bims-placeb 2026-08-09 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–08–09
eight papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Recapitulating gestational progression: a high-throughput 3D bioprinted vascularized human placenta demonstrating stage-specific molecular and functional signatures of human pregnancy.
Evidence that S-phase kinase associated protein 2 (SKP2) is ubiquitinated and degraded via a Rho-related BTB domain containing 1 (RhoBTB1) and Cullin-3 mechanism in placenta.
Maternal obesity restricts fetal growth through placental energy failure and iron-associated oxidative stress in mice†.
Extracellular vesicles derived from M1 macrophages deliver miR-515-5p to suppress trophoblast migration and invasion by targeting YAP in preeclampsia.
Building Efficient Stem Cell-Derived Mouse Blastocyst Models for Environmental Studies.
Maternal High Fat Diet and Acute Viral Mimic Exposure Impact Placental Inflammation, Lipid Peroxidation and Cellular Proliferation-to-Death Ratio Across Mouse Pregnancy.
Triphenyl phosphate inhibit migration and invasion of EVT cells through PPARγ-mediated autophagy.
Localization of Type 1 plasminogen activator inhibitor in early decidua basalis and its role in pregnancy maintenance.

Sci Rep. 2026 Jul 28. pii: 24140. [Epub ahead of print]16(1):

Recapitulating gestational progression: a high-throughput 3D bioprinted vascularized human placenta demonstrating stage-specific molecular and functional signatures of human pregnancy.

Cristina Antich, Yu-Chi Chen, Justine Noel, Yanyan Qu, Yuhong Fang, Shayne Frebert, Dingyin Tao, Lauren S Richardson, Ramkumar Menon, Min Jae Song, Marc Ferrer.

The placenta is a highly dynamic organ that supports the growth and development of the fetus during gestation. Malfunction of the placenta causes disorders of the pregnancy, including preeclampsia and pre-term birth. The study of the pathophysiology of the placenta throughout pregnancy has been hindered by limited access to the human placenta and lack of predictive cellular and animal models. Here, we describe 3D bioprinted human placenta barrier (hPB) tissue models using primary human trophoblasts and stroma cells that recapitulate the physiology of the human placenta at early and late stages of gestation. These bioprinted vascularized hPB tissue models mimic the architecture and function early and late-stages human placenta, including barrier function, nutrient uptake, transporters activity and hormones secretion. Assembled in a 96-well transwell plate format, this deeply characterized platform provides a robust high-fidelity system for predictive screening of therapeutics and potentially hazardous agents for placenta diseases and safety, and a better understanding of placental pathophysiology.

DOI: https://doi.org/10.1038/s41598-026-61708-y
Physiol Rep. 2026 Aug;14(15): e71039

Evidence that S-phase kinase associated protein 2 (SKP2) is ubiquitinated and degraded via a Rho-related BTB domain containing 1 (RhoBTB1) and Cullin-3 mechanism in placenta.

Alina L Tvina, M Christine Livergood, Gaurav Kumar, Valerie W Hole, Megan A Opichka, Luisangeli Muniz Irizarry, Ko-Ting Lu, Kelsey K Wackman, Justin L Grobe, Pablo Nakagawa, Jennifer J McIntosh, Curt D Sigmund.

  Rho related BTB domain containing 1 (RhoBTB1) is highly expressed in placenta and functions to deliver protein targets to the Cullin-3 (CUL3) E3 ubiquitin ligase where they are targeted for ubiquitination and degradation. The targets of RhoBTB1 in placenta have not been identified. Using RNAscope, we show that RhoBTB1 is mainly expressed in syncytiotrophoblasts (SCT) in the human and mouse placenta. We employed ascorbate peroxidase 2-mediated targeted proteomics to identify RhoBTB1 binding proteins in immortalized human extravillous trophoblast (HTR8/SVneo) cells. We selected 9 RhoBTB1-interacting proteins to examine functionally. Two of these, S-Phase Kinase Associated Protein 2 (SKP2) and Rho GTPase-Activating Protein 29 (ArhGAP29), increased in abundance when Cullin activity was blocked by the neddylation inhibitor MLN4924 and co-immunoprecipitated with RhoBTB1. SKP2 increased in abundance in CRISPR-Cas9 HEK293 cells that lack CUL3, and in HTR8/SVneo cells after siRNA-mediated inhibition of RhoBTB1. SKP2 was ubiquitinated by a RhoBTB1- and CUL3-dependent mechanism providing evidence that its stability is regulated by RhoBTB1/CUL3. Like RhoBTB1, SKP2 is highly expressed in the placenta. Reanalysis of single cell RNA sequencing data sets revealed that SKP2 exhibits co-expression with RhoBTB1 in SCT precursor cells, SCTs, and cytotrophoblasts. These findings identify SKP2 as a RhoBTB1/CUL3 target in the placenta.

