bims-placeb 2025-10-19 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–10–19
twelve papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

GDF-11 stimulates human extravillous trophoblast cell invasion by upregulating ANGPTL4 expression.
The downregulation of B2R inhibits spiral artery remodeling by reducing the autophagy of trophoblast cells.
Mechanosensing of Shear Stress and Uterine Spiral Artery Remodeling by Invasive Trophoblasts in Early Pregnancy.
Lactate shuttle between cytotrophoblast and syncytiotrophoblast in the placenta enhances ferroptosis resistance and maintains placental homeostasis: implications for early pregnancy loss.
Hypoxia-driven circ-TBC1D1/miR-520h/EPHB4 impairs trophoblast function in unexplained recurrent spontaneous abortion.
Bisphenol A Interferes with Mast Cell-Mediated Promotion of Cellular Processes Critical for Spiral Artery Remodeling.
Upregulated endoplasmic reticulum oxidoreductin 1-like protein alpha at the mother-fetus interface of preeclampsia promotes trophoblast cell migration and invasion.
UBE3A Inhibits Trophoblast Cell Migration and Invasion by Promoting ITGB1 Degradation and Affecting PI3K/AKT Signaling.
Lnc-HZ14 promotes LLPS-mediated SPHK1 aggrephagy degradation to suppress trophoblast cell proliferation in unexplained recurrent miscarriage.
Non-coding RNAs in congenital heart disease and placental development: Bridging molecular mechanisms to clinical biomarkers and therapies.
Impact of Neutral Sphingomyelinase Inhibition on Small Extracellular Vesicle Production by Mural Granulosa Cells and In Vitro Folliculogenesis in Mice.
Maternal high-fat diet alters fetal autonomic activity independently of leptin receptor genotype in high-risk mouse models of type 2 diabetes mellitus.

Reproduction. 2025 Nov 01. pii: e250244. [Epub ahead of print]170(5):

GDF-11 stimulates human extravillous trophoblast cell invasion by upregulating ANGPTL4 expression.

Ze Wu, Lanlan Fang, Xuan Dang, Yiping Yu, Beibei Bi, Xiaoyu Han, Ying-Pu Sun, Jung-Chien Cheng.

   In brief: How extravillous trophoblast (EVT) invasion is regulated during placental development remains an important question in reproductive biology. This study demonstrates that growth differentiation factor-11 (GDF-11) promotes EVT invasion by upregulating angiopoietin-like 4 (ANGPTL4) via ALK4/ALK5-SMAD3 signaling, revealing a novel mechanism in placental biology.
Abstract: Proper regulation of extravillous trophoblast (EVT) cell invasion is critical for normal placental development and function. Growth differentiation factor 11 (GDF-11), a member of the transforming growth factor-β (TGF-β) superfamily, has been shown to promote EVT cell invasion, yet the underlying molecular mechanisms remain largely unclear. In this study, RNA sequencing identified angiopoietin-like 4 (ANGPTL4), a multifunctional secreted protein, as a novel downstream target of GDF-11. In vitro experiments demonstrated that GDF-11 significantly upregulated ANGPTL4 expression in both HTR-8/SVneo cells and primary human EVT cells. Mechanistically, we found that the type I TGF-β receptors ALK4 and ALK5 were essential for mediating the stimulatory effect of GDF-11 on ANGPTL4 expression. Further analysis revealed that SMAD3, but not SMAD2, was the key transcription factor involved in this process. Using both loss- and gain-of-function approaches, we demonstrated that ANGPTL4 was required for GDF-11-induced EVT cell invasion. Importantly, serum levels of GDF-11 were markedly reduced in patients with preeclampsia (PE), a pregnancy disorder associated with shallow trophoblast invasion and poor placentation. Together, our findings uncover a previously unrecognized GDF-11-ANGPTL4 signaling axis that regulates EVT cell invasion and provides new insight into the pathophysiology of PE.

Keywords:  ANGPTL4; EVT; GDF-11; SMAD; invasion

DOI:  https://doi.org/10.1530/REP-25-0244
Placenta. 2025 Oct 07. pii: S0143-4004(25)00709-X. [Epub ahead of print]171 194-204

The downregulation of B2R inhibits spiral artery remodeling by reducing the autophagy of trophoblast cells.

