bims-placeb 2025-09-07 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–09–07
twenty-two papers selected by
Carlos M Guardia, National Institute of Health

Human Decidual RUNX1 Promotes Angiogenesis and Trophoblast Differentiation by Regulating Extracellular Vesicle Signaling.
Defining cellular diversity at the swine maternal-fetal interface using spatial transcriptomics and organoids.
Evidence for coopetition at the maternal-fetal interface shaping placental invasion.
A single-cell transcriptomic atlas of the pigtail macaque placenta in late gestation.
PFBS disrupts lipid metabolism and mitochondrial function in human trophoblast cells.
Circular RNAs accumulate in aging human placental tissue and in stillbirth, leading to DNA damage and cellular senescence.
Acid sphingomyelinase is a gatekeeper of placental labyrinthine architecture and function.
Role of Serotonin on Gene Expression and Physiology in Human Cytotrophoblasts and Placenta.
Advancing comparative placentation through spatial transcriptomics and organoid models.
BHLHE40 Cooperates with GATA2/3 to Control Human Syncytiotrophoblast Lineage Differentiation.
Placental Igf1 overexpression sex-specifically impacts mouse placenta structure, altering offspring striatal development and behavior.
Modeling the human maternal-fetal interface.
OTUB2/NR4A1 restrains the development of preeclampsia by suppressing macrophage M1 polarization.
A Cxcl15 Cre Recombinase Mouse Model Useful to Study Gland Development in the Uterus.
Impact of hypertensive disorders on disease progression in pregnancies affected by early-onset fetal growth restriction.
An inducible model of human post-implantation development derived from primed and naive stem cells.
Efficient stem cell-derived mouse embryo models for environmental studies.
Dad's Diet Shapes the Future: How Paternal Nutrition Impacts Placental Development and Childhood Metabolic Health.
Effects of iron deficiency anemia on maternal hemodynamics and cardiac function in pregnant spontaneously hypertensive rats.
Sex-Dependent Relationships Between PFAS and Placental Transcriptomics Identified by Weighted Gene Co-Expression Analysis.
MAPK/ERK signaling blocks ectopic H3K9me3 heterochromatin formation to confer mesoderm and endoderm developmental competence.
High-throughput sequencing unravels placental vascular dysfunction and oxidative stress as mechanistic drivers of advanced maternal age-associated pregnancy.

Endocrinology. 2025 Aug 29. pii: bqaf133. [Epub ahead of print]

Human Decidual RUNX1 Promotes Angiogenesis and Trophoblast Differentiation by Regulating Extracellular Vesicle Signaling.

Jacob R Beal, Xiangning Song, Athilakshmi Kannan, Jie Yu, Indrani C Bagchi, Milan K Bagchi.

During early pregnancy, human endometrial stromal cells differentiate into secretory decidual cells via a process regulated by ovarian steroid hormones. Decidual cells play a crucial role by secreting various factors that support essential events in forming a functional placenta, including uterine angiogenesis and the differentiation and development of trophoblasts. We previously reported that the conditional ablation of the transcription factor RUNX1 in the mouse uterus leads to subfertility due to insufficient maternal angiogenesis and impaired trophoblast differentiation. In this study, we examined the role of RUNX1 in facilitating communication mechanisms among human decidual cells and other cell types present in the pregnant uterus. We demonstrate that RUNX1 regulates the conserved HIF2α-RAB27B pathway in primary human endometrial stromal cells (HESC) during decidualization, which promotes the secretion of extracellular vesicles (EVs) by these cells. Consequently, the depletion of RUNX1 in HESC led to reduced EV secretion. Mass spectrometry identified several cargo proteins in decidual EVs, including ANGPTL2 and IGF2, which could regulate angiogenesis or trophoblast differentiation. We found that RUNX1 directly regulates their expression, resulting in partial changes to these cargoes when it is absent. We observed that delivering EVs lacking ANGPTL2 or IGF2 to human endothelial cells significantly decreased the formation of vascular networks compared to introducing control EVs carrying these factors. Furthermore, adding IGF2-depleted EVs to human trophoblast cells inhibited their differentiation into the extravillous trophoblast lineage. These findings collectively highlight the crucial role of decidual RUNX1 in promoting essential cell-cell interactions for angiogenesis and trophoblast differentiation during placenta formation.

DOI: https://doi.org/10.1210/endocr/bqaf133
PLoS Biol. 2025 Aug;23(8): e3003302

Defining cellular diversity at the swine maternal-fetal interface using spatial transcriptomics and organoids.

Cole R McCutcheon, Allyson Caldwell, Liheng Yang, Elisa Crisci, Jonathan Alex Pasternak, Carolyn B Coyne.

The placenta is a dynamic, embryo-derived organ essential for fetal growth and development. While all eutherian mammals have placentas composed of fetal-derived trophoblasts that mediate maternal-fetal exchange, their anatomical and histological structures vary across species due to evolutionary divergence. Despite the cellular heterogeneity of porcine trophoblasts in vivo, understanding the mechanisms driving porcine placental development has been limited by the lack of in vitro models replicating this heterogeneity. In this study, we derived swine trophoblast organoids (sTOs) from full-term porcine placentas, retaining key transcriptional signatures of in vivo trophoblasts. To identify conserved cell populations, we integrated Visium spatial transcriptomics from mid-gestation porcine placentas with single-cell transcriptomics from sTOs. Spatial transcriptomics revealed novel markers of the porcine uterus and placenta, enabling precise separation of histological structures at the maternal-fetal interface. The integration of tissue and sTO transcriptomics showed that sTOs spontaneously differentiate into distinct trophoblast populations, with conserved gene expression and cell communication programs. These findings demonstrate that sTOs recapitulate porcine placental trophoblast populations, offering a powerful model for advancing placentation research. Our work also provides a spatially resolved whole-transcriptome dataset of the porcine maternal-fetal interface, opening new avenues for discoveries in placental development, evolution, and health across mammals.

