bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2026–04–12
fifteen papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. The cytoplasmic lattice in mammalian eggs sequesters ubiquitination machinery and tubulin in reserve.
  2. NLRP14 modulates the activity of E3 ubiquitin ligases during the oocyte-to-embryo transition.
  3. NFYA regulates two sequential genome-wide transcriptional activation events during oocyte to embryo transition.
  4. Regulation of DNA replication and 3D genome organization during early embryogenesis.
  5. ATF4-dependent upregulation of Bruno 1 remodels P-bodies to selectively protect mRNAs during ER stress throughout Drosophila melanogaster oogenesis.
  6. Maternal IntS11 primes embryonic totipotency by organizing early zygotic transcription initiation.
  7. PGC-derived migrasomes couple PGC proliferation with migration.
  8. Single-oocyte full-length isoform sequencing unveils the impact of transposable elements on RNA diversity and stability.
  9. SUMO mediates the coordinate regulation of meiotic chromosome length and crossover rate.
  10. Cell Migration Boundary Motion in Drosophila Egg Chambers: A Combined Phase Field and Chemoattractant Model.
  11. Establishment of DNA methylation during primate germ cell development.
  12. Extracellular matrix: new insights into its role in female reproductive aging and potential therapeutic strategies.
  13. A single-nucleotide enhancer mutation overrides chromosomal sex to drive XX male development.
  14. Dietary restriction shapes intergenerational ribosome abundance and early growth of Caenorhabditis elegans offspring.
  15. Single-cell spatiotemporal dissection of the human maternal-fetal interface.
  1. bioRxiv. 2026 Apr 01. pii: 2026.03.30.715190. [Epub ahead of print]
    The cytoplasmic lattice in mammalian eggs sequesters ubiquitination machinery and tubulin in reserve.
    Yujie Li, Wei Zheng, Jiyeon Leem, Chunxiang Wu, Shaogeng Tang, Binyam Mogessie, Yong Xiong.
      The cytoplasmic lattice (CPL) in mammalian eggs is essential for early embryonic development, but its molecular components, structural organization, and functional capacity have remained elusive. Here, using cryo-electron microscopy, we show that the CPL filament in mouse eggs contains repeating units with a periodicity of ∼37 nm, and determine its high-resolution, native structure and complete subunit composition. The CPL architecture organizes maternal-effect proteins, ubiquitination machinery, and tubulin into a highly structured reservoir. Maternal-effect proteins form the scaffold of the CPL to sequester a UBE2D-UHRF1 E2-E3 ubiquitination module and three distinct FBXW E3 ubiquitin ligases, notably all in activity-excluded states. The CPL further contains an αβ-tubulin heterodimer in a GTP-bound state with a calcium ion coordinated to α-tubulin, suggesting microtubule assembly-competent tubulin held in reserve. The CPL structure is capped at each end by a terminal unit that lacks a PADI6 dimer, a scaffold component, thereby preventing further oligomerization. Interactions between maternal-effect proteins in adjacent CPL units promote the assembly of a three-dimensional lattice in the egg cytoplasm. Taken together, our work defines how CPL assembly and architecture prime mammalian eggs for ubiquitin-mediated protein degradation and cytoskeletal remodeling during the egg-to-embryo transition.
    DOI:  https://doi.org/10.64898/2026.03.30.715190
  2. Nat Commun. 2026 Apr 08.
    NLRP14 modulates the activity of E3 ubiquitin ligases during the oocyte-to-embryo transition.
    Sibei Liu, Qianqian Qi, Pengliang Chi, Haizhan Jiao, Li Yan, Yuechao Lu, Rongrong Zhang, Jinhong Li, Sicheng Ju, Zhuo Han, Zihan Zhang, Qingting Liu, Guojin Ou, Jialu Li, Jing Chen, Xiang Wang, Lei Li, Li Guo, Xue Jiao, Hongli Hu, Yongmei Jiang, Dong Deng.