Weichen Pan, Rongrong Zhu, Xiaoyu Wang, Zhiyin Wang, Dan Liu, Guangfeng Zhao, Mingming Zheng.

  Preeclampsia (PE) is a severe pregnancy complication characterized by hypertension and proteinuria after 20 weeks of gestation, posing significant risks to maternal and fetal health. Although its exact etiology remains unclear, inadequate trophoblast invasion and impaired remodeling of uterine spiral arteries are recognized as key contributors. The Bradykinin B2 receptor (B2R), a G protein-coupled receptor, was found to be downregulated in the placenta of early pregnancies that subsequently progress to PE. Our previous study has also shown that B2R can suppress the proliferation and migration of extravillous trophoblasts (EVT). However, the underlying mechanism remains elusive. By analyzing the transcriptome of HTR8 cells (an EVT cell line) with B2R knockdown, we found that B2R downregulation impairs autophagy in EVTs. Subsequently, we confirmed that autophagy is downregulated in EVTs from the placentas of patients with PE. In vitro experiments further demonstrated that B2R knockdown leads to defective autophagy in HTR8 cells, resulting in decreased cell proliferation, migration, and invasion capabilities. Activating autophagy can alleviate the functional abnormalities of EVT cells caused by B2R downregulation. Mechanistic exploration revealed that B2R knockdown inhibits autophagy through the activation of the Wnt signaling pathway. Furthermore, we generated trophoblast-specific B2R knockout mice and found that the placentas of these mice exhibited reduced autophagy, insufficient EVT invasion, and abnormal spiral artery remodeling. These findings suggest that B2R-regulated autophagy is crucial for proper trophoblast function and spiral artery remodeling. Our study highlights the potential of targeting autophagy as a therapeutic strategy for PE, providing new insights into the molecular mechanisms underlying this complex disorder.

Keywords:  Autophagy; Bradykinin B2 receptor; Preeclampsia; Spiral artery remodeling; Trophoblast

DOI:  https://doi.org/10.1016/j.placenta.2025.10.001
Int J Mol Sci. 2025 Sep 30. pii: 9565. [Epub ahead of print]26(19):

Mechanosensing of Shear Stress and Uterine Spiral Artery Remodeling by Invasive Trophoblasts in Early Pregnancy.

Dariusz Szukiewicz, Seweryn Trojanowski, Edyta Wróbel, Piotr Wojdasiewicz, Grzegorz Szewczyk.

  The development of low-resistance blood flow within the developing placenta in the early weeks of pregnancy requires trophoblast invasion of the uterine spiral arteries. Therefore, understanding the migration and differentiation of trophoblasts is necessary. Recently, researchers have focused increasingly on the regulation of the response of endovascular extravillous trophoblasts (enEVTs) to mechanical stimuli associated with shear stress. The starting point for these studies is that enEVTs, which adopt a pseudoendothelial phenotype, functionally resemble endothelial cells in terms of ability to promote angiogenesis, vascular remodeling and cell-cell communication. The complex process of mechanotransduction requires the coordinated participation of many types of mechanoreceptors, whose activated signaling pathways are translated into whole-cell mechanosensing involving components of the cytoskeleton and extracellular matrix. The aim of this review is to comprehensively present the current knowledge on the importance of mechanical stimuli associated with shear stress in the development of local changes in the vascular system at the site of blastocyst implantation. The characteristics of individual mechanoreceptors are determined, and the most important factors influencing mechanotransduction are discussed. Understanding the importance of mechanosensing disorders in trophoblasts in the pathogenesis of unexplained recurrent abortions or preeclampsia may be helpful in the development of new therapeutic strategies based on the regulation of mechanotransduction in response to shear stress.

Keywords:  extravillous trophoblast; mechanosensing; placental angiogenesis; placentation; preeclampsia/eclampsia; shear stress; trophoblast invasion; uterine spiral arteries; vascular remodeling

DOI:  https://doi.org/10.3390/ijms26199565
Cell Commun Signal. 2025 Oct 14. 23(1): 438

Lactate shuttle between cytotrophoblast and syncytiotrophoblast in the placenta enhances ferroptosis resistance and maintains placental homeostasis: implications for early pregnancy loss.