DOI: https://doi.org/10.1371/journal.pbio.3003302
Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2323038122

Evidence for coopetition at the maternal-fetal interface shaping placental invasion.

Junaid Afzal, Yasir Suhail, Wenqiang Du, Yamin Liu, Ramalakshmi Ramasamy, Zukai Liu, Ruchi Goyal, Ashkan Novin, Sameera Suhail, Jamie Maziarz, Khadija Wali, Paul Robson, Günter P Wagner, Kshitiz.

  Coopetition is a term from game theory that describes a mix of cooperative and competitive behavior. The maternal-fetal interface (MFI) among eutherian mammals presents close interaction of two distinct individuals. These interactions have resulted in a remarkable diversity in MFI structure, often interpreted as the outcome of maternal-fetal conflict. Nevertheless, the fetus and the mother share evolutionary interests since 50% of fetal genes are maternal. In hemochorial species, characterized by invasive placentation, endometrial stromal fibroblasts (ESFs) undergo decidualization to regulate embryo implantation. In great apes, hemochorial placentation is driven by highly invasive extravillous trophoblast cells (EVT). Here, using EVTs differentiated from trophoblast stem cells, term placenta, as well as HTR8/SVneo, we demonstrate that EVTs orchestrate a transformation of the maternal stroma, reducing its resistance to invasion acquired during decidualization. Through paracrine signals, in particular IL-11, trophoblasts transform decidual ESFs from a matrix-producing to a matrix-degrading state. Notably, noninvasive cytotrophoblast cells, do not transform decidual ESFs. We further provide evidence that maternal coadaptation is critical to EVT-induced decidual transformation. Decidual ESFs upregulate expression of Suppressor of Cytokine Signaling 3 in response to EVTs, rewiring downstream IL-11 signaling from JAK/STAT to AP-1 specific transcription. We conclude that the evolution of highly invasive placentation is the outcome of both the evolution of invasive EVTs, as well as the evolution of maternal traits, i.e., the switch from JAK/STAT to AP-1 signaling. We interpret this as evidence for co-opetition (cooperation among competitors).

Keywords:  co-opetition; decidual cells; fetal–maternal interaction; placentation; trophoblast invasion

DOI:  https://doi.org/10.1073/pnas.2323038122
bioRxiv. 2025 Aug 20. pii: 2025.08.15.669966. [Epub ahead of print]

A single-cell transcriptomic atlas of the pigtail macaque placenta in late gestation.

Amanda Li, Richard Li, Hazel Huang, Hong Zhao, Briana Del Rosario, Miranda Li, Edmunda Li, Andrew Vo, Gygeria Manuel, Orlando Cervantes, Raj P Kapur, Jeff Munson, Austyn Orvis, Michelle Coleman, Melissa Berg, Britni Curtis, Brenna Menz, Jin Dai, Inah Golez, Solomon Wangari, Chris English, Audrey Baldessari, Lakshmi Rajagopal, John Cornelius, Kristina M Adams Waldorf.

The placenta is a complex organ with multiple immune and non-immune cell types that promote fetal tolerance and facilitate the transfer of nutrients and oxygen. The nonhuman primate (NHP) is a key experimental model for studying human pregnancy complications, in part due to similarities in placental structure, which makes it essential to understand how single-cell populations compare across the human and NHP maternal-fetal interface. We constructed a single-cell RNA-Seq (scRNA-Seq) atlas of the placenta from the pigtail macaque ( Macaca nemestrina ) in the third trimester, comprising three different tissues at the maternal-fetal interface: the chorionic villi (placental disc), chorioamniotic membranes, and the maternal decidua. Each tissue was separately dissociated into single cells and processed through the 10X Genomics and Seurat pipeline, followed by aggregation, unsupervised clustering, and cluster annotation. Next, we determined the maternal-fetal origins of cell populations and analyzed single-cell RNA trajectory, Gene Ontology enrichment, and cell-cell communication. Single-cell populations in the pigtail macaque were strikingly similar in their identity and frequency to those found in the human placenta, including cells from trophoblast, stromal cell, immune, and macrophage lineages. An advantage of our approach was the deep sequencing of three tissues at the maternal-fetal interface, which yielded a rich diversity of common and rare single-cell populations. The third-trimester pigtail macaque single-cell atlas enables the identification of cellular subclusters analogous to those in humans and provides a powerful resource for understanding experimental perturbations on the NHP placenta.

DOI: https://doi.org/10.1101/2025.08.15.669966
Toxicology. 2025 Aug 28. pii: S0300-483X(25)00228-8. [Epub ahead of print]518 154269

PFBS disrupts lipid metabolism and mitochondrial function in human trophoblast cells.

Julia Happel, Namya Mellouk, Christine Crute, Liping Feng.

