bims-placeb 2026-09-20 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–09–20
fourteen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Combined EP300 and CREBBP Expression Levels Regulate Human Trophoblast Differentiation.
Gestational inhalation of nanoparticles disrupts placental zone structure and induces vascular placentation in rats.
MicroRNA-Mediated Placental Maladaptation in Preeclampsia Pathogenesis.
Autophagy in the Regulation of Placental Development: From Trophoblast Differentiation to Metabolic Stress Adaptation.
Current Translational 3D In Vitro Models of Human Placental Tissue.
Aldo-Keto Reductase 1B10 (AKR1B10) Restrains Trophoblast Cell Invasion via the ERK Signaling Pathway.
Multiscale computational modeling to quantify how spiral artery remodeling alters wall shear stress on placental villi.
Biomechanical modelling of the feto-placental and utero-placental circulations; where to from here?
Derivation of Mouse Dome-Shaped Trophoblast Stem Cells With Low Heterogeneity From Blastocysts.
Mapping Stage-Specific Enhancer Dynamics During the Specification of Human Trophoblast Lineage.
Folate Deficiency Alters microRNA Expression and Transcriptomic Networks in a Human Trophoblast Model.
Segmentation of placental tissue using immunofluorescent staining and an artificial intelligence-based analysis workflow.
The placental maturation inflection point: an integrative biological framework for understanding early-onset versus late-onset preeclampsia.
Exploring the Placental Lipidome in Physically Active vs. Inactive Pregnancies.

Int J Mol Sci. 2026 Aug 25. pii: 7623. [Epub ahead of print]27(17):

Combined EP300 and CREBBP Expression Levels Regulate Human Trophoblast Differentiation.

Fangxu Lin, Remco Keijser, Gijs Afink.

  Extravillous trophoblast (EVT) differentiation is essential for placental development and successful pregnancy, yet the molecular mechanisms regulating this process remain incompletely understood. CREB-binding protein (CREBBP) and E1A-binding protein p300 (EP300) are closely related lysine acetyltransferases that function as transcriptional co-activators. Previous studies reported that EP300 depletion impairs EVT differentiation whereas CREBBP depletion has little or no effect. We found that CREBBP mRNA expression was approximately one-third of EP300 expression in trophoblast stem cells (TSCs) and differentiated trophoblast lineages. To investigate whether differential CREBBP and EP300 expression explains this asymmetry in EVT differentiation initiation, we combined siRNA-mediated knockdown, CRISPR-generated CREBBP-deficient TSCs, pharmacological inhibition, and lentiviral Crebbp overexpression during EVT differentiation. While CREBBP depletion alone produced minimal phenotypic effects, CREBBP-deficient cells displayed increased sensitivity to the CREBBP/EP300 inhibitor A-485, with inhibitory effects appearing at lower A-485 concentrations in cells with reduced CREBBP level. Moreover, increased CREBBP expression partially rescued the EP300-depletion phenotype, including EVT-like morphology and selected differentiation marker expression. Together, these findings demonstrate that CREBBP contributes to EVT differentiation, but its role is obscured by its lower endogenous expression. We propose that the combined contributions of CREBBP and EP300, rather than EP300-specific activity alone, influence human trophoblast differentiation efficiency.

Keywords:  CREB-binding protein; E1A-binding protein p300; extravillous trophoblasts; placenta; trophoblast differentiation

DOI:  https://doi.org/10.3390/ijms27177623
Reprod Toxicol. 2026 Sep 14. pii: S0890-6238(26)00204-2. [Epub ahead of print]146 109361

Gestational inhalation of nanoparticles disrupts placental zone structure and induces vascular placentation in rats.

Talia Seymore, Destiny McWilliams, Kevin Ozkuyumcu, Pedro Louro, Chelsea Cary, Michael Goedken, Laurie Joseph, Phoebe Stapleton.

