Jiang Zhou.

  Polystyrene nanoplastics (PS-NPs) are emerging as potential threats to female reproductive health; however, their impacts on early pregnancy remain poorly understood. This study investigated the effects and underlying mechanisms of PS-NPs exposure on endometrial decidualization in early pregnant mice using both in vivo and in vitro models. Our findings reveal that PS-NPs significantly reduced the number of embryo implantation sites and impaired decidualization. PS-NPs caused defective autophagy characterized by enhanced initiation but impaired completion, and simultaneously trigger ferroptosis via glutathione peroxidase 4 inactivation and iron overload. Notably, pharmacological rescue experiments demonstrate that reactive oxygen species act as the upstream trigger, while autophagy dysfunction and ferroptosis collectively contribute to decidualization defects, with ferroptosis serving as a terminal effector pathway. Strikingly, single or double interventions with the ROS scavenger N-acetylcysteine, the autophagy agonist trehalose, or the ferroptosis inhibitor ferrostatin 1 only partially restored the decidualization marker. In contrast, the simultaneous application of three interventions-ROS inhibition, autophagy activation, and ferroptosis inhibition-substantially reversed PS-NPs-induced decidualization defects. Our findings revealed that PS-NPs compromised decidualization by suppressing autophagy and inducing ferroptosis through oxidative stress. These findings provide novel insights into the reproductive toxicity of nanoplastics, identifying them as a significant risk factor for early pregnancy maintenance.

Keywords:  Autophagy; Embryo implantation; Endometrial decidualization; Ferroptosis; Oxidative stress; PS-NPs

DOI:  https://doi.org/10.1016/j.fct.2026.116359