  Perfluorobutanesulfonic acid (PFBS) is an emerging short-chain per- and polyfluoroalkyl substance (PFAS), a group of persistent environmental contaminants associated with adverse reproductive outcomes. The placenta plays a critical role in the pathogenesis of pregnancy complications, and disrupted placentation is implicated in the mechanistic pathways linking PFBS exposure to these disorders. In particular, placental mitochondria function refines during pregnancy to optimize the dynamic growth of the fetus and placenta. Disruptions in mitochondrial function may therefore mediate the adverse effects of environmental exposure on pregnancy outcomes. This study investigated the effects of PFBS on the metabolism and mitochondrial function of human syncytiotrophoblast (STB), the primary nutrient-transporting cells of the placenta. Using a human trophoblast stem cell model, we differentiated cells into STBs and exposed them to an environmentally relevant dose of PFBS (100 µM) for 24 h. Transcriptomic (RNA-seq) analysis identified 22 downregulated genes and 10 upregulated genes (FDR < 0.05). Integrated transcriptomic and metabolomic analyses revealed that PFBS significantly disrupted lipid metabolism, notably downregulating PPARG, a key regulator of placental lipid homeostasis, and carnitine shuttle genes CPT1A and SLC25A20, which are essential for mitochondrial fatty acid import. Further functional assessments found increased mitochondrial DNA copy number, yet decreased ATP production, indicating mitochondrial dysfunction. However, PFBS exposure did not induce oxidative stress nor alter mitochondrial morphology. These findings demonstrate that PFBS induces metabolic toxicity in human STBs, primarily by disrupting lipid metabolism and mitochondrial energy production. This mechanism may underlie the observed associations between PFBS exposure, placental dysfunction, and adverse pregnancy outcomes.

Keywords:  Human placental trophoblast; Lipid metabolism; Mitochondrial dysfunction; PFAS; PFBS

DOI:  https://doi.org/10.1016/j.tox.2025.154269
Am J Obstet Gynecol. 2025 Aug 29. pii: S0002-9378(25)00587-3. [Epub ahead of print]

Circular RNAs accumulate in aging human placental tissue and in stillbirth, leading to DNA damage and cellular senescence.

Anya L Arthurs, Matilda R Jackson, Dylan McCULLOUGH, Hamish S Scott, Christopher P Barnett, Stuart T Webb, Melanie D Smith, Tanja Jankovic-Karasoulos, Gustaaf A Dekker, Claire T Roberts.

   BACKGROUND: Unexplained stillbirth may occur due to premature placental aging, with unexpected deterioration of placental function for gestational age. Circular RNAs (circRNAs) are enzyme-resistant RNA molecules that accumulate in aging tissues. Furthermore, circRNAs bind gDNA directly, forming complexes which can induce DNA breaks and genomic instability.
OBJECTIVES: This study investigated tissue aging and circRNA accumulation with gestational age in healthy and stillbirth placentae, and determined whether circRNAs directly interact with placental DNA causing DNA damage and cellular senescence.
STUDY DESIGN: Placenta samples (n=60 term uncomplicated; n=4 unexplained stillbirth, 23, 26, 31, 34 weeks' gestation) were assessed. Abundance of 7 candidate circRNAs, and their linear transcripts, was quantified. Physical interaction of candidate circRNAs with DNA was confirmed. Telomere length, relative abundance of senescence-associated genes and DNA damage were assessed. Patient-derived trophoblast stem cells (TSCs) differentiation into syncytiotrophoblasts or extravillous trophoblasts was confirmed prior to circ_0000284 knockdown. Abundance of circRNAs in maternal blood sampled between 15-16 weeks' gestation (n=12 control, n=6 women who went on to have a stillbirth) was determined using qPCR. Appropriate statistical analyses were undertaken (SPSS).
RESULTS: Placental DNA damage, senescence and expression of 7 candidate circRNAs, but not their linear transcripts, were increased in 40 and 41+ weeks' gestation samples, and in stillbirth, compared with earlier gestations (37-39 weeks'). DRIP-qPCR signal size confirmed that all candidate circRNA loci bind to placental DNA. Abundance of circRNA was significantly decreased with the addition of RNase H1, compared with all healthy gestation samples, indicating that stillbirth placentae may lack RNase H1. Telomere length is shorter in placentae from stillbirths compared with healthy 37 weeks' placentae. Depletion of circ_0000284 by specific siRNA in primary cells significantly reduced DNA damage and increased expression of senescence-associated genes compared to control. Abundance of candidate circRNAs are increased in maternal blood at 16 weeks' gestation for women who went on to have a stillbirth compared with women who had live births.
CONCLUSIONS: Stillbirth placentae show accelerated aging with shortened telomeres, premature DNA breaks, increased cellular senescence and accumulation of candidate circRNAs, at levels consistent with older gestation tissue. These circRNAs bind to DNA in the placenta, and circ_0000284 knockdown reduces DNA breaks and senescence in primary placental cells. Therefore, circRNAs play a role in placental aging and associate with stillbirth, likely via decreased RNase H1 abundance, preventing circRNA degradation and facilitating circRNA accumulation, and subsequent circR-loop formation. circRNAs may present a viable method of stillbirth risk screening.

Keywords:  DNA; aging; circular RNA; double stranded breaks; placenta; pregnancy; senescence; stillbirth; telomere

DOI:  https://doi.org/10.1016/j.ajog.2025.08.030
Development. 2025 Sep 01. pii: dev.204425. [Epub ahead of print]

Acid sphingomyelinase is a gatekeeper of placental labyrinthine architecture and function.

Isidora Rovic, Katherine Szelag, Han Li, Rosanne McQuaid, Sara Sugin, Que Wu, Natalia Theodora, John Sled, Andrea Jurisicova.

