bims-placeb 2026-06-14 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2026–06–14
sixteen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Development of a robust method to derive human trophoblast stem cells from late-gestation placentas and its application to preeclampsia.
Protein N-glycosylation supports extravillous trophoblast cell lineage development in hypoxia microenvironment.
Single-cell transcriptomics reveals differences between chorionic and basal plate cytotrophoblasts and 2D-cultured trophoblast stem cells.
The Aryl Hydrocarbon Receptor spectrum in the human placenta: from development to environmental sensing and disease.
Protocol to derive human trophoblast stem cells directly from primed pluripotent stem cells.
TMEM63B regulates nucleocytoplasmic transport and placental development.
A functional placenta-on-chip model for maternal-fetal transport.
Regulation of trophoblast fusion dysfunction in preeclampsia by the NCK1/EIF3D/PPARG axis.
Integrative Proteomic and In Silico Analysis of Perfluorooctanoic Acid Exposures in Primary Human Placental Cytotrophoblasts.
IAPEz retrotransposons regulate the first lineage segregation in mouse pre-implantation development.
Contrast-agent-free visualization of murine embryo-placental vasculature with ultrafast plane-wave ultrasound.
The placental metabolic clock.
Fetal growth is driven by a bimodal fetal beta cell response and reshaped by a ketogenic diet in a mouse model of maternal diabetes.
Two distinct causes contribute to the low efficiency of human pre-implantation development.
Independent and synergistic effects of maternal and paternal obesogenic diets on offspring early-life outcomes in the rat.
Analysis of blastocyst morphokinetics assessed by time-lapse technology and its correlation with human IVF treatment outcome.

Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2537884123

Development of a robust method to derive human trophoblast stem cells from late-gestation placentas and its application to preeclampsia.

Akira Oike, Eri H Kobayashi, Yasuhiro Yamamoto, Hirotaka Hamada, Sota Takahashi, Takanori Shimizu, Akane Kitamura, Asato Sekiya, Norio Kobayashi, Shun Shibata, Shun Endo, Tetsuya Sato, Naoto Kubota, Chie Kikutake, Mikita Suyama, Takahiro Arima, Hiroaki Okae.

  Trophoblasts are multifunctional cells in the placenta and essential for normal pregnancy. Although trophoblast dysfunction can cause pregnancy complications, the underlying mechanisms remain unclear, and effective treatments are limited, partly because of the scarcity of appropriate experimental models. We previously reported the derivation of human trophoblast stem cells (hTSCs) from 1st-trimester placentas and blastocysts, providing a powerful tool to investigate human trophoblast development and function. However, the difficulty in deriving hTSCs from late-gestation placentas has limited their application to pregnancy complication research. Here we report a robust technique to derive hTSCs from term placentas based on the transient expression of a p53 dominant negative mutant, SALL4, and shRNAs against cyclin-dependent kinase inhibitors. Using this technique, we derived and characterized hTSCs from placentas obtained from patients with early-onset preeclampsia (PE). PE-derived hTSCs exhibit impaired trophoblast invasion and reduced placental growth factor secretion, consistent with trophoblast abnormalities reported in PE. Therefore, this study provides a technological basis for investigating pregnancy complications associated with trophoblast dysfunction.

Keywords:  human placenta; preeclampsia; pregnancy complications; trophoblast stem cells

DOI:  https://doi.org/10.1073/pnas.2537884123
Life Sci. 2026 Jun 10. pii: S0024-3205(26)00327-9. [Epub ahead of print] 124518

Protein N-glycosylation supports extravillous trophoblast cell lineage development in hypoxia microenvironment.

Lijie Cao, Yaqi Wang, Linlin Ruan, Hao Chen, Songtao Yang, Jiaqi Xu, Hongyin Ma, Xin Luo, Youlong Xie, Enxiang Chen, Yubin Ding, Jing Tang.