Yuelin Zhu, Qianqian Li, Xin Yu, Yun Yang, Qian Yang, Yongqing Wang, Xuan Shao, Yan-Ling Wang.



Keywords:  Ferroptosis; GPX4; Lactate; Placental trophoblast; Recurrent pregnancy loss; SCD1

DOI:  https://doi.org/10.1186/s12964-025-02450-2
Sci Rep. 2025 Oct 14. 15(1): 35929

Hypoxia-driven circ-TBC1D1/miR-520h/EPHB4 impairs trophoblast function in unexplained recurrent spontaneous abortion.

Rong Hua, Qinshan Xie, Jiaxu Li, Yi Mo, Xiu Lin, Chun Huang, Min He, Fengqiong Liu, Yujie Huang, Jiangfan Wan, Yan Sun.

  Hypoxia during early pregnancy critically regulates trophoblast function, and its dysregulation has been implicated in unexplained recurrent spontaneous abortion (URSA). This study investigated the circ-TBC1D1/miR-520 h/EPHB4 regulatory axis in HTR-8/SVneo trophoblast function under hypoxic conditions (2% O2) and its association with URSA. Clinical analysis of chorionic tissues from 14 URSA patients and 14 controls revealed upregulated EPHB4 expression in URSA samples. EPHB4 suppressed proliferation, migration, and invasion while increasing apoptosis and altering angiogenesis markers (VEGFA, CD31). Mechanistically, circ-TBC1D1 acted as a competitive endogenous RNA by sequestering miR-520 h, thereby elevating EPHB4 expression and modulating HTR-8/SVneo trophoblast function under hypoxia. Additionally, downregulated miR-520 h and a non-significant trend toward elevated circ-TBC1D1 were observed in chorionic tissues from URSA patients. These findings demonstrate that the circ-TBC1D1/miR-520 h/EPHB4 axis may impair extravillous trophoblast cell functionality, and dysregulation of this pathway in URSA patients may correlate with compromised uterine spiral artery remodeling. This study highlights potential molecular targets involved in URSA pathogenesis associated with hypoxic stress.

Keywords:  EPHB4; Extravillous trophoblast cells; Hypoxia; MiR-520 h; Unexplained recurrent spontaneous abortion

DOI:  https://doi.org/10.1038/s41598-025-19797-8
Int J Mol Sci. 2025 Oct 05. pii: 9706. [Epub ahead of print]26(19):

Bisphenol A Interferes with Mast Cell-Mediated Promotion of Cellular Processes Critical for Spiral Artery Remodeling.

Federica Romanelli, Ningjuan Zhang, Mario Bauer, Beate Fink, Ana Claudia Zenclussen, Anne Schumacher, Nicole Meyer.

  Mast cells (MCs) belong to the cell network that regulates uterine spiral artery remodeling (uSAR), a critical vascular adaptation supporting placental development and fetal growth. Our previous in vitro study demonstrated that human MCs promote trophoblast invasion, as well as uterine vascular smooth muscle cells (uVSMCs) migration and transition to a synthetic phenotype-essential steps for a successful uSAR. Although MCs are known targets of bisphenol A (BPA), a widespread endocrine-disrupting chemical, its impact on their supportive role in uSAR is unknown. In this study, we used murine cell lines to investigate whether BPA (0.1-100 µM) affects MC-mediated promotion of cellular processes critical for uSAR. Our results showed that BPA exposure hindered MCs' ability to promote trophoblast invasion and the switch in uVSMCs' synthetic phenotype and migration. The highest concentrations of BPA altered the expression of genes related to MCs activation and proliferation, and of those involved in trophoblasts invasion. In contrast, low doses induced the expression of pro-inflammatory mediators in MCs without detectable effect on trophoblasts at the transcriptional level. These findings confirmed MCs as key mediators of uSAR, and identified BPA as a disruptor of their function, emphasizing its potential harmful impact on reproductive health.

Keywords:  bisphenol A; mast cells; spiral artery remodeling

DOI:  https://doi.org/10.3390/ijms26199706
Gene. 2025 Oct 12. pii: S0378-1119(25)00614-6. [Epub ahead of print] 149825

Upregulated endoplasmic reticulum oxidoreductin 1-like protein alpha at the mother-fetus interface of preeclampsia promotes trophoblast cell migration and invasion.