  Sphingolipids are a class of bioactive signaling lipids that regulate an array of fundamental cellular processes, including cell survival, proliferation, and differentiation. Deficiency of acid sphingomyelinase-an enzyme of the sphingolipid metabolic pathway- has been previously implicated in human placental pathologies. We demonstrate that acid sphingomyelinase (Smpd1) is required for normal placental development in mouse, and its deficiency results in an intrauterine growth restriction phenotype. Smpd1-deficient placentas display several anatomical abnormalities, including reduced labyrinth compartment and increased fetal-maternal interhaemal distance. Finally, we observed several hallmarks of defective autophagy and lysosomal impairment in Smpd1-/- placentas, which could explain the inability of Smpd1-/- trophoblast to respond to nutrient starvation. Fetal growth restriction could not be rescued by transfer of Smpd1 deficient embryos into a wildtype uterine environment, however, restoration of transcription factor EB (TFEB) phosphorylation was detected. Thus, we conclude that due to a smaller labyrinthine area Smpd1 deficiency leads to a decrease in exchange between maternal and fetal blood space, limiting the supply of nutrients to the fetus, resulting in growth restriction.

Keywords:  Acid sphingomyelinase; Lysosome; Phospholipids; Placentation; Trophoblast differentiation

DOI:  https://doi.org/10.1242/dev.204425
Endocrinology. 2025 Jul 08. pii: bqaf124. [Epub ahead of print]166(9):

Role of Serotonin on Gene Expression and Physiology in Human Cytotrophoblasts and Placenta.

Nolwenn S Morris, Seth Guller, Zhonghua Tang, Yuan-Wei Zhang, Erin C Siegman, Kristin M Milano, Gary Rudnick, Harvey J Kliman.

  Serotonin (5-hydroxytryptamine; 5-HT) is transported into the human placenta through the serotonin transporter (SERT/SLC6A4) on the surface of the syncytiotrophoblast. During this transit, a significant amount of 5-HT becomes concentrated in the cytotrophoblast nucleus. We used immunochemistry, inhibitors of SERT and transglutaminase 2, and RNA sequencing to elucidate the mechanism and consequences of this nuclear localization. Exogenous 5-HT recapitulated the uptake of 5-HT into the trophoblasts and its preferential concentration in cytotrophoblast nuclei we observed in the intact placenta. Cystamine eliminated the staining of the nuclei in placental explants by exogenous 5-HT, suggesting that serotonylation mediated this phenomenon. This was confirmed by Western blots and immunoprecipitation that identified histone 3, and specifically the 5th glutamine residue in histone 3, as a site of serotonylation. Inhibiting SERT with escitalopram or transglutaminase 2 with cystamine blocked cytotrophoblast differentiation in vitro and led to marked changes in RNA expression. Of the 38 524 mRNAs identified in these trophoblasts, cystamine changed the expression of 1986 and escitalopram significantly altered 374. Both treatments altered the expression of 155 mRNAs either positively or negatively. The downregulated genes were involved with cell proliferation, morphogenesis, motility, and growth, whereas genes that were upregulated controlled cell survival and protection pathways. These findings suggest that maternal 5-HT promotes placental, embryonic/fetal, and organismal development through histone serotonylation and consequent alterations in gene expression. They raise the possibility that alterations in 5-HT flux in the placenta affect placental and fetal growth, as well as organismal somatic, neurologic developmental, and pathological trajectories.

Keywords:  histones; placenta; serotonin; serotonylation; transporter; trophoblast

DOI:  https://doi.org/10.1210/endocr/bqaf124
PLoS Biol. 2025 Aug;23(8): e3003346

Advancing comparative placentation through spatial transcriptomics and organoid models.

Francesca Soncin.

The placenta is one of the most diverse organs among eutherian mammals, and comparative placentation studies can reveal fundamental processes that support a successful pregnancy. A new study in PLOS Biology uses swine placental organoids and in vivo spatial transcriptomics to uncover key insights into placental cell diversity and evolution.

DOI: https://doi.org/10.1371/journal.pbio.3003346
Adv Sci (Weinh). 2025 Sep 05. e07642

BHLHE40 Cooperates with GATA2/3 to Control Human Syncytiotrophoblast Lineage Differentiation.

Lijin Peng, Weijie Zhao, Chunfang Xu, Yue Li, Jiani Guo, Taotao Zhou, Philip Chiu, Huimei Wu, Qingyu Wu, Yanxing Wei, Shaorong Gao, Meirong Du.

  Syncytiotrophoblasts (STBs) constitute one of the core components of the placenta, responsible for synthesizing pregnancy-sustaining hormones such as human chorionic gonadotropin (HCG). Deficient syncytialization of cytotrophoblasts affects the hormonal secretion and placental development, contributing to pregnancy-associated disorders, including spontaneous miscarriage. To date, the molecular mechanisms, particularly the role of transcription factors (TFs), in STB lineage specification remain incompletely understood. Through targeting direct regulators of a STB lineage-specific marker, CGB (encoding chorionic gonadotropin-β), by DNA pull-down coupled with mass spectrometry, basic helix-loop-helix family member 40 (BHLHE40) has been identified as a key regulator in human STB differentiation. BHLHE40 expression is increased during STB differentiation but reduced in villous samples from women with miscarriages. CRISPR/Cas9-mediated knockout of BHLHE40 in human trophoblast stem cells (TSCs) prevents STB differentiation in vitro, impairing gene expression critical for hormone synthesis and cell syncytialization. Mechanistically, BHLHE40 interacts directly with GATA2 and GATA3 to facilitate their chromatin occupancy, thereby activating transcriptional programs essential for STB differentiation. These findings uncover a BHLHE40-GATA2/3 regulatory network governing human trophoblast lineage commitment, providing insights into placental development and potential therapeutic targets for pregnancy disorders.

