bims-placeb 2026-07-19 papers

Cells. 2026 Jun 24. pii: 1152. [Epub ahead of print]15(13):

Taxifolin Inhibits Invasion and Endovascular Differentiation of Extravillous Trophoblast HTR-8/SVneo Cells.

Aleksandra Vilotić, Janko Legner, Žanka Bojić-Trbojević, Marija Bruić, Biljana Spremo-Potparević, Milica Jovanović Krivokuća, Andrea Pirković.

Adequate placental development and function, prerequisites for the development of a healthy fetus, rely on controlled trophoblast invasion into the decidua and remodeling of the spiral arteries. These tightly regulated processes involve epithelial-mesenchymal transition (EMT) and endovascular differentiation of trophoblast cells. Taxifolin (dihydroquercetin), a natural flavonoid with various pharmacological effects, previously showed cytoprotective, antioxidant, and anti-inflammatory activity on trophoblast cells. Given that the literature indicates that this flavonoid suppresses EMT and can affect angiogenesis across different cell types, we investigated the potential of taxifolin (10 and 100 µM) to modulate invasion and endothelial-like differentiation in human extravillous trophoblast HTR-8/SVneo cells by functional tests. Expression of different molecular markers relevant to these processes was evaluated at the mRNA and protein levels. Our results showed that taxifolin inhibited invasion of HTR-8/SVneo cells, involving downregulation of integrin α5 subunit and modulation of MMP-2 and MMP-9 mRNA expression and secretion. No changes in the concentrations of secreted TIMP-1 and TIMP-2 were observed following taxifolin treatment. Furthermore, downregulation of N-cadherin and vimentin in treated trophoblast cells indicated suppression of EMT. Taxifolin inhibited endothelial-like differentiation of HTR-8/SVneo cells, as evidenced by reduced tube formation and downregulation of VE-cadherin in treated cells. Moreover, expression of TGFB1 was upregulated in treated cells, as were levels of phosphorylated SMAD2/3, indicating involvement of TGF-β signaling in TF-induced effects on trophoblast cells. The in vitro effects of taxifolin on suppression of trophoblast invasion, EMT, and endothelial-like differentiation highlight its potential impact on placental development processes.

Keywords: endovascular differentiation; epithelial–mesenchymal transition; extravillous trophoblast; taxifolin; trophoblast invasion

DOI: https://doi.org/10.3390/cells15131152

Placenta. 2026 Jul 13. pii: S0143-4004(26)00319-X. [Epub ahead of print]182 330-340

Multi-scale computational models of intervillous blood flow in fetal growth restriction: implications of anatomical changes on syncytiotrophoblast shear stress.

Tet Chuan Lee, Teena K J B Gamage, Mary Spring, Isha Ramanlal, Toby Jackson, Alys R Clark, Joanna L James.

INTRODUCTION: The haemodynamics of maternal blood flow in the intervillous space (IVS) impacts placental exchange efficiency. The resulting shear stress can also affect syncytiotrophoblast function, and in turn placental development. Here, we use anatomically-informed multiscale modelling approaches to predict flow in the IVS and syncytiotrophoblast shear stress in fetal growth restriction (FGR).
METHODS: Three-dimensional placentone models were established and parameterised to normal and FGR scenarios. Normal term and FGR placental tissue punches were microCT imaged, segmented, and used in tissue-level computational fluid dynamics simulations to predict syncytiotrophoblast shear stress. Tissue and placentone-level models were combined to predict syncytiotrophoblast shear stress ranges. Mechanosensing protein expression was determined by immunohistochemistry.
RESULTS: Placentone-level models demonstrate variation in IVS flow velocity across the placental depth, with higher velocity regions at spiral artery mouths that extended further in FGR. Tissue-level models predicted higher levels of syncytiotrophoblast shear stress in FGR. Combined models predicted a greater proportion of tissue is exposed to higher shear stresses in FGR, with ∼2-fold increase in peak shear stress proximal to spiral artery openings. Including septal veins increased penetration of maternal blood and the proportion of tissue exposed to higher shear. In FGR, the syncytiotrophoblast had greater Dynein-1 and lower Kinesin-2 and TRVP6 expression, but no difference in IFT88, Polycystin-2 or Piezo-1 expression.
CONCLUSIONS: In FGR, impaired remodelling of the spiral arteries and changes in villous tissue architecture combine to increase the proportion of placental tissue exposed to higher shear stress. Septal veins and central cavities act synergistically to ensure adequate placental perfusion.

Keywords: Fetal growth restriction; Intervillous space; Mechanosensing; Shear stress; Syncytiotrophoblast

DOI: https://doi.org/10.1016/j.placenta.2026.07.007

Dev Reprod. 2026 Jun;30(2): 71-77

Localization of Luteinizing Hormone (LH) Subunits Like Substances in the Mouse Placenta.

Eun Hye Ko, Sung-Ho Lee.

Luteinizing hormone (LH) is a vital reproductive hormone produced by the anterior pituitary gland, essential for both fertility and sexual development. Interestingly, there is evidence indicates that rodent placenta is extrapituitary site of LH synthesis. On this basis, we performed immunohistochemistry (IHC) using specific antisera for LH subunits to investigate the tissue distribution of the LH subunits like molecules in mice placentae. Pregnant mice on gestation day 17 were sacrificed and the placentae were obtained Glycogen rich trophoblast cells (GlyT) in the junctional zone (JZ) were positive for CGα immunohistochemical staining, and the LH-β positive staining was found in all cell layers in both JZ and labyrinth zone (LZ). Immunoreactive LH-receptor (LH-R) staining was observed on the membrane of GlyT in JZ and partial syncytiotrophoblast cells layer in LZ. The present study demonstrated that immunoreactive LH subunits like substances were localized differentially in the microstructures of mice placentae. This finding that the substances exhibiting immune responses to these and their receptors exist in the same type of cells and/or adjacent cells, suggesting the possibility of local regulation through these substances. Further studies will be helpful for understanding the biochemical nature and the role(s) of local LH-like substances in sophisticated placental physiology.