  Extravillous trophoblasts (EVT) are essential for placental invasion into the maternal decidua and spiral artery remodeling, ensuring a successful pregnancy. It is well-established that early placental development occurs under physiologically hypoxic conditions (~2% O2), while the later stages proceed under increased physiological oxygen levels (~8% O2). However, the heterogeneity of EVT across these distinct developmental conditions remains poorly characterized. Moreover, the molecular mechanisms governing EVT lineage development and function under low oxygen conditions remain largely elusive. Herein, we systematically characterize the transcriptome dynamics underlying the differentiation of cytotrophoblasts (VCT) and human trophoblast stem cells (hTSC) into EVT at single-cell resolution. Our analysis reveals pronounced functional and phenotypic heterogeneity among EVT from early versus late gestational stages, as well as between in vivo and in vitro models. We demonstrate that oxygen tension is a pivotal factor driving EVT heterogeneity, giving rise to distinct subtypes with invasive/migratory and secretory potentials. Furthermore, we elucidate that hypoxia impairs EVT lineage development from hTSC in vitro. Hypoxia reduces intracellular UDP-N-acetyl-d-glucosamine (UDP-GlcNAc) level, thereby possibly disrupting protein N-glycosylation. We further demonstrate that N-glycosylation pathway activity is significantly elevated during the differentiation of hTSC into EVT, as pharmacological inhibition with tunicamycin (TM) completely blocks this process. UDP-GlcNAc supplementation rescues the EVT differentiation defect under hypoxia, demonstrating that protein N-glycosylation is essential for EVT lineage commitment under low oxygen conditions. Our findings uncover a hypoxia-sensitive glycosylation in EVT development and provide new insights into early placental development.

Keywords:  Cell differentiation; Extravillous trophoblast; Human trophoblast stem cells; Hypoxia; Protein N-glycosylation

DOI:  https://doi.org/10.1016/j.lfs.2026.124518
Commun Biol. 2026 Jun 10.

Single-cell transcriptomics reveals differences between chorionic and basal plate cytotrophoblasts and 2D-cultured trophoblast stem cells.

Robert Morey, Francesca Soncin, Sampada Kallol, Nirvay Sah, Zoe Manalo, Tony Anh Bui, Jaroslav Slamecka, Virginia Chu Cheung, Donald Pizzo, Daniela F Requena, Ching-Wen Chang, Omar Farah, Ryan Kittle, Kelly Lam, Morgan Meads, Mariko Horii, Kathleen M Fisch, Mana M Parast.

Cytotrophoblast (CTB) of the early gestation human placenta are bipotent progenitor epithelial cells, which can differentiate into invasive extravillous trophoblast (EVT) and multinucleated syncytiotrophoblast (STB). Trophoblast stem cells (TSC), derived from early first trimester placentas, have also been shown to be bipotential; however, their cell-of-origin has not been identified. In this study, we set out to probe the transcriptional diversity of early and late first trimester villous CTB (vCTB) and compare these to TSC. To this end, we performed single-cell RNA sequencing (scRNA-seq) on placental villous tissue from early (6-8 weeks) and late (12-14 weeks) first trimester placentas; we also evaluated CTB within basal (maternal) and chorionic (fetal) regions of early first trimester placenta, both by scRNA-seq and GeoMx-based spatial transcriptomics. Finally, we performed scRNA-seq on three TSC lines, derived from 6-8 week gestation placentas, as well as on early first trimester CTB at several timepoints during TSC derivation. We observed differences within CTB clusters associated with gestational age, further influenced by location near the basal or chorionic plates. We identified trophoblast states representing "initial state" vCTB (in vivo CTB progenitors), as well as additional CTB subtypes, precursor STB, and precursor and mature EVT. CTB progenitors appeared enriched in early first trimester placentas at the basal plate; additionally, basal plate CTB showed transcriptional features consistent with EVT bias, whereas chorionic plate CTB showed features associated with STB precursors. Clustering and trajectory inference analysis indicated that TSC were most like EVT precursor cells. In fact, vCTB lost their in vivo "initial state" markers, including PAGE4, as they transitioned to TSC during in vitro culture. This was confirmed by flow cytometric analysis of 6 different TSC lines, which showed uniform expression of proximal column markers ITGA2 and ITGA5. Additionally, we found that ITGA5+ CTB could be plated in 2D, readily differentiating only into EVT in the absence of lineage-directed cues, but failed to form self-renewing organoids; conversely, ITGA5- CTB could not be plated in 2D, but readily formed organoids. Our findings suggest that distinct CTB states exist in different regions of the placenta as early as six weeks gestation and that current TSC lines most closely resemble ITGA5+ proximal column trophoblast, biased toward the EVT lineage.