Keywords:  BHLHE40; GATA2/3; human trophoblast stem cells; syncytiotrophoblasts

DOI:  https://doi.org/10.1002/advs.202507642
Exp Neurol. 2025 Sep 02. pii: S0014-4886(25)00318-8. [Epub ahead of print] 115453

Placental Igf1 overexpression sex-specifically impacts mouse placenta structure, altering offspring striatal development and behavior.

Annemarie J Carver, Faith M Fairbairn, Robert J Taylor, Shanmukh Boggarapu, Njenga R Kamau, Amrita Gajmer, Hanna E Stevens.

  Insulin-like growth factor 1 (IGF1) is primarily produced in the placenta and is essential for neurodevelopment. Specifically, how placental IGF1 production persistently influences the brain is unclear, but with rates of complicated pregnancies on the rise, understanding placental contributions to child outcomes is paramount. We hypothesize that placental Igf1 expression alters fetal neurodevelopment relevant to neurodevelopmental disorders. Therefore, this study evaluated the effects of placental Igf1 overexpression on embryonic and postnatal brain development, particularly for striatum, a region highly linked to neurodevelopmental disorders. Placental overexpression altered placenta structure and function distinctly in females and males. Early differences in placental function altered the trajectory of striatal development, as adult females showed persistent changes in striatal cell composition and behavior while males were less affected. Overall, these results demonstrate that placental Igf1 expression alters striatal development and behavior relevant to neurodevelopmental disorders. These findings expand our understanding of placental influence on neurodevelopment and will aid in targeting placental biology in preventive interventions.

Keywords:  CRISPR; Insulin-like growth factor 1; Neurodevelopment; Neurodevelopmental disorders; Placenta; Striatum

DOI:  https://doi.org/10.1016/j.expneurol.2025.115453
Cell Stem Cell. 2025 Sep 04. pii: S1934-5909(25)00296-6. [Epub ahead of print]32(9): 1321-1345

Modeling the human maternal-fetal interface.

Vladyslav Bondarenko, Margherita Yayoi Turco.

  Stem cells and organoids enable the modeling of various aspects of human development in vitro, yet integrating them to study maternal-fetal interactions remains challenging. In this review, we explore the current in vitro models of the endometrium, placenta, and embryo and identify key challenges associated with their integration, including the establishment of morpho-functional complexity, spatiotemporal coordination, and appropriate in vivo benchmarking. We propose an interdisciplinary perspective that emphasizes a shift from "building blocks" to "building interactions." Altogether, we provide a discussion on the challenges and prospects for advancing mechanistic understanding of intrauterine human development and the maternal-fetal interface.

Keywords:  bioengineering; embryo; endometrium; human development; maternal-fetal interactions; organoids; placenta; stem cells

DOI:  https://doi.org/10.1016/j.stem.2025.08.004
Commun Biol. 2025 Aug 29. 8(1): 1304

OTUB2/NR4A1 restrains the development of preeclampsia by suppressing macrophage M1 polarization.

Yue Wang, Yang Wang, Fei Tong, Qianqian Gao, Baoxuan Li, Yan Zhao.

Preeclampsia is one of the most common pregnancy disorders, and characterized by insufficient trophoblast invasion and placental inflammation. Our RNA sequencing results showed that OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2) was downregulated in placenta from preeclampsia patients, compared with the healthy control. Clinical and experimental data demonstrated that OTUB2 was expressed in macrophages. Gain- and loss-of-function experiments revealed that OTUB2 overexpression blocked M1 polarization of macrophages, and attenuated macrophages-induced apoptosis, and impaired migration and invasion of trophoblasts. Moreover, OTUB2 alleviated LPS-induced preeclampsia-like symptoms in rats, including hypertension, proteinuria, inflammation in placenta and insufficient infiltration of trophoblasts. Additionally, OTUB2 mediated deubiquitination of nuclear receptor subfamily 4 group A member 1 (NR4A1) and suppressed its degradation, and the Cys51 is crucial for catalytic activity of OTUB2. The effects of OTUB2 were partially reversed by shNR4A1. In conclusion, OTUB2 suppressed macrophage M1 polarization, macrophages-induced trophoblast damage, and restrained experimental preeclampsia in rodents by mediating deubiquitination of NR4A1. These findings may provide novel insight for clinical prevention and diagnosis of preeclampsia.

DOI: https://doi.org/10.1038/s42003-025-08755-9
Genesis. 2025 Oct;63(5): e70026

A Cxcl15 Cre Recombinase Mouse Model Useful to Study Gland Development in the Uterus.

Andrew M Kelleher, Hong Im Kim, Greeshma Sai Bayammagari, Daniel J Davis, Thomas E Spencer.

  The mammalian uterus contains glands in the endometrium that develop only or primarily after birth. In the mouse, endometrial glands govern post implantation pregnancy establishment via regulation of blastocyst implantation, stromal cell decidualization, and placental development. Here, we describe a new uterine glandular epithelium (GE) specific Cre recombinase mouse line that is useful to study endometrial gland development and function. Utilizing CRISPR-Cas9 genome editing, improved Cre recombinase (iCre) was inserted into the endogenous C-X-C motif chemokine ligand 15 (Cxcl15) gene. Cxcl15 mRNA, Cxcl15 protein, and Cxcl15-iCre recombinase activity were specific to the developing GE of the uterus. Cxcl15-iCre mice were crossed with floxed Foxa2 mice to conditionally delete Foxa2 specifically in the glands of the neonatal mouse uterus. This conditional deletion of Foxa2 in the developing neonatal uterus resulted in adult mice that lacked Foxa2 in the GE of the uterus, and the adult mice were infertile. The studies described here establish that Cxcl15-iCre mice are a valuable resource to elucidate and explore mechanisms regulating the development and function of glands in the uterus.