  Airborne contaminants represent a significant environmental health concern for vulnerable populations, including pregnant individuals. In particular, maternal inhalation of particulate matter (PM) during pregnancy has been linked to adverse outcomes such as fetal growth restriction (FGR). Increasing evidence identifies placental dysfunction as a mechanism for this condition. Placental efficiency, defined as the ratio of fetal mass to placental mass, is frequently altered in FGR. Many aspects contribute to placental efficiency including surface area available for nutrient and waste exchange and placental vascularization. In this study, we hypothesized that maternal inhalation of ultrafine PM during pregnancy would reduce the size and/or number of placental structures that are necessary for nutrient transport. Engineered titanium dioxide nanoparticles (nano-TiO2) were used as a proxy for ultrafine PM and pregnant Sprague Dawley rats were exposed via whole-body inhalation to nano-TiO2 aerosols (9.23 ± 0.39 mg/m3) from gestational day (GD) 5-19. On GD 20, placentas were collected and processed for histological evaluation. While gestational inhalation of nano-TiO2 did not affect placental weight or efficiency, it reduced decidua and labyrinth zone size. Exposed placentas exhibited compensatory adaptations characterized by increased blood space number and maternal blood space expansion. Together, these findings indicate that inhalation of nanoparticles disrupts placental structure while simultaneously eliciting changes in vascular architecture that may preserve nutrient exchange capacity. By characterizing the effects of PM exposure on placental morphology and structure, this study highlights the placenta as a vulnerable target of inhaled pollutants and provides mechanistic insight into pathways contributing to PM-induced FGR.

Keywords:  Fetal growth restriction; Inhalation; Particulate matter; Placenta; Placental morphology; Placental vascularization; Titanium dioxide nanoparticles

DOI:  https://doi.org/10.1016/j.reprotox.2026.109361
FASEB Bioadv. 2026 Sep;8(9): e70132

MicroRNA-Mediated Placental Maladaptation in Preeclampsia Pathogenesis.

Sarbani Saha, Rupasri Ain.

  Preeclampsia (PE) is a pregnancy-specific disorder characterized by maternal hypertension and proteinuria, typically manifesting in the late second or third trimester. It affects approximately 5%-8% of pregnancies worldwide and accounts for nearly 10%-15% of maternal deaths. PE is also associated with adverse neonatal outcomes, including preterm birth, fetal growth restriction, and low birth weight, with long-term cardiovascular and metabolic consequences for both mother and offspring. Although clinical symptoms appear in the latter half of pregnancy, substantial evidence indicates that PE originates earlier during placental development. Impaired trophoblast invasion and defective spiral artery remodeling result in placental insufficiency, compromised uteroplacental perfusion, and a hypoxic placental microenvironment, which are hallmark features of the disease. Despite extensive research, PE remains a heterogeneous disorder lacking reliable early diagnostic markers or effective targeted therapies, with placental delivery remaining the only definitive treatment. MicroRNAs (miRNAs) have emerged as critical regulators of placental development and function. Owing to their abundance, evolutionary conservation, and ability to modulate multiple gene networks, miRNAs regulate trophoblast proliferation, migration, invasion, angiogenesis, and apoptosis, processes that are profoundly disrupted in PE. Genome-wide expression studies have revealed widespread dysregulation of placental miRNAs in PE, frequently associated with hypoxia and angiogenic imbalance. This review summarizes current advances in miRNA expression and function in the preeclamptic placenta, focusing on their roles in trophoblast dysfunction and disease pathogenesis. We highlight differentially expressed placental miRNAs, their targets, and the regulatory pathways they influence, emphasizing the central role of miRNA-mediated gene regulation in the development and progression of PE.

Keywords:  angiogenesis; apoptosis; invasion; mesenchymal stem cell; miRNA; pathogenesis; placenta; preeclampsia; trophoblast

DOI:  https://doi.org/10.1096/fba.2026-00062
Cells. 2026 Aug 27. pii: 1552. [Epub ahead of print]15(17):

Autophagy in the Regulation of Placental Development: From Trophoblast Differentiation to Metabolic Stress Adaptation.

Chloe Lee, Hoi Kit Matthew Leung, Yanjie Guo, Sam Chak Sum Wong, Ruiqing Zhang, Lee Tung Chan, Yang Dong, Qingqing Zhang, Ka-Wang Cheung, Philip C N Chiu, Cheuk-Lun Lee.