Tao Qu, Zhenhao Li, Yanjuan Jia, Xueping Yang, Xiyan He, Ruiyang Pu, Qing Yang, Qian Ma, Chaojun Wei, Yonghong Li, Xiaotong Sun.

  Endoplasmic reticulum oxidoreductin 1-like protein alpha (ERO1A) is a disulfide oxidoreductase involved in the formation of protein disulfide bonds. However, the relationship between ERO1A and preeclampsia onset remains unclear. The aim of this study was therefore to clarify the role of ERO1A in regulating trophoblast cell migration and invasion. Placental tissues were collected from participants with normal pregnancies (n = 17) and pre-eclampsia (n = 15). Immunohistochemistry was performed to detect the expression and localization of ERO1A. Next, stable cell lines with ERO1A overexpression and knockout were constructed in human trophoblast cells (HTR-8/SVneo). HTR-8/SVneo migration and invasion were then detected using Transwell assays. The ability of trophoblasts to invade the endothelial tube was analyzed using DiO- and DiI-stained cells. Finally, ERO1A and collagen type III alpha 1 (COL3A1) expression was detected using Western blotting. Our results showed that ERO1A expression was significantly upregulated in the villous tissues of women with early-onset preeclampsia. Overexpression of ERO1A promoted HTR-8/SVneo cell invasion, the ability to penetrate the endothelial tube, and enhanced the expression of COL3A1. Our findings suggest that high ERO1A expression in early-onset preeclampsia plays a protective role in alleviating disease progression.

Keywords:  Endoplasmic reticulum oxidoreductin 1-like protein alpha; Preeclampsia; Trophoblast; collagen type III alpha 1

DOI:  https://doi.org/10.1016/j.gene.2025.149825
Kaohsiung J Med Sci. 2025 Oct 15. e70122

UBE3A Inhibits Trophoblast Cell Migration and Invasion by Promoting ITGB1 Degradation and Affecting PI3K/AKT Signaling.

Xiu-Jun Li, Ning Wang, Fan Jiang, Jie-Cheng Yang, Yan-Yun Wang, Kun Wang.

  Preeclampsia (PE) is an obstetric disease that is characterized by reduced migration and invasion of placental trophoblast cells. Here, the effects of the E3 ubiquitin ligase UBE3A on the migration and invasion of trophoblast cells were evaluated. RT-qPCR and Western blotting were used to measure the expression of genes and proteins. Immunohistochemical (IHC) staining was used to determine UBE3A and ITGB1 levels in the placental tissues of PE patients. Cell viability was evaluated with a CCK-8 assay. Wound healing and Transwell assays were used to evaluate cell migration and invasion, respectively. Cell cycle progression and apoptosis were analyzed by flow cytometry. Co-immunoprecipitation (Co-IP) was used to verify molecular interactions. Our results revealed that the mRNA and protein levels of UBE3A were upregulated, whereas ITGB1 expression was downregulated in the placental tissues of PE patients. Depletion of UBE3A promoted the migration and invasion of HTR-8/SVneo cells while inhibiting apoptosis. The phosphorylation of PI3K and AKT increased after UBE3A was silenced. Mechanistically, UBE3A induced the ubiquitination and degradation of ITGB1. Functionally, UBE3A reduced cell migration and invasion, as well as induced apoptosis by negatively regulating ITGB1 mediating PI3K/AKT signaling. In summary, our results revealed that UBE3A hindered the migration and invasion of trophoblast cells by facilitating ITGB1 degradation and affecting PI3K/AKT signaling, providing a new therapeutic target for PE treatment.

Keywords:  ITGB1; PI3K/AKT signaling; UBE3A; preeclampsia

DOI:  https://doi.org/10.1002/kjm2.70122
Autophagy. 2025 Oct 14.

Lnc-HZ14 promotes LLPS-mediated SPHK1 aggrephagy degradation to suppress trophoblast cell proliferation in unexplained recurrent miscarriage.

