bims-placeb 2025-08-03 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–08–03
nine papers selected by
Carlos M Guardia, National Institute of Health

Human placentation: foundations and implications for reproductive endocrinology and infertility.
PIEZO1 drives trophoblast fusion and placental development.
Alterations in P-glycoprotein Expression in the Placenta of Obese Rats and Humans.
Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst.
Formation of the placental membranes and pathophysiological origin of associated Great Obstetrical Syndromes.
Monocyte chemoattractant Protein-1 (MCP-1) decreases mineralization of the villous stroma in the macaque placenta.
Impact of excessive hypercholesterolemia in pregnancy on the placentas of the male and female offspring.
Exploration of normal placental blood flow characteristics in middle and late pregnancy based on microvascular flow imaging.
Recent progress in 2D, 3D, and on-a-chip models of the placenta.

Syst Biol Reprod Med. 2025 Dec;71(1): 279-306

Human placentation: foundations and implications for reproductive endocrinology and infertility.

Elakkiya Prabaharan, D Randall Armant, Sascha Drewlo.

  Human fetal development requires sustenance via the placenta, which mediates molecular transport between maternal and fetal circulations. Placental formation begins as cells of the trophoblast lineage differentiate and the extraembryonic mesoderm becomes vascularized, assembling a unique organ de novo that facilitates nutrient and gas exchange, waste removal, hormone production and immune modulation. We describe how placentation is orchestrated to keep pace with fetal growth, but is vulnerable to disruption by medical interventions for infertility. Initially, trophoblast stem cells differentiate into proliferating mononuclear cytotrophoblasts (CTBs) that fuse to form the multinucleated syncytiotrophoblast (STB). The STB ensheathes the chorionic villi, bathed in maternal blood. As fetal blood vessels develop within the mesodermal core of villi, the maternal-fetal interface is established. Where the villi meet the decidua, CTBs further differentiate into extravillous trophoblasts, which invade and remodel uterine arteries into high-conductance, low-resistance vessels, enhancing maternal blood flow to the placenta. Among the critical intercellular axes that govern trophoblast differentiation, invasion, and vascular remodeling hormonal cues, particularly those associated with the corpus luteum, are critical; their alteration in certain assisted reproductive technology (ART) protocols can contribute to incomplete arterial remodeling. Malplacentation is linked to miscarriage, fetal growth restriction, and preeclampsia, affecting over 10% of pregnancies, and occurring at higher rates in patients diagnosed with infertility, especially those who conceive through ART. Understanding the mechanisms driving these pathologies is essential for improving pregnancy outcomes. Strategies to optimize ART protocols and therapeutic interventions targeting key signaling pathways offer potential avenues to mitigate risks associated with malplacentation.

Keywords:  Placenta; assisted reproduction; perinatal disorders; trophoblast

DOI:  https://doi.org/10.1080/19396368.2025.2533992
Nat Commun. 2025 Jul 26. 16(1): 6895

PIEZO1 drives trophoblast fusion and placental development.

Yang Zhang, Ke Z Shan, Pengfei Liang, Augustus J Lowry, Liping Feng, Huanghe Yang.

PIEZO1, a mechanosensor in endothelial cells, plays a critical role in fetal vascular development during embryogenesis. However, its expression and function in placental trophoblasts remain unexplored. Here, we demonstrate that PIEZO1 is expressed in placental villus trophoblasts, where it is essential for trophoblast fusion and placental development. Mice with trophoblast-specific PIEZO1 knockout exhibit embryonic lethality without obvious vascular defects. Instead, PIEZO1 deficiency disrupts the formation of the syncytiotrophoblast layer in the placenta. Mechanistically, PIEZO1-mediated calcium influx activates TMEM16F lipid scramblase, facilitating the externalization of phosphatidylserine, a key "fuse-me" signal for trophoblast fusion. These findings reveal PIEZO1 as a crucial mechanosensor in trophoblasts and highlight its essential role in regulating trophoblast fusion and placental development, expanding our understanding of PIEZO1's functions beyond endothelial cells during pregnancy.

DOI: https://doi.org/10.1038/s41467-025-62254-3
Int J Mol Sci. 2025 Jul 20. pii: 6976. [Epub ahead of print]26(14):

Alterations in P-glycoprotein Expression in the Placenta of Obese Rats and Humans.

Péter Szatmári, Kata Kira Kemény, Andrea Surányi, Yakov Rachamim, Eszter Ducza.