  Successful pregnancy depends on precise placental development, where trophoblast differentiation, syncytialization, invasion, and adaptation to metabolic stress are critical. Autophagy, a lysosome-mediated degradation pathway, has emerged as an important regulator of cellular homeostasis, yet its integrated role in trophoblast fate and functions has not been comprehensively summarised. This review synthesises current evidence on autophagy's functions throughout placentation, from trophoblast differentiation to syncytialization and extravillous trophoblast invasion. We examine how autophagy enables cellular remodelling during differentiation, supports metabolic adaptation under hypoxia and nutrient stress, and maintains mitochondrial quality control through selective mitophagy. Autophagy is essential for syncytiotrophoblast formation via endoplasmic reticulum stress-coordinated activation and p53 downregulation. However, its effects on trophoblast invasion are context-dependent, influenced by oxygen tension, autophagic flux completeness, and differentiation state, which can potentially be shaped by parent-offspring genetic conflicts through genomic imprinting. Both excessive and insufficient autophagy contribute to pregnancy complications, including pre-eclampsia, foetal growth restriction, gestational diabetes mellitus, preterm birth, recurrent spontaneous abortion and obstetric antiphospholipid syndrome through distinct molecular mechanisms. Autophagy functions as a dynamically tuned homeostatic mechanism in placental development. Understanding condition-specific autophagy dysregulation is thereby crucial for improving pregnancy outcomes.

Keywords:  autophagy; differentiation; foetal growth restriction; gestational diabetes mellitus; invasion; obstetric antiphospholipid syndrome; placental development; pre-eclampsia; pregnancy complications; preterm birth; recurrent spontaneous abortion; syncytialization; trophoblasts

DOI:  https://doi.org/10.3390/cells15171552
Stem Cell Rev Rep. 2026 Sep 12.

Current Translational 3D In Vitro Models of Human Placental Tissue.

Ananya Raman, Niamh E P Mills, Louise Cole, Claire Richards, Lana McClements.

  Cellular models of placental tissue have the potential to recapitulate normal physiology, model disease, and facilitate therapeutic drug testing. In vivo or two-dimensional (2D) in vitro models of placental conditions have not been sufficiently representative of whole human tissue, thus have limited physiological relevance. This can be attributed to interspecies differences in placental physiology or a lack of structural complexity. In comparison, three-dimensional (3D) multicellular model systems provide a more sophisticated analogue of human placental tissue. Newer models of human placenta include 3D organoids, placenta-on-a-chip and organoid-on-a-chip, employing a range of materials and methods including pluripotent or trophoblast stem cells, microfluidics and 3D bioprinting. Accurately mimicking in vivo human tissue is crucial to the success of these translational 3D models of the placenta.In turn, a reliable representation of placental tissue architecture will allow discovery of the mechanisms underlying abnormal placental development and inform the prevention, diagnosis and treatment of pregnancy-related disorders such as preeclampsia and fetal growth restriction. Here, we provide a comprehensive critical appraisal of recent advances in 3D placental models, which aim to elucidate placental physiology, development and dysfunction. Additionally, we discuss how these platforms can accelerate the development of better monitoring and treatment strategies for pregnancy complications induced by a dysfunctional placenta.

Keywords:  Bioprinting; Organoids; Placenta; Placenta-on-a-chip; Pregnancy; Trophoblast cells

DOI:  https://doi.org/10.1007/s12015-026-11231-4
Int J Mol Sci. 2026 Aug 28. pii: 7728. [Epub ahead of print]27(17):

Aldo-Keto Reductase 1B10 (AKR1B10) Restrains Trophoblast Cell Invasion via the ERK Signaling Pathway.

Suohao Peng, Jiaxuan Cai, Xiaohua Lei, Chen Huang.