Rong Wang, Yi Sun, Jingsong Zhao, Zhongyan Xu, Qi Wei, Tao Zhang, Yanbing Lin, Geng Guo, Xun Li, Wenxin Huang, Jiang Qian, Shuaishuai Xing, Manli Wang, Min Qi, Huidong Zhang.

  High incidence of recurrent miscarriage (RM, recurrent abnormal early embryo loss) largely limits global human reproduction. However, it is unclear how the pathogenesis greatly restricts its effective clinical treatment. In our previous studies, we have identified a group of novel long non-coding RNAs (lncRNAs), which might regulate the occurrence of RM through unknown biological mechanisms. In this study, we confirm that a novel lncRNA, lnc-HZ14, which is highly expressed in unexplained RM vs healthy control (HC) villous tissues, is associated with RM using a new RM case-control group (n = 50). In trophoblast cellular assays, lnc-HZ14 suppresses trophoblast cell proliferation by specifically downregulating SPHK1 (sphingosine kinase 1) protein levels. In terms of mechanism, lnc-HZ14 upregulates SQSTM1/p62 protein levels, enhances its protein interactions with polyubiquitin-modified SPHK1, promotes the formation of SQSTM1-SPHK1 bodies through liquid-liquid phase separation (LLPS), and accelerates SPHK1 aggrephagy degradation. Meanwhile, lnc-HZ14 also promotes autophagy by activating ETV4-mediated transcription of ATG101 and PPP1R15A/GADD34. The cellular mechanisms are consistent with those in villous tissues of RM patients and in placental tissues of a mouse miscarriage model, excepting that there is no lnc-HZ14 homolog in mouse. As for miscarriage treatment, therapeutic upregulation of SPHK1 by treatment with phorbol 12-myristate 13-acetate (PMA), an SPHK1 agonist recovers mouse placental proliferation and alleviates mouse miscarriage. Collectively, this study shows for the first time the regulatory roles of lnc-HZ14, LLPS, and aggrephagy degradation of SPHK1 in unexplained recurrent miscarriage, uncovering novel pathogenesis and biological mechanisms of unexplained RM and also providing potential targets for treatment against miscarriage.

Keywords:  Aggrephagy degradation of SPHK1; human trophoblast cells; liquid-liquid phase separation (LLPS); lncRNA or lnc-HZ14; unexplained recurrent miscarriage

DOI:  https://doi.org/10.1080/15548627.2025.2574963
Noncoding RNA Res. 2026 Feb;16 1-20

Non-coding RNAs in congenital heart disease and placental development: Bridging molecular mechanisms to clinical biomarkers and therapies.

Haoxuan Wang, Xinzhe Chen, Yinghui Li, Shudan Xiao, Tianqi Teng, Sumin Yang, Kun Wang, Meihua Zhang.

  Non-coding RNAs (ncRNAs) have emerged as pivotal regulators of gene expression, orchestrating embryonic development and disease pathogenesis. This review synthesizes current knowledge on the origin, biogenesis, and functional diversity of ncRNAs, with a focus on their regulatory crosstalk in congenital heart disease (CHD) and placental development. The fetal heart-placenta axis, a bidirectional signaling network essential for cardiogenesis and placental morphogenesis, is spatiotemporally modulated by ncRNAs through epigenetic and post-transcriptional mechanisms. Through precise regulation of cardiac cell differentiation, angiogenesis, and trophoblast invasion, ncRNAs maintain developmental homeostasis, whereas their dysregulation disrupts these processes, contributing to CHD pathogenesis and positioning them as promising biomarkers. Collectively, this review establishes ncRNAs as molecular bridges between the fetal heart-placenta axis and clinical translation, underscoring their dual utility as diagnostic biomarkers for CHD and modifiable targets to correct placental maldevelopment, thereby advancing precision therapies for congenital disorders.

Keywords:  Biomarker; CHDs; Epigenetics; Heart-placenta axis; Placenta; ncRNA

DOI:  https://doi.org/10.1016/j.ncrna.2025.08.006
Mol Reprod Dev. 2025 Oct;92(10): e70063

Impact of Neutral Sphingomyelinase Inhibition on Small Extracellular Vesicle Production by Mural Granulosa Cells and In Vitro Folliculogenesis in Mice.