  Obesity affects approximately 30% of pregnancies worldwide and is one of the leading metabolic disorders among pregnant women. Maternal obesity is often associated with placental dysfunction and structural alterations, which increase the risk of developing complications. Efflux transporters, including P-glycoprotein (P-gp), may impact placental function and fetal development. Consequently, our research examined the effects of obesity on P-glycoprotein expression in both a rat model and human placental tissue. P-gp expression was measured by RT-PCR and Western blot techniques in human and rat placental tissues. Moreover, we further characterized the high-fat and high-sugar diet (HFHSD)-induced gestational obesity rat model by measuring tissue weights. Significant decreases were observed in fetal, placental, and uterus weights in the obese animals near the end of pregnancy. In obese rats, mRNA and protein expression of placental P-gp showed a reduction on gestation days 15, 20, and 22. A similar P-gp reduction was observed in the term placenta in obese women in mRNA and protein levels. We hypothesize that the reduced expression of P-gp may heighten the susceptibility of both the fetus and placenta to P-gp substrates. This alteration could potentially result in an increased risk of pregnancy complications and obesity-related drug contraindications linked to P-gp transport during pregnancy.

Keywords:  ABC transporter; P-glycoprotein; drug exposure; human; obesity; placenta; pregnancy complications; rat

DOI:  https://doi.org/10.3390/ijms26146976
Nat Commun. 2025 Jul 28. 16(1): 6922

Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst.

Claire S Simon, Afshan McCarthy, Laura Woods, Desislava Staneva, Martin Proks, Nazmus Salehin, Georgia Lea, Qiulin Huang, Madeleine Linneberg-Agerholm, Alex Faulkner, Athanasios Papathanasiou, Kay Elder, Phil Snell, Leila Christie, Patricia Garcia, Valerie Shaikly, Mohamed Taranissi, Meenakshi Choudhary, Mary Herbert, Courtney W Hanna, Joshua M Brickman, Kathy K Niakan.

Studies in the mouse demonstrate the importance of fibroblast growth factor (FGF) and extra-cellular receptor tyrosine kinase (ERK) in specification of embryo-fated epiblast and yolk-sac-fated hypoblast cells from uncommitted inner cell mass (ICM) cells prior to implantation. Molecular mechanisms regulating specification of early lineages in human development are comparatively unclear. Here we show that exogenous FGF stimulation leads to expanded hypoblast molecular marker expression, at the expense of the epiblast. Conversely, we show that specifically inhibiting ERK activity leads to expansion of epiblast cells functionally capable of giving rise to naïve human pluripotent stem cells. Single-cell transcriptomic analysis indicates that these epiblast cells downregulate FGF signalling and maintain molecular markers of the epiblast. Our functional study demonstrates the molecular mechanisms governing ICM specification in human development, whereby segregation of the epiblast and hypoblast lineages occurs during maturation of the mammalian embryo in an ERK signal-dependent manner.

DOI: https://doi.org/10.1038/s41467-025-61830-x
Am J Obstet Gynecol. 2025 Jul 29. pii: S0002-9378(25)00519-8. [Epub ahead of print]

Formation of the placental membranes and pathophysiological origin of associated Great Obstetrical Syndromes.

Graham J Burton, Eric Jauniaux, Ashley Moffett.

  Formation of the smooth membranes is an essential phase of human placentation to allow safe rupture of the chorionic sac and birth of the fetus without damaging the placenta. The membranes form through regression of two-thirds of the villi that cover the early gestational sac shortly after implantation. Regression is associated with locally high levels of oxidative stress secondary to partial onset of the maternal arterial circulation to the placenta. Onset starts preferentially in the peripheral zone from ∼6-8 weeks of gestation, reflecting the lesser extent of plugging of maternal spiral arteries by endovascular trophoblast in this region. Plugging is part of the arterial remodeling essential to control adequate and even perfusion of the placenta. As the chorionic sac expands extensive necrosis occurs in the overlying decidua capsularis, which consequently makes no contribution to the mature membranes. Once the sac fuses with the decidua parietalis lining the opposite wall of the uterus, at around 16 weeks of gestation, the cytotrophoblast cells of the chorionic epithelium proliferate and form a stratified epithelium with features reminiscent of the skin barrier. A sharp demarcation exists between this epithelium and the cells of the decidua parietalis in the mature membranes, with no evidence of trophoblast migration. Pre-term premature rupture of the membranes and pre-term labor are associated with deficient remodeling of the spiral arteries that is mediated by extravillous trophoblast derived from the cytotrophoblastic shell. The resultant placental malperfusion causes maternal and placental oxidative stress, as in the other Great Obstetrical Syndromes (GOS), causing release of pro-inflammatory cytokines and stimulating uterine contractility. Deficient remodeling is also likely a proxy marker for poor development of the cytotrophoblastic shell. The shell anchors the gestational sac at the maternal-placental interface post-implantation, and weakness of this interface predisposes to subchorionic hemorrhage. Hemorrhages that abut the membranes may induce local inflammation, senescence and weakening. Ensuring normal development of the cytotrophoblastic shell is therefore essential to prevent the GOS. At this stage of pregnancy, placental development is supported by histotrophic nutrition from the decidua. Hence, optimising endometrial function prior to conception should become a health-care priority.