DOI: https://doi.org/10.1038/s42003-026-10460-0
Environ Res. 2026 Jun 09. pii: S0013-9351(26)01290-9. [Epub ahead of print] 124959

The Aryl Hydrocarbon Receptor spectrum in the human placenta: from development to environmental sensing and disease.

Romane Person, Gaëlle Deval, Ioana Ferecatu, Xavier Coumoul.

  While xenobiotic receptors biology is well characterized in organs such as the liver and the intestine, it remains poorly explored in the placenta. As an exchange interface, the human placenta tightly regulates the transfer of endogenous and exogenous compounds between maternal and fetal circulations, through the coordinated expression of multiple transporters and metabolizing enzymes. These processes can be regulated by xenosensors such as the Aryl hydrocarbon Receptor (AhR), a transcription factor whose placental expression and activity significantly increase along pregnancy. AhR is a highly plastic multifunctional receptor, capable of binding various xenobiotics and endogenous compounds present in maternal blood and of activating a multitude of pathways, including xenobiotic metabolism, cell invasion, apoptosis, immunity and steroidogenesis. This review synthetises literature evidences supporting a key role of AhR in human placental development and functions throughout pregnancy. In line with the concept of the developmental origin of health and diseases (DOHaD), inappropriate non-physiological activation of AhR signaling could draw a bridge between in utero environmental exposures and adverse pregnancy outcomes. Epidemiologic and mechanistic clues pointing to a dysregulation of AhR pathways in various placental pathologies, including recurrent miscarriage, intra-uterine growth restriction (IUGR) and preeclampsia, emphasise the crucial role for this receptor during pregnancy and gives way to new clinical and therapeutic hypotheses.

Keywords:  Barrier functions; Early life exposure; Endocrine disruption; Environmental signaling; Maternal-fetal communication; Trophoblast; Xenobiotic receptor

DOI:  https://doi.org/10.1016/j.envres.2026.124959
STAR Protoc. 2026 Jun 09. pii: S2666-1667(26)00290-X. [Epub ahead of print]7(2): 104637

Protocol to derive human trophoblast stem cells directly from primed pluripotent stem cells.

Yanxing Wei, Lu Xiao, Lishi Ma, Zhijian Wang, Liping Huang, Huiying Li, Guangjin Pan, Stephen J Lye, Yongli Shan.

DOI: https://doi.org/10.1016/j.xpro.2026.104637
Nat Commun. 2026 Jun 08.

TMEM63B regulates nucleocytoplasmic transport and placental development.

Mengya Cai, Ruijia Lai, Wanshan Zheng, Jianmin Huang, Kun Cao, Xiang Liu, Bin Cao, Yang Zhang.

The placental development requires coordinated trophoblast proliferation and differentiation, processes tightly coupled to cell cycle control. Here, we identify TMEM63B, an osmo/mechano-sensitive ion channel, as a key regulator of trophoblast cell cycle progression and placental development. TMEM63B modulates nucleocytoplasmic transport (NCT) by stabilizing NCT components, which govern the nuclear shuttling of key cell cycle regulators in response to osmo/mechanical cues. Loss of TMEM63B compromises Ran protein expression and Ran-XPO1 complex, impairing the nuclear export of CDKN1A/p21. This disruption leads to defective trophoblast proliferation, placental dysfunction, and ultimately perinatal lethality. Our findings establish TMEM63B as a pivotal osmo/mechano-sensitive molecule that regulates nucleocytoplasmic shuttling, providing new insights into how mechanical cues are integrated into nuclear mechanoresponses and placental development.