      NLRP14 is an essential maternal factor for mammalian embryonic development. Maternal ablation of NLRP14 in mice impairs DNA demethylation and calcium homeostasis in zygotes, causing early embryonic arrest. However, the underlying biochemical events remain largely unknown. Here, we identified two binding partners (KDM2A and UHRF1) of NLRP14 and further solved structures of NLRP14-KDM2A-SKP1 and NLRP14-UHRF1. Structural analysis revealed that NLRP14 modulates the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase and the RING-type E3 ubiquitin ligase UHRF1 through two distinct mechanisms. Mechanistically, NLRP14 competitively inhibits KDM2A-mediated SCF assembly or allosterically inhibits the activity of UHRF1 by occupying the E2 ubiquitin-conjugating enzyme (UBE2D) binding site of the ubiquitin-like (UBL) domain. Deletion of NLRP14 in mice increases ubiquitination levels in oocytes during maturation and after fertilization. Collectively, our findings identify NLRP14 as a dual regulator that restrains E3 ubiquitin ligase-driven ubiquitination by limiting SCF complex assembly and attenuating UHRF1 activity. This regulatory role is required to prevent excessive protein ubiquitination and maintain proteostasis during the oocyte-to-embryo transition, thereby supporting early embryonic development. Our study uncovers maternal regulation of proteostasis in oocytes and suggests that dysregulating proteostasis is an important factor in the pathogenesis of reproductive disorders.
    DOI:  https://doi.org/10.1038/s41467-026-71519-4
  3. bioRxiv. 2026 Apr 01. pii: 2026.03.30.715371. [Epub ahead of print]
    NFYA regulates two sequential genome-wide transcriptional activation events during oocyte to embryo transition.
    Qianying Yang, Shan Jiang, Boyan Wang, Yi Zhang.
      Primordial follicle oocyte activation (PFA) and zygotic genome activation (ZGA) represent two major waves of transcription activation respectively required for oocyte growth and preimplantation embryo development. Although many shared molecular hallmarks between PFA and ZGA suggest potential common factors and mechanisms driving both waves of transcriptional activation, such factors are yet to be identified. Here we demonstrate that the pioneer factor NFYA belongs to such regulators. Oocyte-specific Nfya deletion impairs open chromatin establishment and transcriptional activation during PFA, which triggers non-canonical ferroptosis leading to early folliculogenesis failure. Moreover, acute NFYA depletion in zygotes causes defective ZGA and predominantly two-cell embryo arrest. Mechanistically, although NFYA exhibits distinct chromatin-binding preferences predominantly targeting promoters during PFA and enhancers during ZGA, pre-occupied NFYA regulates chaperones and histone genes in both PFA and ZGA through conserved promoter binding. Together, our studies establish NFYA as a multifaceted regulator of genome activation during both PFA and ZGA.
    Highlights: NFYA deficiency impairs primordial follicle oocyte activation (PFA) and triggers non-canonical ferroptosis resulting in early folliculogenesis failureNFYA depletion impairs zygotic genome activation (ZGA) and causes predominantly 2-cell embryo arrestConserved and distinct NFYA-chromatin interactions drive both PFA and ZGAChaperones are pre-occupied and regulated by NFYA and their inhibition impairs both PFA and ZGA.
    DOI:  https://doi.org/10.64898/2026.03.30.715371
  4. Curr Opin Genet Dev. 2026 Apr 08. pii: S0959-437X(26)00036-5. [Epub ahead of print]98 102469
    Regulation of DNA replication and 3D genome organization during early embryogenesis.
    Ichiro Hiratani.
      Three-dimensional (3D) genome organization underlies virtually all DNA-based transactions. To fully appreciate its functional impact, we must first elucidate how it is established. DNA replication in early embryos offers a unique window into this process, as replication timing (RT) closely mirrors 3D genome architecture, which is absent at fertilization but progressively acquired during development. Here, recent single-cell studies of mouse embryos are synthesized, with a particular focus on how RT emerges during early post-fertilization development. The emerging picture suggests that a somatic-cell-like RT program arises shortly after zygotic genome activation (ZGA). This transition likely unfolds as a series of events, offering a valuable entry point for exploring the biological significance of 3D genome organization and understanding how diverse DNA-based processes are coordinated.
    DOI:  https://doi.org/10.1016/j.gde.2026.102469
  5. bioRxiv. 2026 Apr 05. pii: 2026.04.01.715972. [Epub ahead of print]
    ATF4-dependent upregulation of Bruno 1 remodels P-bodies to selectively protect mRNAs during ER stress throughout Drosophila melanogaster oogenesis.
    Samantha N Milano, Livia V Bayer, Julie J Ko, Gwendolyn S Posner, Albina H Granovsky, Diana P Bratu.