Keywords:  RhoBTB1; SKP2; placenta; proteomics; ubiquitination

DOI:  https://doi.org/10.14814/phy2.71039
Biol Reprod. 2026 Aug 07. pii: ioag131. [Epub ahead of print]

Maternal obesity restricts fetal growth through placental energy failure and iron-associated oxidative stress in mice†.

Yeqianli Wo, Jiabin Mao, Zeou Wei, Ye Xu, Xiaohong Wang, Dadan Liu, Shusong Wu, Jianhua He, Martine Schroyen, Bao Yi, Liang Chen, Hongfu Zhang.

  Maternal obesity compromises placental development and fetal growth, yet the mechanisms remain unknown. Here, we investigated the impact of high-fat diet (HFD) on placental energy homeostasis in mice. Female C57BL/6 mice were fed a control diet or an HFD, with a subset receiving FerroTerminator-1 (FOT1) to modulate metabolic dysfunction. At embryonic day 18.5, maternal metabolic status, fetal growth, placental morphology, energy metabolism, and oxidative stress were assessed. HFD-fed dams developed dyslipidemia and insulin resistance, and exhibited placental lipid accumulation and impaired labyrinth zone development, resulting in reduced fetal weight and altered fetal liver lipid and glycogen contents. The placenta showed mitochondrial damage, accompanied by reduced ATP content, mitochondrial membrane potential, mitochondrial DNA copy number, and suppressed respiratory chain complex activities. Placental metabolomic profiling showed that HFD was associated with altered levels of metabolites in glycolysis and oxidative phosphorylation pathways. These alterations coincided with placental iron-associated oxidative stress, evidenced by elevated non-heme iron, lipid peroxidation products, upregulation of transferrin receptor (TFRC) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), downregulation of ferritin heavy chain 1 (FTH1) and solute carrier family 40 member 1 (SLC40A1), a reduced glutathione to oxidized glutathione ratio, and impaired glutathione peroxidase 4 (GPX4) expression and activity. Meanwhile, FOT1 administration attenuated placental oxidative stress, partially restored ATP production and mitochondrial function, and improved fetal growth in HFD-fed mice. Collectively, maternal obesity was associated with placental iron-associated oxidative stress and bioenergetic impairment, which may contribute to reduced placental efficiency and FGR.

Keywords:  energy metabolism; fetal growth restriction; maternal obesity; placenta

DOI:  https://doi.org/10.1093/biolre/ioag131
Int Immunopharmacol. 2026 Aug 01. pii: S1567-5769(26)01066-0. [Epub ahead of print]187 117220

Extracellular vesicles derived from M1 macrophages deliver miR-515-5p to suppress trophoblast migration and invasion by targeting YAP in preeclampsia.

Hanhui Nie, Xiufang Wang, Heyi Tian, Siyi Yang, Xiaoqing Hui, Jiao Li, Xiaofeng Yang, Yuchen Zhang, Genxia Li.

  Trophoblast migration and invasion are critical processes in the pathogenesis of preeclampsia (PE), with maternal-fetal cellular communication playing a key role in their regulation. Among the immune components at the maternal-fetal interface, M1-like macrophages are known to influence trophoblast behavior, however, the specific underlying mechanisms remain unclear. Here, we reveal a novel pathway through which M1-like macrophages regulate trophoblast function through extracellular vesicle (EV)-mediated communication. We demonstrated that M1-derived extracellular vesicles (M1-EVs) inhibit trophoblast migration and invasion in vitro. miRNA sequencing and validation revealed that miR-515-5p as one of the most significantly upregulated miRNAs in recipient trophoblast cells following M1-EVs treatment. Mechanistically, miR-515-5p is delivered into trophoblasts via M1-EVs, where it directly targets and downregulates Yes-associated protein (YAP), a central regulator of cellular motility. In vivo, the administration of M1-EVs to pregnant mice induced hallmark PE phenotypes, including hypertension and proteinuria. Importantly, mechanistic studies demonstrating the role of miR-515-5p in targeting YAP were conducted in human trophoblast cells, as miR-515-5p is primate specific and not endogenously expressed in mice. Clinically, miR-515-5p expression was significantly upregulated in human PE placental tissues and inversely correlated with YAP levels. Collectively, the results of our study reveal that M1-EVs deliver miR-515-5p to trophoblasts, leading to YAP downregulation and suppression of migration and invasion, thereby providing new insights into immune-mediated regulation of trophoblast function in preeclampsia.