DOI: https://doi.org/10.1038/s41467-026-73992-3
Biofabrication. 2026 Jun 10.

A functional placenta-on-chip model for maternal-fetal transport.

Anshul Bhide, Sourav Mukherjee, Kinjalka Ghosh, Abhijit Majumder, Deepak Modi.

  The human placenta functions as a highly specialised barrier that integrates trophoblast differentiation, endocrine activity, and regulated transport of molecules to sustain fetal development. Experimental interrogation of placental barrier function remains challenging due to limited access to human placental tissue and the complexity of existing in vitro models. Here, we report a static, two-chamber placenta-on-chip platform designed to recapitulate key structural and functional attributes of the human placental barrier within an experimentally accessible format. The device design prioritises open maternal compartmentalisation and diffusion-dominated transport, reflecting the haemochorial nature of human placentation. It also remains compatible with standard multi-well plate formats for parallel experimentation. In this two-chambered device, separated by an extracellular matrix-loaded/coated microporous membrane, the trophoblast supports trophoblast syncytialisation, sustained β-human chorionic gonadotropin secretion, and selective barrier function. The engineered barrier restricts macromolecular transport while permitting controlled diffusion of small solutes. Glucose transport across the device is strongly dependent on cellular configuration, with inclusion of the endothelial layer significantly modulating nutrient flux and yielding fetal-to-maternal glucose ratios comparable to those reported in vivo. The platform further supports directional transfer of urea from the fetal to the maternal compartment, demonstrating bidirectional metabolite exchange relevant to placental waste clearance. Under hyperglycemic conditions, glucose transport across the barrier increases without evidence of barrier breakdown, indicating sensitivity to metabolic perturbation. This scalable design of a placenta-on-chip platform provides a robust framework for studying placental transport, metabolic regulation, and barrier integrity. It offers broad application in placental biology, pregnancy-associated pathologies, and screening for pregnancy-safe drugs.

Keywords:  Human Placental Barrier; Maternal-fetal interface; Non-Animal Model (NAM); Organ-On-chip; Placenta-on-chip; Static diffusion model

DOI:  https://doi.org/10.1088/1758-5090/ae7bc8
Biol Res. 2026 Jun 10.

Regulation of trophoblast fusion dysfunction in preeclampsia by the NCK1/EIF3D/PPARG axis.

Ying Shen, Xiaolin Gao, Jiashi Wang, Yingying Hao.

   BACKGROUND: Abnormal syncytialization of cytotrophoblast (CTB) cells is known to be associated with preeclampsia (PE), however, the underlying molecular mechanisms remain elusive.
RESULTS: In this study, proteomic analysis of placental tissues was performed to identify proteins involved in PE pathogenesis. NCK Adaptor Protein 1 (NCK1) was found to be downregulated in placental tissues from patients with early-onset PE. In vitro functional assays revealed that NCK1 was markedly increased during spontaneous syncytialization of CTB cells. NCK1 overexpression alleviated hypoxia-induced defects in CTB cell fusion. Mechanistically, NCK1 upregulated both the expression and stability of Peroxisome Proliferator-Activated Receptor Gamma (PPARG), accompanied by increased m6A modification of its mRNA. Overexpression of PPARG significantly rescued hypoxia-induced syncytialization impairment, whereas PPARG deficiency abolished the promotive effects of NCK1 on CTB syncytialization. Additionally, phosphorylation of Eukaryotic Translation Initiation Factor 3 Subunit (EIF3D) was significantly increased during spontaneous syncytialization, and NCK1 overexpression partially reversed hypoxia-induced suppression of EIF3D phosphorylation. EIF3D knockdown significantly reduced m6A levels on PPARG mRNA, likely due to impaired NCK1-mediated suppression of Alpha-Ketoglutarate-Dependent Homolog 5 (ALKBH5), an m6A demethylase. Furthermore, NCK1 enhanced EIF3D phosphorylation by inhibiting its O-GlcNAcylation.
CONCLUSIONS: Our findings demonstrate that NCK1 stabilizes PPARG by modulating the crosstalk between O-GlcNAcylation and phosphorylation of EIF3D, thereby restoring hypoxia-impaired syncytialization in CTB cells. This study identifies the NCK1/EIF3D/PPARG axis as a molecular pathway potentially relevant to trophoblast fusion dysfunction in PE.