Keywords:  Cre recombinase; Cxcl15; gland; mouse; uterus

DOI:  https://doi.org/10.1002/dvg.70026
Acta Obstet Gynecol Scand. 2025 Sep 01.

Impact of hypertensive disorders on disease progression in pregnancies affected by early-onset fetal growth restriction.

Basia Chmielewska, Claire Pegorie, Michelle Jie, Nishita Mehta, Daniel McStay, Amar Bhide, Basky Thilaganathan.

   INTRODUCTION: Fetal growth restriction is a leading cause of perinatal morbidity, often linked to placental insufficiency. Hypertensive disorders frequently coexist with fetal growth restriction and may alter its clinical course. The objective of this study is to examine how hypertensive disorders influence the onset, progression, and timing of birth in pregnancies affected by fetal growth restriction. Secondary outcomes were indications for delivery and neonatal outcomes.
MATERIAL AND METHODS: A retrospective cohort study of pregnancies diagnosed with fetal growth restriction prior to 36 weeks' gestation and monitored under the TRUFFLE protocol between January 2013 and July 2024 at a tertiary fetal medicine unit in the UK. Pregnancies were stratified by maternal blood pressure status: normotensive, hypertensive disorder of pregnancy, or preexisting chronic hypertension. Clinical characteristics, antenatal surveillance findings, delivery indications, and neonatal outcomes were compared between groups.
RESULTS: One hundred and ninety-six singleton pregnancies met the inclusion criteria. 68% of the cohort were affected by chronic hypertension or new-onset hypertensive disorders of pregnancy. Hypertensive pregnancies had significantly shorter intervals from fetal growth restriction diagnosis to delivery (9 days (IQR 5-19) for chronic hypertension, 12 days (IQR 3-24) for hypertensive disorders of pregnancy, 23 days (IQR 8-35) in normotensive pregnancies (p = 0.001)) and earlier gestational age at delivery (29 + 5 weeks (IQR 27 + 3-32 + 3) for chronic hypertension and 30 + 5 weeks (IQR 28 + 4-32 + 6) for hypertensive disorders of pregnancy - versus 32 + 0 weeks (IQR 29 + 1-33 + 6) in normotensive cases; p = 0.023). A higher proportion of hypertensive pregnancies were delivered for maternal indications (37.5% hypertensive disorders of pregnancy, 39.5% chronic hypertension) compared to 14.5% in normotensive pregnancies (p = 0.004), while normotensive pregnancies were more frequently delivered due to abnormal umbilical artery Dopplers (29.0% vs. 14.6% hypertensive disorders of pregnancy, 13.2% chronic hypertension; p = 0.041). Neonates of mothers with chronic hypertension had higher birthweight centiles (p = 0.004), but neonatal outcomes were comparable across all groups.
CONCLUSIONS: Incidence of hypertension in the context of fetal growth restriction significantly impacts timing and gestational age of delivery and birthweight centile. An integrated approach to combine maternal and fetal monitoring in these pregnancies is required to optimize birth outcomes.

Keywords:  TRUFFLE; chronic hypertension; hypertensive disorders of pregnancy; placental insufficiency; preeclampsia

DOI:  https://doi.org/10.1111/aogs.70049
Cell Stem Cell. 2025 Aug 25. pii: S1934-5909(25)00297-8. [Epub ahead of print]

An inducible model of human post-implantation development derived from primed and naive stem cells.

Seiya Oura, Leijie Li, Jun Wu.

  Early post-implantation human development is poorly understood due to limited access to natural embryos. Integrated stem cell-based embryo models (SCBEMs) offer an alternative, but current models face challenges in reproducibility, efficiency, and genomic stability. Here, we developed inducible SCBEMs (iSCBEMs) by combining primed human pluripotent stem cells (hPSCs) with transgene-induced extraembryonic cells derived from naive hPSCs. iSCBEMs recapitulate several key features of early post-implantation development, including amniotic-, yolk sac-, and chorionic-like cavity formation, differentiation of syncytiotrophoblast-like cells forming lacunae, bilaminar disk formation, anterior-posterior axis establishment, and early gastrulation. Single-cell RNA sequencing revealed that iSCBEMs recapitulate key cell types and developmental transitions characteristic of Carnegie stage 5-6 (CS5-CS6) embryos. We further traced the origins of amnion-, yolk sac endoderm-, and extraembryonic mesoderm-like cells, providing insights into their developmental trajectories. Although imperfect, human iSCBEMs represent a robust and valuable model for studying early post-implantation development, overcoming the limitations of natural embryo accessibility.

Keywords:  SCBEM; amniotic cavity; bilaminar disk; gastrulation; human pluripotent stem cells; hypoblast; stem cell-based embryo model; trophoblast; yolk sac

DOI:  https://doi.org/10.1016/j.stem.2025.08.005
Dev Cell. 2025 Aug 26. pii: S1534-5807(25)00504-0. [Epub ahead of print]

Efficient stem cell-derived mouse embryo models for environmental studies.

Victoria Jorgensen, Min Bao, Sergi Junyent, Christoph M Häfelfinger, Laura Amaya, Zhaodi Liao, Brian A Williams, Dong-Yuan Chen, Amanda Wu, Matt Thomson, Magdalena Zernicka-Goetz.