Kodai Matsushita, Yuta Matsuno, Kazuma Kita, Ayaka Ichikawa, Natsumi Maruyama, Wataru Fujii, Tsutomu Endo, Koji Sugiura.

  Small extracellular vesicles (sEVs) function as critical regulators of ovarian follicular development. Although several pathways, including one involving neutral sphingomyelinase (nSMase), contribute to sEV production, the specific pathway active in ovarian follicles has not been clearly identified. In this study, we investigated GW4869, a specific inhibitor of nSMase activity, to determine its impact on sEV production by mouse mural granulosa cells (MGCs), the primary source of follicular sEVs. We also examined how nSMase inhibition affects the in vitro growth of oocyte‒granulosa cell complexes (OGCs) derived from secondary follicles. Transcripts encoding nSMases (Smpd2 and Smpd4) were detected in MGCs, and GW4869 treatment significantly reduced sEV production in MGC monolayer cultures. Control OGCs developed into antral follicle-like structures, with the antrum-like structure separating granulosa cells into cumulus-like and MGC-like cells. However, GW4869 treatment impaired OGC development. MGC-like cells from GW4869-treated OGCs exhibited significantly lower Cyp19a1 levels, whereas adding MGC-derived sEVs promoted Cyp19a1 expression. These results suggest that nSMase activity, likely involving Smpd2 and Smpd4, is required for sEV production by MGCs and that follicular sEVs may regulate Cyp19a1 expression in MGCs.

Keywords:  extracellular vesicles; granulosa cells; mice; ovarian follicles

DOI:  https://doi.org/10.1002/mrd.70063
J Nutr. 2025 Oct 09. pii: S0022-3166(25)00613-3. [Epub ahead of print]

Maternal high-fat diet alters fetal autonomic activity independently of leptin receptor genotype in high-risk mouse models of type 2 diabetes mellitus.

Yoshiyuki Kasahara, Chihiro Yoshida, Yoshitaka Kimura, Masatoshi Saito.

   BACKGROUND: The Developmental Origin of Health and Disease (DOHaD) concept suggests fetal environmental factors influence disease vulnerability later in life. Type 2 diabetes mellitus (T2DM), a metabolic disease, is associated with autonomic dysfunction. Some T2DM pathophysiological manifestations may exhibit DOHaD features and these autonomic changes could originate during fetal development.
OBJECTIVE: This study investigated genetic and environmental T2DM risks on fetal autonomic activity, focusing on leptin receptor gene mutation, maternal high-fat diet, and their interactions.
METHODS: Pregnant leptin receptor gene mutant (Leprdb) heterozygous mice received standard chow (normal diet, 11% energy from fat) or high-fat diet (60% energy from fat) from gestational day 0.5, while C57BL/6J mice received control diet (10% energy from fat) or high-fat diet to verify maternal dietary effects without genetic factors. Fetal electrocardiograms were measured at gestational day 18.5 to assess autonomic activity. The impact of intrauterine conditions due to maternal Leprdb genotype was also evaluated. Statistical analysis was performed using ANOVA with main effects for fetal genotype, maternal diet, or maternal genotype to distinguish genetic and environmental factors.
RESULTS: When dams were fed normal diet, no difference in fetal autonomic activity was observed based on fetal Leprdb genotype. Similarly, no difference was found when dams were fed high-fat diet. However, maternal high-fat diet significantly reduced fetal autonomic activity, regardless of fetal Leprdb genotype. This pattern was confirmed in C57BL/6J mice, where fetuses exposed to maternal high-fat diet showed decreased autonomic activity. Maternal Leprdb genotype did not significantly influence fetal autonomic activity.
CONCLUSIONS: These findings indicate maternal high-fat diet during pregnancy may reduce fetal autonomic activity, potentially increasing T2DM risk. Environmental factors appear to impact fetal autonomic activity more than genetic factors. Maternal diet during pregnancy could be crucial for offspring's metabolic health, emphasizing proper maternal nutrition's importance for preventing metabolic disorders.

Keywords:  DOHaD; Fetal ECG; Fetal autonomic activity; HRV; Leptin receptor; Maternal high-fat diet; T2DM

DOI:  https://doi.org/10.1016/j.tjnut.2025.10.002