Keywords:  Extracellular vesicles; M1-like macrophages; Preeclampsia; Trophoblast; YAP; miR-515-5p

DOI:  https://doi.org/10.1016/j.intimp.2026.117220
J Vis Exp. 2026 Jul 14.

Building Efficient Stem Cell-Derived Mouse Blastocyst Models for Environmental Studies.

Sergi Junyent, Manasvi Pinnaka, Magdalena Zernicka-Goetz.

Stem cell-based embryo models offer a powerful platform for investigating early mammalian development and its sensitivity to environmental perturbations. Here, a robust and accessible protocol is presented for generating high-fidelity mouse blastoids using embryonic stem cells (ESCs), trophoblast stem cells (TSCs), and embryonic stem cells engineered for inducible GATA4 expression (iGATA4-ESCs). This system produces iGATA4-blastoids that accurately recapitulate natural E4.5 blastocyst morphology, lineage proportions, and transcriptional signatures, providing a reliable in vitro model of the primitive endoderm (PE), epiblast (EPI), and trophectoderm (TE) compartments. This protocol first demonstrates how to maintain and prepare the three stem cell populations required for blastoid formation. The step-by-step assembly of iGATA4-blastoids under pre-implantation culture conditions is then outlined, highlighting critical experimental parameters. To enable rigorous characterization, a tested workflow for blastoid fixation, staining, and imaging is provided. Finally, an example is presented demonstrating how iGATA4-blastoids can be used for high-throughput assays. By exposing large cohorts of blastoids to defined environmental factors, changes in morphology, lineage allocation, and developmental progression can be quantified rapidly and reproducibly. Together, this protocol establishes a scalable platform for modeling pre-implantation development, dissecting early lineage decisions, and performing multiparametric screens to assess environmental or molecular influences on blastocyst formation.

DOI: https://doi.org/10.3791/70796
Am J Reprod Immunol. 2026 Aug;96(2): e70290

Maternal High Fat Diet and Acute Viral Mimic Exposure Impact Placental Inflammation, Lipid Peroxidation and Cellular Proliferation-to-Death Ratio Across Mouse Pregnancy.

Thaina Ferraz, Lucas Cardoso, Sadra Mohammadkhani, Enrrico Bloise, Kristin L Connor.

   PROBLEM: Maternal obesity and viral infection induce placental inflammation, but how their co-exposure influence fetoplacental development remains unclear. We hypothesised that maternal high fat (HF) diet and viral infection would independently induce placental inflammation and lipid peroxidation, reduce antioxidant defence, and cellular turnover. Further, HF diet would compromise placental capacity to adapt to infection.
METHOD OF STUDY: Female C57BL/6J mice were fed a control (CON) or 62% HF diet six weeks before and throughout pregnancy and injected with poly(I:C) (viral mimic) or vehicle (VEH) 24 h before sacrifice at gestational days (GD) 12.5, 15.5, and 18.5 (n = 5-8/group/GD). Placental inflammasome (NLRP3), oxidative stress (4-HNE), antioxidant defence (GPx-4), and cellular proliferation-to-death ratio (Ki-67, Caspase-3) were assessed by immunohistochemistry, and mRNA expression of Tlr3, Irf3, Tlr4, Tirap, and Il-1β were measured by qPCR. Data were analysed by linear mixed models (p ≤ 0.05).
RESULTS: At GD12.5, infection was associated with increased Tlr3 mRNA and immunoreactive (ir)-4-HNE, and reduced ir-GPx-4 expression in the placental labyrinth zone (LZ). By GD15.5, HF diet was associated with increased ir-NLRP3 in both LZ and junctional zones (JZ). Exposure to infection alone and co-exposure to HF diet and infection further increased LZ ir-NLRP3. At GD18.5, HF diet was associated with increased Tirap and Il-1β mRNA expression, ir-4-HNE in the JZ and ir-Caspase-3 in the LZ.
CONCLUSIONS: Maternal HF diet and infection exert distinct effects on the placenta across gestation, suggesting that maternal overnutrition might reduce the placenta's capacity to handle adverse exposures, which may increase susceptibility to poor fetal outcomes.