  Trophoblast invasion is crucial for the establishment of a functional placenta. Defects in this process can cause adverse pregnancy outcomes, such as miscarriage and preeclampsia. Aldo-keto reductase family 1 member B10 (AKR1B10), a key cytoplasmic oxidoreductase that converts retinoids, retinaldehyde isoprenoids, and lipid peroxidation-derived reactive aldehydes into their corresponding alcohols, regulates cell proliferation, inflammation, and metastasis in cancers. Here, our results demonstrated that AKR1B10 is highly expressed in the ectoplacental cone (EPC) of the mouse placenta. Deficiency of AKR1B10 leads to excessive trophoblast giant cell (TGC) invasion, impaired trophoblast cell differentiation of the junctional zone, and accelerated maternal spiral artery remodeling. Mechanistically, loss of AKR1B10 suppressed extracellular regulated protein kinase (ERK) phosphorylation in both murine placentas and human HTR8/SVneo cells, further promoting HTR8 cell migration and invasion in vitro. Our findings identify AKR1B10 as a critical regulator that restrains trophoblast invasion in the placenta, suggesting it as a new therapeutic target for placental disorders.

Keywords:  AKR1B10; ERK signaling pathway; placenta; trophoblast invasion

DOI:  https://doi.org/10.3390/ijms27177728
PLoS Comput Biol. 2026 Sep 16. 22(9): e1014769

Multiscale computational modeling to quantify how spiral artery remodeling alters wall shear stress on placental villi.

Armita Najmi, Noelia Grande Gutiérrez.

Proper placental development is essential for a healthy pregnancy. It depends on the remodeling of the maternal uterine vasculature to meet fetal demands while maintaining physiological intervillous space (IVS) hemodynamics for biochemical exchange. Terminal villi, the primary sites of feto-maternal exchange, exhibit impaired development in pregnancies complicated by intrauterine growth restriction and preeclampsia, which are also associated with incomplete spiral artery (SA) remodeling. Despite this association, the mechanistic link between maternal blood flow and villous development remains unclear. Here, we investigate whether incomplete SA remodeling alters IVS hemodynamics and increases wall shear stress (WSS) on placental villi, potentially impairing terminal villi formation. Computing WSS throughout an entire placentone is challenging due to uncertainty in placental microstructure and the computational cost of resolving microscale hemodynamics. We propose a novel multiscale computational framework to quantify WSS on placental villi at the end of the second trimester, when WSS may affect terminal villi development. A macroscale placentone model is used to compute IVS velocities, which are coupled with microscale models of intermediate villi to estimate villous WSS across physiologically relevant flow conditions. We simulate IVS hemodynamics in healthy pregnancy and varying degrees of incomplete SA remodeling. Our results show that IVS velocity is the primary determinant of mean villous WSS, whereas villous type and orientation have comparatively weaker effects. In healthy placentones, most villi experience a mean WSS of 0.001-1 Pa, with higher stresses localized near the free-of-villi cavity. By correlating these estimates with regions naturally devoid of terminal villi, we identify a mean WSS range of approximately 0.71-1.44 Pa that may inhibit terminal villi formation. Incomplete SA remodeling significantly increases WSS, reaching levels consistent with villous tissue loss and placental lake formation. These findings suggest a mechanistic link between uteroplacental hemodynamics and villi development, establishing physiological shear-stress thresholds relevant to placental health.

DOI: https://doi.org/10.1371/journal.pcbi.1014769
Placenta. 2026 Sep 09. pii: S0143-4004(26)00674-0. [Epub ahead of print]

Biomechanical modelling of the feto-placental and utero-placental circulations; where to from here?

Sahan Jayatissa, Joanna L James, Alys R Clark.

  Biomechanical computational modelling has been used since the 1980s to understand the health of the placenta, and to interpret clinical imaging in pregnancy. In the last few decades, alongside rapid advances in computing power and imaging technologies, biomechanical computational models have been developed that enable researchers to link anatomy to function across temporal and spatial scales. Blood flow through the feto-placental or utero-placental circulations has been a key focus of many of these models, due to the functional importance of these dynamically linked circulations in facilitating exchange of nutrients, oxygen and wastes, and in turn ensuring healthy fetal growth. This review aims to analyse the current state-of-the-art biomechanical models of fetal and maternal blood flow in the placenta, including lumped parameter, computational fluid dynamics, and network models. We consider how different models have been parameterized by data from an array of imaging technologies, from in vivo ultrasound or magnetic resonance imaging, to ex vivo computed tomography and histology data. Building on this, we incorporate learnings from the wider field of cardiovascular biomechanics to suggest future focus areas to further improve the insight gained from computational modelling approaches in pregnancy, and improve future interpretation of diagnostic imaging in this setting.