Keywords:  EIF3D; NCK1; O-GlcNAcylation; PPARG; Preeclampsia; m6A

DOI:  https://doi.org/10.1186/s40659-026-00704-y
Environ Sci Technol. 2026 Jun 10.

Integrative Proteomic and In Silico Analysis of Perfluorooctanoic Acid Exposures in Primary Human Placental Cytotrophoblasts.

Mengjing Wang, Hao Chen, Mirhan Kapidzic, Matthew Gormley, Sami Tuomivaara, Amanda M Gutierrez, Lin Li, Jessica Chen, Dimitri P Abrahamsson, Steven Hall, Nuno M S Almeida, Anatoly A Soshilov, Tracey J Woodruff, Susan J Fisher, Joshua F Robinson.

  Perfluorooctanoic acid (PFOA), a major persistent per- and polyfluoroalkyl substance (PFAS), remains ubiquitous in humans, including pregnant women, despite regulatory actions to limit its production and use. The placenta has been proposed as a target of PFOA, however, the underlying mechanisms remain poorly defined. We exposed primary human placental cytotrophoblasts (CTBs) isolated from three second-trimester placentas to PFOA (0.1-25 μM) for 48 h. SWATH-MS identified 3,240 proteins, 274 of which were differentially expressed. Proteins involved in lipid and amino acid metabolism and innate immunity pathways were significantly enriched among these targets. Integration of protein and mRNA data sets revealed key molecules linking PFOA exposure to altered immune defense and placental dysfunction. Molecular docking and dynamic simulations predicted that PFOA and other PFAS directly interact with master regulators, including peroxisome proliferator-activated receptors α and γ (PPARα, PPARγ) and novel targets such as signal transducer and activator of transcription 1/2 (STAT1, STAT2) and interferon regulatory factor 1/3 (IRF1, IRF3). Benchmark modeling indicated that significant protein-level changes can occur at concentrations relative to reported serum concentrations and associated with placental toxicity in rodents. We propose that PFOA and other PFAS directly interact with these candidate regulators, contributing to placental dysfunction.

Keywords:  Benchmark concentration modeling (BMC); Innate immune response; Lipid metabolism; Molecular docking; PPAR/STAT/IRF signaling; Perfluorooctanoic acid (PFOA); Placental cytotrophoblasts (CTBs); Proteomics (SWATH-MS)

DOI:  https://doi.org/10.1021/acs.est.5c12107
Nucleic Acids Res. 2026 Jun 08. pii: gkag577. [Epub ahead of print]54(11):

IAPEz retrotransposons regulate the first lineage segregation in mouse pre-implantation development.

Rujin Huang, Zhaoya Han, Zhongqi Liufu, Xiongzhi Quan, Danfeng Li, Hongzhi Dong, Guangliang Hong, Ruhai Chen, Man Zhang, Guangdun Peng, Duanqing Pei, Jiekai Chen, Jiangping He.

Transposable elements (TEs) comprise nearly half of mammalian genomes and drive species-specific regulatory innovation, but their contributions to the first lineage segregation-establishing trophectoderm versus inner cell mass (ICM)-remain largely unexplored. Here, we identify IAPEz, a rodent-specific retrotransposon, as a key regulator of this process in mouse pre-implantation embryos. IAPEz is highly expressed in the extraembryonic lineage but silenced in the ICM via H3K9me3-dependent heterochromatin. Genome-wide interaction analyses reveal that IAPEz physically contacts hundreds of trophectoderm-associated genes, repressing trophoblast programs in the ICM to ensure proper lineage allocation. CRISPR-mediated activation of IAPEz in embryonic stem cells accelerates direct conversion to trophoblast stem cells, while zygotic activation induces defective lineage specification at the morula stage. These findings highlight how repression of lineage-specific TEs orchestrates early embryonic fate decisions, offering insights into genome evolution and species-specific development.