Keywords:  Amnion; chorion laeve; decidualisation; placental development; premature delivery; prematurity; preterm labor; preterm premature rupture membranes; smooth membranes; threatened miscarriage

DOI:  https://doi.org/10.1016/j.ajog.2025.07.039
Placenta. 2025 Jul 23. pii: S0143-4004(25)00315-7. [Epub ahead of print]169 72-81

Monocyte chemoattractant Protein-1 (MCP-1) decreases mineralization of the villous stroma in the macaque placenta.

Logan T Keding, Jessica Vazquez, Ruo-Yu Liu, Emily Bove, Jessica Dorobek, Heather A Simmons, Kathleen M Antony, Jenna L Racine, Dinesh M Shah, Oliver Wieben, Thaddeus G Golos, Aleksandar K Stanic.

   INTRODUCTION: Placental insufficiency occurs when a fetus does not receive adequate oxygen and/or nutrients, leading to adverse pregnancy outcomes (APOs). Increased leukocyte density has been observed in placental inflammatory lesions, resulting in placental insufficiency and APOs. MCP-1 is a chemokine associated with inflammatory disease, that actively attracts leukocyte populations. We investigated the effects of a supraphysiological MCP-1 injection into the maternal-fetal interface (MFI), using the macaque pregnancy model.
METHODS: A placental injection of MCP-1 or saline was administered to macaques between gestational day (GD) 100-105, along the MFI. Acute effects (n = 2) and full-term effects (n = 8) were studied. Full-term pregnancies had maternal placental blood perfusion measured via dynamic contrast enhanced MRI, before and after injection. Fetoplacental tissues were collected near term (GD 155). Placental histopathology was investigated, along with decidual immune populations, MRI-defined maternal blood metrics, and fetal biometrics.
RESULTS: Acutely, increased leukocyte clustering and decreased mineralization were observed within the villous stroma of MCP-1-treated cotyledons. Decreased villous mineralization with MCP-1 injection was also noted in full-term pregnancies, along with a proportional increase in decidual dendritic cells. MRI placental analysis revealed a trend of increased maternal blood flow and reduced fill time after MCP-1 injection, alongside healthy fetal biometrics.
DISCUSSION: Although MCP-1 is typically associated with inflammation and tissue pathology, our study demonstrates that supraphysiological MCP-1 levels led to increased leukocyte clustering and reduced mineralization in the villous stroma, without impairing maternal blood perfusion or fetal growth. These findings suggest a beneficial role for MCP-1 in the context of placental function.

Keywords:  Blood flow; MCP-1; Macaque; Mineralization; Placenta; Villous stroma

DOI:  https://doi.org/10.1016/j.placenta.2025.07.083
Sci Rep. 2025 Jul 28. 15(1): 27431

Impact of excessive hypercholesterolemia in pregnancy on the placentas of the male and female offspring.

Amanda A de Oliveira, Angie Stokes, Anita Quon, Murilo E Graton, Floor Spaans, Christy-Lynn M Cooke, Sandra T Davidge.

  Excessive hypercholesterolemia (eHC) in pregnancy reduces placental efficiency in both fetal sexes, but the mechanisms are not known. In this study, Sprague Dawley rats received a control or high cholesterol diet (to model eHC) during pregnancy, after which various markers of placental function were assessed. Lipid levels, but not reactive oxygen species levels, were increased in both the male and female eHC placentas vs. controls. However, compared to control placentas, eHC reduced cholesterol receptors, increased cholesterol transporters, lowered fetal cholesterol levels, and altered the unfolded protein response in a sex-specific manner. Moreover, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) levels were increased in only the male eHC placentas, and associated with reduced interleukin 1β levels, likely due to its rapid secretion into the circulation. The levels of caspase 8, but not caspase 1, were increased in only the male eHC placentas vs. controls, suggesting that the processing of interleukin 1β may have happened via a non-canonical pathway. In conclusion, eHC in pregnancy impacts the placentas of both the male and female offspring, but the activation of the NLRP3 inflammasome in only the male placentas suggests that the male offspring may be more susceptible to excessive increases in maternal cholesterol levels.

