bims-placeb 2026-03-15 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–03–15
six papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

The dynamics of glycosylation in trophoblast cells: development, function, and pregnancy-related disorders.
HAND1 controls the lineage bifurcation of trophoblast and amnion from human pluripotent stem cells.
Steroidogenic compensation and lipid deficiency with enhanced NAD+ salvage in small-for-gestational-age placenta.
Differential methylation of lipid metabolism and X-linked inheritance genes is associated with low placental efficiency, impaired fatty acid metabolism and oxidative stress in the placenta of hypercholesterolemic mothers.
O-GlcNAcylation regulates endometrial decidualization through dual mechanisms: PI3K-AKT axis-mediated phosphorylation and direct modification of FOXO1.
Preparation of placenta-tropic mRNA lipid nanoparticles for pregnancy disorders.

Ann Med. 2026 Dec;58(1): 2593420

The dynamics of glycosylation in trophoblast cells: development, function, and pregnancy-related disorders.

Tiantong Wang, Yan Wang, Yilun Wu, Yi Zhang, Fang Ma.

   BACKGROUND: Trophoblast cells are essential for embryo implantation and placental development, with their functional versatility critically regulated by dynamic glycosylation modifications. These post-translational modifications create a spatiotemporally-defined molecular code that directs trophoblast behavior throughout pregnancy, though its comprehensive role in both physiological and pathological contexts remains to be fully elucidated.
DISCUSSION: Glycosylation orchestrates key trophoblast functions in a stage-specific manner. During early pregnancy, specific glycan patterns mediate blastocyst adhesion and trophoblast invasion via modifications to integrins, cadherins, and selectins. As placental development progresses, spatially restricted glycosyltransferases guide cytotrophoblast differentiation into syncytiotrophoblasts and extravillous trophoblasts, modulating critical signaling pathways including Wnt, Notch, and FGF. Glycosylation further regulates maternal-fetal immune tolerance through cytokine receptor modifications and sialylated glycan interactions with inhibitory immune receptors. Disruptions to this spatiotemporal glycan landscape-manifested as aberrant sialylation, fucosylation, and N-glycan branching-are mechanistically linked to pregnancy disorders including preeclampsia, gestational diabetes, recurrent pregnancy loss, and choriocarcinoma. Emerging technologies such as single-cell glycomics and trophoblast organoids are now decoding this intricate regulatory system with unprecedented resolution, bridging molecular mechanisms with clinical phenotypes.
CONCLUSION: Glycosylation constitutes a master regulatory code that coordinates trophoblast development and function across gestation. The spatiotemporal specificity of glycosylation patterns ensures proper placentation and maternal-fetal interface maintenance, while its dysregulation contributes significantly to pregnancy pathologies. Understanding this dynamic system opens new avenues for biomarker discovery and therapeutic interventions, with emerging glycomic technologies poised to translate these findings into clinical applications for managing complicated pregnancies.

Keywords:  Glycosylation; glycobiology; maternal–fetal interface; placenta; pregnancy disorders; trophoblast

DOI:  https://doi.org/10.1080/07853890.2025.2593420
Cell Mol Life Sci. 2026 Mar 10.

HAND1 controls the lineage bifurcation of trophoblast and amnion from human pluripotent stem cells.

Changmiao Pang, Qifeng Yang, Yulong Zhong, Jinhao Ye, Yufang Lv, Shufei Xie, Yanqing Tang, Xianhua Ye, Feifan Zhang, Chao Li, Jingyi Zhang, Liangzhong Sun, Shanshan Ai, Xuefei Gao.

  Trophoblast and amniotic lineages, representing key extra-embryonic tissues, can be differentiated from human pluripotent stem cells (hPSCs) under chemically defined conditions. However, the regulatory mechanisms coordinating the fate decision between these lineages during PSC differentiation remain incompletely understood. Leveraging CRISPR/Cas9-mediated loss-of-function screening in lineage-reporter PSCs, we identified the transcription factor HAND1 as a critical determinant controlling the bifurcation of trophoblast and amniotic lineages. Genetic ablation of HAND1 effectively abrogated the amniotic differentiation capacity of PSCs while concomitantly enhancing their trophoblast differentiation potential. Conversely, ectopic HAND1 overexpression impaired trophoblast differentiation. Notably, forced HAND1 expression in human trophoblast stem cells (TSCs) induced transcriptional reprogramming toward an amniotic fate, indicating its lineage-instructive capability. Mechanistic analyses demonstrated that HAND1 interacts with the TCFs and Wnt signaling effectors β-catenin to form a transcriptional complex that antagonistically modulates the balance between trophoblast- and amnion-associated gene regulatory networks. Collectively, our findings establish HAND1 as a master regulator orchestrating the amniotic versus trophoblast lineage choice during human PSC differentiation, thereby illuminating fundamental regulatory mechanism underlying extra-embryonic lineage specification.