  Blastoids are stem cell-derived structures that mimic natural blastocysts by incorporating all three lineages: trophectoderm, epiblast, and primitive endoderm. However, current methods often yield incomplete structures that fail to cavitate or to form a proper primitive endoderm. To overcome these limitations, we develop a modular approach by aggregating three murine stem cell types: embryonic stem cells (ESCs), ESCs with inducible GATA4 expression (iG4-ESCs), and trophoblast stem cells (TSCs). This method yields cavitated blastocyst-like structures-termed iG4-blastoids-with approximately 80% efficiency. Single-cell RNA sequencing confirms their close resemblance to mature mouse blastocysts. Notably, culturing iG4-blastoids without FGF4 enhances specification of the invasive mural trophectoderm, and approximately 12% of structures undergo post-implantation-like morphogenesis in vitro. Using this model, we show that caffeine, alcohol, nicotine, and amino acid variations affect iG4-blastoids and natural embryos similarly, underscoring their utility as a robust model for investigating the impact of diverse environmental factors on embryogenesis.

Keywords:  GATA4; blastocyst; blastoid; embryo models; epiblast; primitive endoderm; screening; trophectoderm; xenobiotics

DOI:  https://doi.org/10.1016/j.devcel.2025.08.004
Mol Nutr Food Res. 2025 Sep 06. e70261

Dad's Diet Shapes the Future: How Paternal Nutrition Impacts Placental Development and Childhood Metabolic Health.

David A Skerrett-Byrne, Anne-Sophie Pepin, Katharina Laurent, Johannes Beckers, Robert Schneider, Martin Hrabě de Angelis, Raffaele Teperino.

  Early-life programming is a major determinant of lifelong metabolic health, yet current preventive strategies focus almost exclusively on maternal factors. Emerging experimental and preclinical data reveal that a father's diet before conception, particularly high-fat intake, also shapes offspring physiology. Here, we synthesize the latest evidence on how such diets remodel the sperm epigenome during two discrete windows of vulnerability: (i) testicular spermatogenesis, via DNA methylation and histone modifications, and (ii) post-testicular epididymal maturation, where small non-coding RNAs are selectively gained. We examine how these epigenetic signals influence pregnancy, placental development, and ultimately, metabolic trajectories in progeny. To extend published work, we sourced publicly available diet-induced sperm epigenome datasets and provide new potential connections of these changes to genes governing placental development, vascularization and size using the International Mouse Phenotyping Consortium data. Moreover, we further interrogate these overlaps with intricate in-silico analyses to examine their potential consequences. To foster meaningful interactions with these findings, we have developed a web application for ease (ShinySpermPlacenta). Collectively, these findings support a biparental model of preconception care and position the sperm epigenome as a promising tractable biomarker platform for personalized paternal nutrition counselling aimed at improving fertility and reducing intergenerational metabolic disease risk.

Keywords:  ShinyApp; epigenetics; inheritance; nutrient; paternal preconception health; placenta

DOI:  https://doi.org/10.1002/mnfr.70261
Cardiovasc Res. 2025 Aug 28. pii: cvaf149. [Epub ahead of print]

Effects of iron deficiency anemia on maternal hemodynamics and cardiac function in pregnant spontaneously hypertensive rats.

Jad-Julian R Rachid, Jennie Vu, Si Ning Liu, Sareh Panahi, Navdeep S Badhan, Claudia D Holody, Rohini Roy Roshmi, Alyssa R Wiedemeyer, Ronan M N Noble, Stephane L Bourque.

   AIM: Hypertensive disorders of pregnancy (HDP) are characterized by adverse or inadequate maternal cardiovascular adaptations and are associated with poor perinatal outcomes. Iron deficiency (ID) is a common pregnancy complication that elicits numerous cardiovascular adaptations. Though generally considered deleterious in pregnancy, whether ID mitigates or exacerbates maternal cardiovascular dysfunction in HDP has not been investigated.
METHODS AND RESULTS: Pregnant spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were fed either an iron-replete or an iron-restricted diet prior to and throughout pregnancy. Pregnant dams underwent tail-cuff plethysmography and echocardiography throughout pregnancy, as well as pressure-volume loop assessments and in-vivo blood pressure (BP) measurements on GD21 (term=GD22). Data were analyzed by 2-Way ANOVA with Holm-Šídák's post-hoc test. Dietary iron restriction caused progressive BP lowering throughout gestation that was most apparent in SHR dams. By GD21, all ID dams had moderate anemia, whereas ID fetuses of both strains exhibited signs of severe anemia, asymmetric growth restriction, and placentomegaly. Maternal ID was associated with left ventricular remodeling in both strains, albeit circulating NT-proBNP levels-a marker of pathological stretch-were reduced in ID-SHR dams. Maternal ID hearts exhibited enhanced ventricular performance reflected by increased stroke volume and cardiac output relative to their iron-replete counterparts. ID also improved cardiac efficiency and ventriculo-arterial coupling, and these latter effects were most pronounced in SHR dams.
CONCLUSIONS: ID in pregnancy was associated with greater BP lowering and improved cardiac performance in SHR dams compared to normotensive WKY dams, albeit ID fetuses from both strains exhibited growth restriction and placentomegaly. These findings highlight a complex interaction between ID anemia in pre-existing hypertension in pregnancy, and if translated to humans, could have important implications for the identification and management of both prevalent health conditions.

Keywords:  Anemia; echocardiography; heart; hypertension; pregnancy; pressure-volume loops

DOI:  https://doi.org/10.1093/cvr/cvaf149
Environ Res. 2025 Sep 01. pii: S0013-9351(25)01997-8. [Epub ahead of print] 122745

Sex-Dependent Relationships Between PFAS and Placental Transcriptomics Identified by Weighted Gene Co-Expression Analysis.