Keywords: Localization; Luteinizing Hormone (LH); Placenta; Rat; Substances; Subunit like

DOI: https://doi.org/10.12717/DR.2026.30.2.71

Cell Commun Signal. 2026 Jul 15.

Trophoblast cells rewire the epigenetic landscape of vascular smooth muscle cells to modulate plasticity: a regulatory axis disrupted in intrauterine growth restriction.

Poulomi Sarkar, Rupasri Ain.

BACKGROUND: Uterine spiral artery remodelling (SAR) is a fundamental developmental process that facilitates optimal placental perfusion and supports fetal growth. Central to SAR is the phenotypic transformation of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state, directed by invasive trophoblast cells. To advance these findings, we sought to elucidate the epigenetic mechanisms governing trophoblast-induced reprogramming of VSMC identity, enabling plasticity required for uterine vascular adaptation.
METHODS: VSMC dedifferentiation was assessed by qRT-PCR, Western blotting, and immunofluorescence. Epigenetic alterations were evaluated by Western blotting. A chromatin remodelling PCR array was performed and validated by qRT-PCR and Western blotting. Chromatin remodelling factors were downregulated using antisense oligonucleotides (ASOs), and VSMC dedifferentiation was confirmed by Western blotting. E13.5 and E16.5 rat metrial glands were used for in vivo validation. An IUGR rat model was generated by administering dexamethasone from E13.5 to E20.5. In IUGR tissues, trophoblast invasion, VSMC dedifferentiation, and chromatin remodelling factor expression were validated by Western blotting.
RESULTS: Co-culture of primary E16.5 rat trophoblast cells with VSMCs revealed a trophoblast-induced shift in the expression landscape of epigenetic regulators, resulting in upregulation of chromatin-modifying "writers" (CBP, DNMT1, DNMT3A), downregulation of "erasers" (HDAC 1,2,3), and an increase in both transcription activation marks (H3K27ac, H3K9ac) and repression marks (H3K27me3, H3K9me3). Targeted real-time PCR array profiling identified coordinated downregulation of 13 chromatin remodelling genes (ARID1B, SMARCAD1, SMARCD1, SMARCD3, BMI1, EZH2, CBX2, CBX5, CBX6, BAZ1B, ZMYND8, CHD1, MBD3,) during VSMC de-differentiation. This change in the epigenetic landscape was recapitulated in vivo within the metrial gland, the entry point of uterine spiral arteries, on E16.5. Knockdown of these factors impaired the phenotypic transition of VSMCs, establishing their mechanistic role in enabling vascular adaptation. Notably, in a model of intrauterine growth restriction (IUGR), the normal expression dynamics of chromatin remodelling factors and VSMC phenotypic markers were reversed, indicating the need for the dynamic epigenetic regulatory axis, which is essential for vascular adaptation in healthy pregnancies.
CONCLUSIONS: These findings uncover a trophoblast-driven epigenetic axis that governs VSMC plasticity during SAR and highlight its dysregulation as a potential contributor to the pathogenesis of IUGR.

Keywords: Epigenome; IUGR; Phenotype switching; Pregnancy; Spiral artery remodeling; VSMC dedifferentiation

DOI: https://doi.org/10.1186/s12964-026-03042-4

Biol Reprod. 2026 Jul 11. pii: ioag142. [Epub ahead of print]

Spontaneous Uterine and Fetal Recombination in TetO-Cre Mice: Implications for Pregnancy Studies.

Keisuke Kozai, Hruda N Malik, Gracy X Rosario, Sabita Dhal, Prashanth Anamthathmakula, Nihar R Nayak.

Keywords: Cre leakiness; TetO-Cre; placenta; spontaneous recombination; uterus

DOI: https://doi.org/10.1093/biolre/ioag142

Dev Cell. 2026 Jul 17. pii: S1534-5807(26)00239-X. [Epub ahead of print]

Live imaging captures the events immediately following fertilization.

Robin M Skory, Ana Domingo-Muelas, Sarah Declercq, Winter Vandenberghe, Piotr Tetlak, Blake Hernandez, Dominic Stoop, Colin C Conine, Maté Biro, Björn Heindryckx, Nicolas Plachta.

Fertilization involves dynamic sperm-egg interactions, yet has been primarily studied in static samples. Here, we use high-resolution live imaging to capture fertilization from the moment of sperm binding in zona-intact mouse oocytes. We identify two phases of sperm remodeling: a static phase, during which sperm remain beneath the oocyte cortex as DNA decondensation and histone loading occur, and a mobile phase characterized by stereotyped sperm movement. Initial displacement away from the spindle is driven by cytoplasmic streaming, with manipulations in mouse indicating that sperm movement requires chromatin decondensation and oocyte polarization. Subsequently, polar body cytokinesis generates convergent cortical flows that draw sperm toward the emerging female pronucleus. Finally, we capture sperm-egg fusion in human oocytes and characterize post-fusion events including meiotic resumption and sperm movement, offering a live-imaging description of human fertilization dynamics. Together, these findings provide a continuous spatiotemporal framework for mammalian fertilization, extended by initial observations in human oocytes.

Keywords: ICSI; IVF; chromatin remodeling; cortical flow; cytoplasmic streaming; fertilization; live imaging; oocyte; sperm; zygote

DOI: https://doi.org/10.1016/j.devcel.2026.06.015