Keywords:  CRISPR screening; Lineage specification; Reporter cell lines; Transcriptional complex; Trophoblast development

DOI:  https://doi.org/10.1007/s00018-026-06120-5
FEBS J. 2026 Mar 10.

Steroidogenic compensation and lipid deficiency with enhanced NAD+ salvage in small-for-gestational-age placenta.

Serena Xodo, Lorenza Driul, Vanessa Tolotto, Eros Di Giorgio, Luigi E Xodo.

  Fetal growth restriction (FGR) affects approximately 8% of pregnancies in Western countries and is characterised by complex placental adaptations at both metabolic and transcriptional levels. In this study, we integrated RNA sequencing and metabolomic analyses to investigate alterations in steroidogenesis, NAD+ metabolism and ω-3/ω-6 polyunsaturated fatty acid (PUFA) pathways in placental biopsies and trophoblast organoids. Placentas from small-for-gestational-age (SGA10 and SGA3) infants, compared with appropriate-for-gestational-age (AGA) controls, showed increased cholesterol uptake and enhanced steroid biosynthesis. In SGA3 placentas, these changes were accompanied by activation of the NAD+ salvage pathway, supporting elevated steroidogenesis, redox balance and energy metabolism. Despite this compensatory response, concentrations of key steroid metabolites, including androstenedione sulfate and oestrogens, were reduced. Metabolomic profiling further revealed a marked depletion of lysophospholipids enriched in ω-3 and ω-6 PUFAs, along with decreased levels of free arachidonic acid (ARA), docosahexaenoic acid (DHA) and selected prostaglandins and thromboxanes. These alterations suggest mobilisation of lipid stores to counteract reduced PUFA-derived eicosanoid production, a process that may compromise placental vascular regulation and fetal neurodevelopment. Collectively, our results highlight the metabolic plasticity of the FGR placenta and identify coordinated alterations in lipid and NAD+ metabolism as key adaptive responses to placental insufficiency.

Keywords:  NAD+ salvage pathway; SGA placenta; cholesterol uptake; steroidogenesis; ω‐3/ω‐6 PUFAs

DOI:  https://doi.org/10.1111/febs.70475
Atherosclerosis. 2026 Mar 06. pii: S0021-9150(26)00060-2. [Epub ahead of print]415 120694

Differential methylation of lipid metabolism and X-linked inheritance genes is associated with low placental efficiency, impaired fatty acid metabolism and oxidative stress in the placenta of hypercholesterolemic mothers.

V S Jayalekshmi, Budhaditya Basu, Sreelekshmi Srijith, Geethu Krishna, P Rafeekha, R Vidyalekshmy, Surya Ramachandran.

   BACKGROUND: Maternal hypercholesterolemia (MHC), characterized by elevated cholesterol levels in mothers during gestation, increases the risk of atherosclerosis in offspring. This study seeks to uncover how in-utero fetal programming may be linked to changes in methylation patterns in the placenta, potentially affecting fetal gene expression.
METHODS: Pregnant subjects who were within the first 100 days of gestation were recruited and classified as either normocholesterolemic (NC) or hypercholesterolemic (MHC). Lipid profiling was conducted throughout all trimesters. Post delivery, placental samples were collected, and newborn parameters were recorded. A genome-wide methylation EPIC array and histological analysis were performed on the placental samples, with results validated using quantitative real-time PCR and immunohistochemistry.
RESULTS: EPIC array analysis revealed significant methylation changes in genes linked to X-linked inheritance and lipid metabolism pathways. Combined gene expression studies and histopathological analysis indicated disrupted fatty acid metabolism and elevated oxidative stress in placentas affected by maternal hypercholesterolemia (MHC). Furthermore, MHC was associated with decreased placental efficiency, lower birth weight, elongated umbilical cords in newborns.
CONCLUSIONS: Maternal hypercholesterolemia is associated with methylation changes in the placenta that disrupt metabolic pathways and compromise placental function. This study offers strong experimental evidence that the MHC placenta plays a role in fetal programming, contributing to clinical manifestations in offspring.