Keywords:  Computational modelling; Fetal cardiovascular biomechanics; Feto-placental circulation; Materno-placental circulation; Placenta; Vascular biomechanics

DOI:  https://doi.org/10.1016/j.placenta.2026.08.341
Cell Prolif. 2026 Sep 18. e70280

Derivation of Mouse Dome-Shaped Trophoblast Stem Cells With Low Heterogeneity From Blastocysts.

Minli Liu, Shaofang Ren, Xinyu Xia, Guanlin Lu, Haojie Yang, Yi Zheng, Jiexiang Zhao, Xiao-Yang Zhao, Mei Wang.

  Trophoblast stem cells (TSCs) have emerged as a valuable model for investigating placentation and related disorders. Despite their ability to be maintained over multiple passages without losing stemness, conventional TSCs are characterised by notorious heterogeneity and a spontaneous differentiation tendency. In this study, we established a type of mouse TSCs with dome-shaped colonies (dTSCs). The dTSCs expressed canonical markers of conventional TSCs and exhibited relatively low levels of heterogeneity and spontaneous differentiation when cultured in conventional trophoblast stem cell medium. Additionally, dTSCs retained robust potential to differentiate into all trophoblast lineages in vitro, as well as the capacity to contribute to placental development in vivo. Furthermore, the functions of Foxo4 and Slc16a3 (MCT4) could be effectively explored in trophoblast development by using our established dTSCs. Collectively, our findings establish a type of high-quality TSCs and define dTSCs as a promising and refined model for investigating trophoblast development.

Keywords:  differentiation; heterogeneity; mouse; placenta; trophoblast; trophoblast stem cells

DOI:  https://doi.org/10.1111/cpr.70280
Methods Mol Biol. 2027 ;3074 301-316

Mapping Stage-Specific Enhancer Dynamics During the Specification of Human Trophoblast Lineage.

Joonhyuk Choi, Qingqing Guo, Jonghwan Kim.

  Chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) is a powerful technique for mapping cis-acting regulatory elements in DNA regions, such as enhancers and promoters, that are associated with specific histone modification marks or bound by transcription factors (TFs). By systematically mapping enhancer landscapes across various cell types or differentiation trajectories, this methodology facilitates the discovery of highly regulated genes specific to certain cell types, as well as the underlying transcriptional and epigenetic regulatory mechanisms that establish cellular identity and function. Particular emphasis has been placed on mapping large clusters of enhancers known as super-enhancers (SEs), which are often associated with cell-type-specific master TFs. Unlike typical enhancers, SEs can help to identify previously unknown key TFs specific to certain cell types. Follow-up studies can systematically validate these master regulators and their mechanisms of action, providing a comprehensive framework for deciphering the regulatory architecture underlying cellular identity. This protocol outlines how to map dynamic changes in enhancer and SE usage during human trophoblast differentiation using human trophoblast stem cells (TSCs) and their subsequent differentiation into more specialized cell types.

Keywords:  Enhancer mapping; Stem cells; Super-enhancers; Transcription factors; Trophoblasts

DOI:  https://doi.org/10.1007/978-1-0716-5539-9_18
Nutrients. 2026 Aug 26. pii: 2785. [Epub ahead of print]18(17):

Folate Deficiency Alters microRNA Expression and Transcriptomic Networks in a Human Trophoblast Model.

Bernadette C Baker, Georgia Fakonti, Abigail R Byford, Fiona L Mackie, Samantha C Lean, Ainslie Garrod, Lucy Poffley, Leo A H Zeef, Susan L Greenwood, Alexander E P Heazell, Rebecca L Jones, Karen Forbes.