DOI: https://doi.org/10.1093/nar/gkag577
Placenta. 2026 May 23. pii: S0143-4004(26)00188-8. [Epub ahead of print]

Contrast-agent-free visualization of murine embryo-placental vasculature with ultrafast plane-wave ultrasound.

Mark T Burgess, Orlando Aristizábal, Youssef Z Wadghiri, Jeffrey A Ketterling.

   BACKGROUND: In vivo assessment of the embryonic mouse placenta and vasculature is challenging, and ultrasound remains the most commonly used imaging modality. However, even with contrast agents, conventional preclinical ultrasound lacks the temporal resolution required to resolve complex vascular networks. Ultrafast Doppler methods offer a contrast-agent-free approach for visualizing embryonic placental and vascular flow.
METHODS: A 15-MHz linear array was used to acquire 0.5 sec of ultrafast ultrasound data at mouse embryonic day 13.5 (E13.5) using a semi-invasive, non-destructive preparation in which a single embryo within the uterine horn was imaged in vivo. Adjacent image planes were acquired at 0.25-mm spacing to generate a 3D dataset. The data were post-processed to produce power Doppler, color Doppler, and Doppler waveforms. Image data were also segmented to facilitate visualization of distinct organ systems, including the feto-placental vascular tree.
RESULTS: Ultrafast Doppler ultrasound provided greater detail of vascular flow than a 30-MHz preclinical ultrasound system. Power Doppler maps delineated the feto-placental vascular tree and the umbilical, vitelline, and yolk sac circulations. Color Doppler enabled visualization of pulsatile flow over nearly two cardiac cycles in vessels such as the vitelline artery. Following segmentation, flow within the aorta, heart, placental labyrinth, and umbilical vessels could be clearly distinguished.
CONCLUSION: Ultrafast Doppler ultrasound enables in vivo contrast-agent-free visualization of embryonic feto-placental circulation in the mouse. The method provides high-resolution vascular structural and dynamic flow information across the placenta, embryo, and uterus. This approach is well suited for longitudinal studies of embryonic and placental development.

Keywords:  3D ultrasound; Contrast-agent free; Embryonic vasculature; Mouse placenta; Ultrafast Doppler; Ultrasound

DOI:  https://doi.org/10.1016/j.placenta.2026.05.026
Science. 2026 Jun 11. 392(6803): 1128-1129

The placental metabolic clock.

Kiyoshi Yoshioka, Shin-Ichiro Imai.

NAD+ depletion triggers a countdown to birth in mice.

DOI: https://doi.org/10.1126/science.aei4119
Diabetologia. 2026 Jun 09.

Fetal growth is driven by a bimodal fetal beta cell response and reshaped by a ketogenic diet in a mouse model of maternal diabetes.

Omer Cohenshtam, Amnon Zung, Amy Yu, Hadar King, Polina Kotova, Ofer Gover, Itia Magenheim Samuel, Sarit Helman, Michael D Walker, Danny Ben-Zvi, Naama Kanarek, Aharon Helman.