Keywords:  Cardiovascular diseases; DNA methylation; Maternal hypercholesterolemia; Placenta

DOI:  https://doi.org/10.1016/j.atherosclerosis.2026.120694
Biol Direct. 2026 Mar 12.

O-GlcNAcylation regulates endometrial decidualization through dual mechanisms: PI3K-AKT axis-mediated phosphorylation and direct modification of FOXO1.

Qianyi Sun, Yingxin Gao, Ao Wang, Xinmei Chen, Linping Fan, Shanyuan Jin, Lin Guo, Hongshuo Zhang, Ying Kong.

   BACKGROUND: Steroid hormone-driven endometrial decidualization involves the differentiation of endometrial stromal cells into decidual cells, which form the decidua for blastocyst implantation. This process is a prerequisite for successful embryo implantation. O-GlcNAcylation is a nutrient-sensitive post-translational modification. Our prior work demonstrated that O-GlcNAcylation promotes embryo recognition by enhancing endometrial epithelial cell proliferation, migration and invasion, thereby facilitating embryo implantation. However, its regulatory role in endometrial stromal cell decidualization remains unknown.
RESULTS: In this study, we found that O-GlcNAcylation was upregulated during mouse embryo implantation and in vitro decidualization, and its downregulation impaired both embryo implantation efficiency and decidualization. Transcriptome sequencing revealed that the PI3K-AKT pathway was significantly enriched upon OGT inhibition. Mechanistically, O-GlcNAcylation likely promotes decidualization by attenuating PI3K-AKT signaling to reduce phosphorylation of the key decidualization transcription factor FOXO1, while simultaneously increasing direct O-GlcNAcylation of FOXO1, thereby enhancing its stability and nuclear retention to promote decidualization.
CONCLUSIONS: This study elucidates how O-GlcNAcylation orchestrates decidualization through FOXO1 regulation, providing important insights into the role of O-GlcNAcylation signaling in normal pregnancy and its dysregulation in decidualization-related disorders.

Keywords:   O-GlcNAcylation; Decidualization; FOXO1; PI3K-AKT pathway

DOI:  https://doi.org/10.1186/s13062-026-00750-2
Nat Protoc. 2026 Mar 10.

Preparation of placenta-tropic mRNA lipid nanoparticles for pregnancy disorders.

Kelsey L Swingle, Michael J Mitchell.

Lipid nanoparticles (LNPs) have garnered tremendous enthusiasm in preclinical and clinical settings for the delivery of nucleic acids such as mRNA. With applications in protein replacement therapies, vaccines and gene editing, mRNA LNPs have only recently been explored in the context of pregnancy disorders. There is a significant need for the design of novel therapeutic technologies such as mRNA LNPs to treat obstetric disorders like pre-eclampsia that are associated with placental pathology and detrimental effects on maternal and fetal health. Here, we present a step-by-step procedure for the preparation and evaluation of placenta-tropic mRNA LNPs for researchers from varied disciplines to explore their application in treating pregnancy disorders. In this Protocol, we describe steps for synthesizing and purifying the key ionizable lipid excipient of the placenta-tropic LNP formulation (4 d) before preparing mRNA LNPs using microfluidic mixing (1 d). Then, we detail in vitro mechanistic evaluations of the effect of protein adsorption on LNP-mediated mRNA transfection to placental trophoblasts (3 d). Finally, we outline methods for isolating reproductive tissues from time-dated pregnant mice to assess in vivo LNP biodistribution and mRNA transfection to the murine placenta (16 d). Compared to alternative LNP formulation procedures, this Protocol focuses on delivering mRNA LNPs to the placenta with a workflow that can be applied for a range of obstetric disorders. This Protocol seeks to increase interdisciplinary work at the interface of nanomedicine, gene modulation and reproductive health.

DOI: https://doi.org/10.1038/s41596-025-01325-7