  Background: Low maternal folate status is associated with placental dysfunction and adverse pregnancy outcomes; however, the mechanisms linking reduced folate availability to altered placental function remain incompletely understood. We investigated whether folate deficiency directly alters trophoblast function and microRNA (miRNA) expression, and whether folate-responsive miRNAs mediate these functional changes. Methods and Results: Human placental villous explants, BeWo choriocarcinoma cells, and primary human cytotrophoblasts were cultured under physiological or folate-deficient conditions to assess the direct impact of reduced folate availability. Although intracellular folate depletion was achieved in all models, only primary cytotrophoblasts reproduced functional changes consistent with those observed in placentas from folate-deficient pregnancies, exhibiting increased apoptosis and reduced system A amino acid transport. Of sixteen miRNAs previously associated with low maternal folate status, miR-30e-3p and miR-34b-5p were significantly reduced in trophoblast following folate depletion. Targeted inhibition of either miRNA did not alter apoptosis or system A activity. Pathway analysis of differentially expressed genes following miRNA inhibition identified processes related to cytoskeletal organisation, cell adhesion, PI3K/AKT and MAPK signalling. Conclusions: Folate deficiency directly impairs trophoblast survival, amino acid transport, and miRNA expression in primary trophoblasts. Our findings demonstrate that only a subset of folate-associated placental miRNAs respond directly to folate depletion and that inhibition of individual folate-responsive miRNAs is insufficient to reproduce the trophoblast phenotype. These results indicate that trophoblast adaptation to reduced folate availability is likely mediated through coordinated nutrient-sensitive regulatory networks rather than individual miRNAs acting in isolation.

Keywords:  folate; functional enrichment analysis; microRNA; nutrition; placenta

DOI:  https://doi.org/10.3390/nu18172785
Biol Reprod. 2026 Sep 17. pii: ioag201. [Epub ahead of print]

Segmentation of placental tissue using immunofluorescent staining and an artificial intelligence-based analysis workflow.

Rebecca Reif, Stephanie K Yanow, Denise G Hemmings.

  The placenta continuously remodels in response to maternal and fetal signals, with proteins dynamically regulated across placental regions. However, methods to evaluate proteins within these distinct regions are limited. To address this, we developed a placental tissue classifier to segment regions corresponding to the villous core, villous trophoblast (VT) and the intervillous space (IVS) using HALO AI imaging analysis. Tissue sections of biopsies from human term placentas embedded in OCT or paraffin (FFPE) were stained by immunofluorescence with antibodies to placental alkaline phosphatase (PLAP), syndecan-1 (SDC-1), vimentin or E-cadherin. The placental tissue classifier was trained using PLAP and DAPI staining with distinct image-feature patterns to distinguish VT from the villous core and the IVS on stained sections. The accuracy of HALO to measure area and intensity of staining in classified regions was demonstrated by staining for SDC-1 on VT and vimentin on stromal cells. As expected, SDC-1 staining was low in the villous core, and higher on VT than in the IVS, whereas vimentin staining was only detected in the villous core. By applying this analysis method to images collected by whole slide scanning microscopy, the area of staining was increased 245 times compared to a single field of view, which increases the probability of detecting pathological changes in different regions of the placenta. The advantages of using this validated classifier are the speed and accuracy of analysis across large tissue areas, the flexibility to detect other cell types, and to expand to single villi analysis.

Keywords:  Image analysis; Intervillous space; Placenta; Syncytiotrophoblast; Tissue classifier

DOI:  https://doi.org/10.1093/biolre/ioag201
Front Endocrinol (Lausanne). 2026 ;17 1899767

The placental maturation inflection point: an integrative biological framework for understanding early-onset versus late-onset preeclampsia.

Ho Yen Chueh, Chia Lin Chang.