Keywords:  Inflammation; Maternal; Morphology; Obesity; Oxidative stress; Placenta; Poly(I:C)

DOI:  https://doi.org/10.1111/aji.70290
Ecotoxicol Environ Saf. 2026 Aug 05. pii: S0147-6513(26)00937-1. [Epub ahead of print]323 120607

Triphenyl phosphate inhibit migration and invasion of EVT cells through PPARγ-mediated autophagy.

Fuhui Yan, Liwen Peng, Xiao Han, Xingxing Han, Miaoliang Wu, Zhi Bai, Xiaoshan Liu.

  Triphenyl phosphate (TPhP) is a commonly used organophosphorus flame retardant, and its potential health risks to mothers and infants are considerable. Our previous research revealed that gestational TPhP exposure significantly reduces the depth of placental implantation and impairs uterine spiral arteries remodelling, leading to preeclampsia (PE)-like symptoms, but the underlying mechanism remains unclear. In this study, we further demonstrate that TPhP activated the transcription of Phosphatase and tensin homolog (PTEN) by activating peroxisome proliferator activated receptor gamma (PPARγ). This activation subsequently inhibits the PI3K-AKT-mTOR signaling pathway, modulates autophagy homeostasis, and inhibits the migration and invasion of extravillous trophoblast (EVT) cells. Notably, knockdown of PTEN or PPARγ with shRNA, or inhibition of autophagy with chloroquine (CQ) alleviates the TPhP-induced inhibition of EVT cells migration or invasion. Furthermore, using an established murine intrauterine exposure model, we confirmed that TPhP activates PPARγ, increases PTEN expression in placental trophoblast, inhibits the PI3K-AKT-mTOR signaling pathway and disturbs autophagy homeostasis. Collectively, these findings elucidate that TPhP inhibits EVT cells migration and invasion via the PPARγ-PTEN-PI3K-AKT-mTOR mediated autophagy pathway, providing a new toxicity pathway in placental toxicology. Additionally, this study provides new insights into the etiological research of PE.

Keywords:  Autophagy; PPARγ; Placenta; Triphenyl phosphate

DOI:  https://doi.org/10.1016/j.ecoenv.2026.120607
Biomed Res. 2026 ;47(4): 147-152

Localization of Type 1 plasminogen activator inhibitor in early decidua basalis and its role in pregnancy maintenance.

Yuka Sakakibara, Chizuko Yaguchi, Shuhei So, Toshihiko Asahina, Tomoaki Oda, Naomi Isomura, Masako Matsumoto, Hiroaki Itoh, Fumiko Tawara, Naohiro Kanayama.

Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor that controls trophoblast invasion by inhibiting fibrinolysis at the feto-maternal interface. This study aimed to compare PAI-1 expression patterns in decidual cells between different abortion types and investigate the role of PAI-1 in early pregnancy. Missed abortion (n = 22) and incomplete abortion (n = 16) cases were compared with induced abortion serving as normal pregnancy control (n = 16). PAI-1 localization and expression levels were evaluated using immunohistochemistry. PAI-1 was distributed in the cytoplasm of decidual cells. In addition, many PAI-1-positive cells were observed in the decidua basalis just under the Nitabuch fibrinoid layer, where many extravillous trophoblasts (EVTs) invaded. The percentage of PAI-1-positive decidual cells was not reduced in missed abortion (49.7 ± 29.6%) but was significantly reduced in incomplete abortion (11.6 ± 12.6%) compared to induced abortion as control (44.4 ± 10.9%). The significant reduction of PAI-1-positive decidual cells in incomplete abortion, which is characterized by bleeding, suggests that PAI-1 deficiency may cause excessive fibrinolysis leading to this clinical outcome.

DOI: https://doi.org/10.2220/biomedres.47.147