   AIMS/HYPOTHESIS: Maternal diabetes confers two opposing risks to fetal growth, resulting in macrosomia in mild cases and intrauterine growth restriction (IUGR) in severe cases. The mechanisms governing these divergent responses are poorly understood, given the intimate regulation of insulin by glucose and insulin's fetal growth-promoting effects. We hypothesised that the degree of maternal hyperglycaemia dictates a bimodal pattern of fetal insulin secretion that determines fetal growth, and that use of a ketogenic diet (KD) as a nutritional intervention could modify this outcome.
METHODS: We used the Insulin-rtTA;TET-DTA mouse model to induce preconception diabetes. Dams were stratified based on maternal blood glucose, namely non-diabetes (glucose <9.6 mmol/l), mild diabetes (glucose range 9.6-16.7 mmol/l) or severe diabetes (glucose >16.7 mmol/l), and maintained on either a normal diet or a KD. We assessed fetal growth and plasma C-peptide, performed islet functional assays ex vivo, and characterised changes in plasma metabolites. Fetal pancreases were analysed by immunohistochemistry for beta cell area, proliferation, maturation and mechanistic target of rapamycin complex 1 (mTORC1) activity.
RESULTS: Mild maternal diabetes induced fetal macrosomia, driven by beta cell hyperplasia, hyperinsulinaemia and premature beta cell functional maturation, as reflected by glucose-stimulated insulin secretion and upregulated MafA expression. This was associated with strong activation of the mTORC1 pathway. In contrast, severe diabetes caused IUGR associated with reduced beta cell mass and profound functional impairment. The KD had divergent effects: it normalised fetal growth in the mild diabetes group by preventing beta cell proliferation and premature maturation, thereby reducing insulin secretion, but failed to rescue IUGR in the severe diabetes group, despite partially restoring beta cell function. Notably, the KD uncoupled the positive correlation between fetal insulin and body weight, revealing a primary, insulin-independent, growth-restrictive effect.
CONCLUSIONS/INTERPRETATION: Fetal growth in a mouse model of diabetes in pregnancy is governed by a bimodal beta cell response to the maternal glycaemic environment, orchestrated at the molecular level by the mTORC1 pathway. A KD can prevent diabetes-derived macrosomia by reducing beta cell stimulation and through insulin-independent mechanisms, but cannot reverse IUGR, warranting further studies of its role in diabetes during pregnancy.

Keywords:  Beta cell maturation; Fetal beta cell; Fetal growth; IUGR; Insulin secretion; Ketogenic diet; Macrosomia; Maternal diabetes; Pregnancy; mTORC1

DOI:  https://doi.org/10.1007/s00125-026-06771-w
Cell. 2026 Jun 11. pii: S0092-8674(26)00637-9. [Epub ahead of print]

Two distinct causes contribute to the low efficiency of human pre-implantation development.

Zixuan Li, Lizhi Leng, Jinglei Zhai, Xiaowen Wang, Wuling Yang, Shuhui Wang, Haifeng Wan, Shuoping Zhang, Fei Gong, Xi Liao, Yuhui Li, Qing Zeng, Yansu Chen, Zhenyu Xiang, Feiyao Liu, Fuchu He, Yun Yang, Hongmei Wang, Xiaoming Xu, Ge Lin, Chun So.

  ∼50% of fertilized eggs arrest during human pre-implantation development, representing a major bottleneck for assisted reproductive technology. The underlying causes remain controversial. By imaging ∼150 live human and monkey fertilized eggs for up to 5 days, we uncovered that the second mitotic divisions are the most error-prone, accounting for early embryonic arrest. Stochastic centriole overduplication, which could be effectively suppressed by transient treatment with PLK4 inhibitor centrinone, predisposed 2-cell blastomeres to assembling multipolar spindles and missegregating chromosomes. Missegregated chromosomes in turn resulted in the formation of most micronuclei in human embryos and led to the arrest or death of daughter blastomeres. By contrast, late embryonic arrest was largely independent of chromosome missegregations but involved the activation of endoplasmic reticulum stress response, which could impair the expression of subsets of junctional and cell polarity proteins required for blastocyst formation. Thus, two distinct causes contribute to the low efficiency of human pre-implantation development.

Keywords:  aneuploidy; centrosome; chromosome segregation; embryonic arrest; endoplasmic reticulum stress response; human embryo; long-term live-cell imaging; micronuclei; pre-implantation development; spindle

DOI:  https://doi.org/10.1016/j.cell.2026.05.037
Exp Physiol. 2026 Jun 12.

Independent and synergistic effects of maternal and paternal obesogenic diets on offspring early-life outcomes in the rat.