   Background: Preeclampsia (PE) is clinically classified into early-onset (EOPE, <34 weeks) and late-onset (LOPE, ≥34 weeks) phenotypes that differ in epidemiology, angiogenic profiles, and outcomes. Although the 34-week cutoff is widely adopted, its biological rationale remains formally unarticulated in terms of placental developmental biology.
Objective: To propose and evaluate the Placental Maturation Inflection Point (PMIP) - the transition from parenchymal expansion (Phase I) to functional optimization (Phase II) at approximately 34-36 weeks - as an integrative biological framework explaining the EOPE/LOPE phenotype division. The PMIP is conceptualized as a distributed developmental transition zone (~30-36 weeks) rather than a discrete biological event at a single gestational age.
Methods: Narrative synthesis integrating evidence from placental morphometry, villous stereology, molecular trophoblast biology, endocrine and angiogenic biomarkers, imaging, and senescence biology, with structured engagement of competing frameworks.
Results: Seven converging, partly interrelated lines of evidence may identify a placental developmental transition zone spanning ~34-36 weeks: (1) volumetric growth deceleration on MRI; (2) vasculosyncytial membrane attenuation and terminal villus predominance by stereology; (3) molecular regulators of syncytialization (p45 NF-E2, GCM1, Syncytin-1) showing trajectory shifts consistent with maturation; (4) human placental lactogen (hPL) near-plateau at ~34 weeks, reflecting maximal syncytiotrophoblast mass; (5) placental growth factor (PlGF) peak at ~30 weeks and subsequent soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio shift; (6) placental calcification accelerating after the 36-week Grannum threshold; and (7) differential senescence and stress-pathway activation in EOPE versus LOPE. Evidence strength varies across pillars and is graded explicitly. No prior framework has anchored the 34-week cutoff to a convergent multi-domain placental developmental transition.
Conclusions: The PMIP offers a biologically plausible framework for understanding why the 34-week cutoff has proven clinically productive. Within this hypothesis, EOPE reflects a pattern consistent with arrested Phase I, in which defective placentation may prevent functional maturity, whereas many LOPE cases may arise in the setting of a relatively mature placenta whose capacity is exceeded by maternal demand. Mixed phenotypes are expected; EOPE evidence is multi-stranded while LOPE evidence rests primarily on one molecular comparison and absence-of-pathology inference. This framework has implications for biomarker interpretation, therapeutic windows, and trial design.

Keywords:  early-onset; human placental lactogen; late-onset; placental maturation; placental senescence; preeclampsia; sFlt-1/PlGF ratio; vasculosyncytial membrane

DOI:  https://doi.org/10.3389/fendo.2026.1899767
J Appl Physiol (1985). 2026 Sep 14.

Exploring the Placental Lipidome in Physically Active vs. Inactive Pregnancies.

Meaghan L MacDonald, Anahita Yadegari, Justine T Chittaro, Arthur Dantas, Karl Wasslen, Christian A Rosales, Jane Shearer, Leanne M Redman, Jeff Smith, Kristi B Adamo.

  Physical activity during pregnancy is highly beneficial, but the mechanisms underlying these benefits have not been elucidated. Given its central role in supporting pregnancy, the placenta is a primary target for investigation. We implemented untargeted lipidomic analysis on 36 human placenta samples collected at term from uncomplicated pregnancies. Participant activity levels were objectively measured using accelerometry and participants were categorized as active or inactive. Samples were assessed by LC-MS/MS. The docosahexaenoic acid (DHA) transporter major facilitator superfamily domain-containing 2a (MFSD2a) was analyzed with western blot. A total of 192 lipids were annotated. Among these, 34 lipid species differed significantly between groups (|log2FC| ≥ 0.58; FDR-adjusted p value < 0.05). Multivariate analyses demonstrated modest separation between groups. DHA was identified in 17 lipid species, and seven were higher in the active group. Area under the receiver operating characteristic curve (AUROC) revealed five lipids with perfect group separation. Pathway analysis showed enrichment of the phosphatidylserine decarboxylase (PISD) pathway in the active group. No differences in MFSD2a expression were identified. The results demonstrate a relationship between physical activity and the placental lipidome. Several DHA species are higher in the active group, suggesting improved fetal availability for brain and retinal development. Lipids with perfect group separation may represent biomarkers of physical activity. Multiple lipid species and pathways warranting future targeted investigation are highlighted.

Keywords:  lipidomics; physical activity; placenta; pregnancy

DOI:  https://doi.org/10.1152/japplphysiol.00357.2026