Keywords:  Cholesterol receptors and transporters; Hypercholesterolemia in pregnancy; NLRP3 inflammasome; Placenta; Unfolded protein response

DOI:  https://doi.org/10.1038/s41598-025-11416-w
Pak J Med Sci. 2025 Jul;41(7): 2010-2016

Exploration of normal placental blood flow characteristics in middle and late pregnancy based on microvascular flow imaging.

Chuanfen Gao, Chaoxue Zhang, Ying Zhang, Yi Zhou, Xiufang Shuai, Lin Gao.

   Objective: To explore the micro blood flow characteristics of normal singleton pregnancy placenta in middle and late pregnancy based on microvascular flow (MV-Flow) imaging.
Methods: We conducted a retrospective cohort study. Clinical records and placental ultrasound images of 485 patients in mid to late pregnancy with normal fetal development who underwent MV-Flow microvascular imaging in The First Affiliated Hospital of Anhui Medical University from January 2023 to December 2023 were retrospectively analyzed. The gestational age of patients ranged from 22 to 38 weeks, and the biological measurements of the fetus during pregnancy were within the normal range. The patients were divided into six groups according to gestational age: 22-24W, 25-27W, 28-30W, 31-33W, 34-36W, and 37-39W.
Results: During the middle and late stages of normal pregnancy, the placental microvasculature displayed grade three or higher blood flow branches. As the gestational age increased, the peak systolic velocity (PSV) of the fetal umbilical artery (UA) and middle cerebral artery (MCA) gradually increased. The UA pulsatility index (PI), MCA-PI, and ductus venosus (DV) - PI gradually decreased with the gestational age (all P<0.05). There were statistically significant differences in the PSV and PI of various branches of the chorionic vascular tree in different gestational age groups (all P<0.05). However, there was no statistically significant difference in vascular index from MV-Flow (VIMV) (P>0.05), with no significant changes at different gestational weeks.
Conclusions: Placental microvascular imaging based on MV-Flow can demonstrate a gradual increase in the microvascular flow velocity inside the placenta and a gradual decrease in the blood flow resistance with gestational age.

Keywords:  MV-Flow; Micro blood flow; Middle and late pregnancy; Placenta; Singleton pregnancy

DOI:  https://doi.org/10.12669/pjms.41.7.12135
Cells Tissues Organs. 2025 Jul 28. 1-50

Recent progress in 2D, 3D, and on-a-chip models of the placenta.

Alexandra M Harrison, Christina M Bailey-Hytholt.

BACKGROUND: The placenta is a temporary organ that develops throughout pregnancy, connecting a developing fetus to the maternal uterine wall. The placenta's structure is species specific and complex, resulting in recent advancements with in vitro models to help study this dynamic organ. The main cell type composing the placenta, trophoblast cells, serve several roles and have been incorporated within biomaterials and devices to recapitulate the placental microenvironment.
SUMMARY: This review highlights in vitro 2D, 3D, and on-a-chip models of two placental interfaces: the interface between the endometrium and extravillous trophoblast cells and the interface between the chorionic villi and intervillous space. First, an overview of placental cell types and in vitro model types used in the discussed studies is provided. Next, models of invasive trophoblasts cells at the endometrium where the placenta is anchored and the spiral arteries are remodeled are discussed. Next, the review highlights models of the chorionic villi and intervillous space, an interface where cytotrophoblast cells fuse into syncytiotrophoblasts. Finally, we discuss key takeaways and future directions in creating representative placental models.
KEY MESSAGES: The combination of biomaterial and engineering approaches has led to the development of physiologically relevant models, allowing placental trophoblast functions to be investigated with more clarity. Each cell type (e.g. trophoblast cell line vs. stem cells vs. primary placental cells) and biomaterial system (e.g. organoid vs. on-a-chip) that is selected for a given model has a unique combination of advantages and limitations, which are detailed within this review. Overall, the placental models discussed enable trophoblast cell behavior to be studied in vitro with the inclusion of extracellular matrix materials, growth factors, and other environmental cues. While one model alone does not fully recapitulate every function of the placenta, individual models are tailored to inform on specific placental trophoblast behaviors.

DOI: https://doi.org/10.1159/000547560