Khurram Jahangir Toor, Mehwish Abbasi, Swetha Muralidharan, Elisa Weiss, Elwyn C Firth, Anna P Ponnampalam, David S Musson, Mark H Vickers, Benjamin B Albert.

  Independent effects of maternal obesogenic diets on offspring outcomes are acknowledged, but data on paternal and combined maternal-paternal obesity remain limited. We investigated independent and combined maternal-paternal effects of an obesogenic (OB) high-fat, high-sugar diet on offspring outcomes. Male (pat) and female (mat) rats were fed a control diet (CON) or OB diet for 5 weeks pre-mating. Four groups were established: matCON-patCON, matCON-patOB, matOB-patCON and matOB-patOB. Offspring outcomes included birth weight and naso-anal length, survival rates to weaning, weaning weight, retroperitoneal fat mass and plasma leptin. Mating success was reduced in OB-exposed fathers. Male and female offspring from mothers fed the OB diet had lower birth weights. In males, birth weights were further reduced in the matOB-patOB group. Combined maternal-paternal obesity was also associated with shorter body length and higher neonatal mortality in offspring of both sexes. Postnatal survival was lower with maternal obesity and worsened with combined maternal-paternal obesity. At weaning, male offspring exposed to maternal or combined maternal-paternal obesity showed increased body weight, adiposity and plasma leptin concentrations. In females, body weight at weaning was higher across all parental obesogenic diet groups, and increased adiposity and plasma leptin concentrations were observed in maternal and combined maternal-paternal obesity. Parental obesity had independent, combined and sex-specific effects on early-life outcomes, most severe with combined maternal-paternal obesity. These findings emphasise the interacting role of maternal and paternal nutrition in shaping early-life outcomes and highlight the need for research to determine effective strategies to optimise the health of both parents prior to conception.

Keywords:  developmental programming; high fat; high sugar; maternal obesity; obesity; parental obesity; paternal obesity

DOI:  https://doi.org/10.1113/EP093885
Physiol Int. 2026 Jun 11. pii: 2060.2026.00830. [Epub ahead of print]

Analysis of blastocyst morphokinetics assessed by time-lapse technology and its correlation with human IVF treatment outcome.

Adrienn Zakár, Annamária Nemes, Kata Joó, Beáta Dudás, Éva Berkes-Bara, Anikó Árokszállási, Ákos Murber, János Urbancsek, Péter Fancsovits.

  Human embryo selection in in vitro fertilisation (IVF) treatments is traditionally based on evaluating cell number, morphology, and fragmentation to select the most viable embryos. However, this static evaluation method has limitations, as it captures only a snapshot of the embryo at a single time point. Recent advancements in time-lapse imaging and artificial intelligence (AI) have improved embryo assessment by enabling dynamic and continuous observation of embryonic development.This retrospective cohort study aimed to evaluate morphometric and morphokinetic parameters of 102 human embryos cultured during IVF cycles. Embryos were included if they reached the blastocyst stage on Day 5 and were selected for fresh single embryo transfer. Morphological and morphokinetic parameters were assessed using time-lapse technology to compare embryos resulting in clinical pregnancy and those that did not.Clinical pregnancy was achieved in 47.1% of transfers. Although no significant differences were observed in blastocyst area, diameter, or inner cell mass (ICM) size between embryos that implanted (P+) and those that did not (P-), trends toward larger dimensions were observed in the P+ group. Morphokinetic parameters showed slightly faster developmental kinetics in P+ embryos, although not significantly.Morphokinetic scores were calculated using time-lapse embryo evaluation systems (KIDScore D5 and iDAScore, Vitrolife). iDAScore values were significantly higher in implanted embryos. iDAScore, which incorporates AI-based scoring, showed better predictive performance compared with KIDScore in ROC and logistic regression analyses, indicating its potential as a reliable tool for embryo selection. These findings support the use of AI-based morphokinetic analysis for improved embryo selection in IVF.

Keywords:  IVF outcome; artificial intelligence; embryo morphokinetics; embryo morphology; human IVF

DOI:  https://doi.org/10.1556/2060.2026.00830