Cynthia Perez, Kyle Campbell, Dana Boyd Barr, Kartik Shankar, Clark Sims, Kevin J Pearson, Aline Andres, Todd M Everson.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are environmental toxicants associated with adverse neonatal outcomes. The exact mechanisms by which PFAS impairs neonatal health are undefined, but the placenta is a likely target.
OBJECTIVE: We applied a systems biology approach to identify placental RNA co-expression modules (gene sets) associated with PFAS exposure and birth weight.
METHODS: Placental tissue samples (n = 147) from the GLOWING study underwent RNA-sequencing, and PFAS concentrations were quantified using liquid chromatography-tandem mass spectrometry. We constructed a weighted gene co-expression network using Spearman correlations across 15,028 transcripts, identifying 20 gene modules. Linear regression models were used to examine associations between PFAS and module eigengenes, adjusting for potential confounders. Effect modification by fetal sex was also tested.
RESULTS: One module showed a negative association with perfluorononanoic acid (PFNA; β = -0.012, q = 0.009). This association was sex-specific, with the sexes exhibiting varied PFAS associations but similar directional effects. Genes within the PFNA-associated module were involved in histone modification (q ≤ 0.05) and were enriched for targets of the Vitamin D Receptor (VDR), a transcription factor previously linked to PFAS.

DOI: https://doi.org/10.1016/j.envres.2025.122745
bioRxiv. 2025 Aug 29. pii: 2025.08.25.672203. [Epub ahead of print]

MAPK/ERK signaling blocks ectopic H3K9me3 heterochromatin formation to confer mesoderm and endoderm developmental competence.

Satoshi Matsui, Marissa Granitto, Samuel Sampson, Gerardo Mirizio, Ryo Maeda, Makoto Tachibana, Christopher Ahn, Hee-Woong Lim, Makiko Iwafuchi.

During gastrulation, dynamic interplay among cell signaling pathways dictates cell fate decisions. While extensive studies have elucidated their critical roles in morphological regulation, how these signals orchestrate the epigenome to confer developmental competence remains unclear. In this study, we demonstrate that H3K9me3-marked facultative heterochromatin domains undergo global reorganization during differentiation of human pluripotent stem cells into mesoderm and endoderm, which arise through epithelial-mesenchymal transition (EMT), but not into ectoderm, which retains epithelial state. We identify the MAPK/ERK pathway, acting downstream of FGF signaling, as a key mediator of this reorganization. Specifically, the MAPK/ERK pathway prevents ectopic formation of H3K9me3 domains at EMT- and lineage-specific gene loci whose expression is necessary for mesoderm and endoderm differentiation. Collectively, our findings reveal a previously unrecognized role for MAPK/ERK signaling in reorganizing the H3K9me3 landscape to enable mesoderm and endoderm differentiation, bridging a critical gap in our knowledge of how cell signaling pathways shape the epigenetic landscape during development.

DOI: https://doi.org/10.1101/2025.08.25.672203
Front Genet. 2025 ;16 1636834

High-throughput sequencing unravels placental vascular dysfunction and oxidative stress as mechanistic drivers of advanced maternal age-associated pregnancy.

Xin Sun, Yao Chen, Feifei Hu, Yumeng Qiao, He Wu, Yao Su, Yue Hu, Jie Wu, Mingli Huang.

   Introduction: Women with advanced maternal age (AMA) face a higher risk of pregnancy complications including preeclampsia, fetal growth restriction, and preterm birth. While placental dysfunction is implicated, the underlying mechanisms remain unclear. This study employs high-throughput sequencing-based transcriptomics to investigate AMA-associated dysregulation in placental angiogenesis, exploring links to redox imbalance. Our goal is to establish mechanistic and functional links between altered gene expression and perinatal complications.
Methods: Placental pathology from 129 cases was analyzed to identify risk factors for maternal vascular malperfusion (MVM), a key pathological condition known to impair placental function. Building upon this pathological context, placental RNA-seq data from AMA and control pregnancies, combined with public datasets, were analyzed to identify differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify functional pathways of dysregulated genes. Weighted gene co-expression network analysis (WGCNA) was utilized to detect AMA-related modules and hub genes, which were subsequently validated via Western blotting, qPCR, and immunohistochemistry (IHC).
Results: Analysis of placental pathology (n = 129) identified advanced maternal age (AMA) as an independent risk factor for maternal vascular malperfusion (MVM) (OR = 3.022, 95% CI 1.337-6.832). RNA-seq revealed 731 differentially expressed genes (DEGs) in AMA placentas, which were enriched in energy metabolism, oxidative stress, angiogenesis, and NAD(P)H metabolic pathways. Weighted gene co-expression network analysis (WGCNA) identified six co-expression modules, of which the black module (most strongly AMA-associated) contained six hub genes (SIRT3, TLR6, AOX1, ARG1, CRYAB, HGF) exhibiting high intramodular connectivity. Functional studies confirmed that placental SIRT3 expression was markedly reduced in AMA (P < 0.05), while both impaired vascular perfusion and oxidative stress were significantly more severe.
Conclusion: Our findings indicate that reduced placental SIRT3 expression is a key molecular feature in advanced maternal age. This reduction may be related to increased risk of maternal vascular malperfusion and adverse pregnancy outcomes, potentially through mechanisms involving exacerbated oxidative stress and impaired placental vascular function; however, further studies are needed to clarify these associations.

Keywords:  SIRT3; advanced maternal age; oxidative stress; placental transcriptome sequencing; placental vascular injury

DOI:  https://doi.org/10.3389/fgene.2025.1636834