      P-bodies are cytoplasmic membraneless organelles involved in mRNA storage, yet their role in cellular stress responses remains poorly understood. Here, we demonstrate that P-bodies are rapidly and selectively remodeled during the early response to endoplasmic reticulum (ER) stress in D. melanogaster oogenesis, positioning them as key early stress responders. Notably, this remodeling occurs within minutes of stress induction and precedes stress granule formation. This early remodeling is characterized by changes in P-body morphology and internal organization and promotes selective mRNA regulation. Specifically, ER stress leads to the recruitment and stabilization of maternal mRNAs and those encoding P-body components, while transcripts not associated with P-bodies are degraded. These observations indicate that P-body remodeling is not merely structural but functionally linked to the selective preservation of mRNA populations during stress. Mechanistically, we find that this process is driven by transcriptional upregulation of the RNA-binding protein, Bruno 1, downstream of ATF4-dependent stress signaling, thereby establishing a direct connection between the unfolded protein response and condensate regulation. Consistent with this model, loss of Bruno 1 abolishes, whereas its overexpression enhances P-body remodeling, demonstrating that stress-induced changes in RNA binding protein levels can actively reprogram condensate properties. Together, our findings reveal that P-bodies function as dynamic, stress-responsive hubs that integrate transcriptional signaling with post-transcriptional control, enabling the selective preservation of essential mRNAs during ER stress. More broadly, this work uncovers a previously unrecognized mechanism by which stress signaling pathways reorganize cytoplasmic architecture to shape mRNA fate.
    DOI:  https://doi.org/10.64898/2026.04.01.715972
  6. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2531899123
    Maternal IntS11 primes embryonic totipotency by organizing early zygotic transcription initiation.
    Liangliang Wang, Yiru Wang, Yaqi Miao, Yuan Song, Jialiang Zhou, Yuanxiang Zhu, Ying Cheng, Wenxin Zhang, Qinmiao Sun, Fan Lai, Guoqiang Zhang, Dahua Chen.
      Zygotic genome activation (ZGA) marks the first transcriptional milestone and establishes embryonic totipotency. Although pioneer factors have been reported to initiate this process, how chromatin is primed for the totipotent state, allowing the binding of pioneer factors for successful ZGA, remains unclear. Here, we identify IntS11, the catalytic subunit of the Integrator complex, as a totipotent determinant of embryonic chromatin governing ZGA in Drosophila. We show that IntS11 functions upstream of pioneer factors in early embryos: Maternal IntS11 depletion substantially impairs RNA polymerase II (Pol II) recruitment, thereby preventing pioneer factors Zelda and GAGA factor (GAF) from accessing regulatory elements and initiating genome-wide zygotic transcription. Mechanistically, IntS11 exerts dual roles: its canonical endonuclease activity is required to sustain major-wave zygotic transcription, while a distinct enzyme-independent function drives de novo Pol II loading and pioneer factor engagement. These findings uncover a fundamental maternal-specific mechanism whereby IntS11 establishes transcriptional competence, ensuring totipotent chromatin states and successful ZGA.
    Keywords:  Drosophila; Integrator complex; early embryo; zygotic genome activation
    DOI:  https://doi.org/10.1073/pnas.2531899123
  7. Nat Commun. 2026 Apr 10.
    PGC-derived migrasomes couple PGC proliferation with migration.
    Boqi Liu, Zheng Jiang, Wenhao Song, Zhaocheng Zhai, Yaqi Li, Weiying Zhang, Anming Meng, Li Yu.
      The coordination of cell migration and proliferation is essential for embryogenesis and tissue homeostasis. However, the classical gradient signaling model is insufficient to explain how stable mitogenic signaling is maintained within migratory cells. Here, we reveal that primordial germ cells (PGCs) in zebrafish employ migrasomes-vesicular organelles formed during migration-to couple their proliferation with migration, ensuring germline expansion. Migrasomes, generated at retraction fibers via tspan7-dependent biogenesis, deliver the growth factor GDF3 specifically to neighboring PGCs through contact-dependent interactions. GDF3 activates the TGF-β receptor acvr1ba, driving proliferation in a spatiotemporally restricted manner. This homocrine signaling mechanism allows migrating PGCs to autonomously sustain proliferation, circumventing signal dilution in embryonic environments. This work uncovers migrasomes as a bridge linking migration and proliferation, with implications for understanding collective cell behaviors in development and disease.
    DOI:  https://doi.org/10.1038/s41467-026-71616-4
  8. Nat Commun. 2026 Apr 07.
    Single-oocyte full-length isoform sequencing unveils the impact of transposable elements on RNA diversity and stability.
    Yuqian Wang, Wei Wang, Yujun Liu, Yiming He, Hongyu Song, Ming Yang, Nan Wang, Xiaomeng Wang, Ling Ding, Ying Kuo, Yuwen Xiu, Zhengrong Du, Lu Chen, Ying Lian, Qiang Liu, Liying Yan, Jie Qiao, Peng Yuan.
      Oocyte-specific isoforms play crucial roles in oocyte maturation, while current understanding of the oocyte transcriptome is mainly focused on gene level. Here, we utilize single-cell full-length isoform sequencing to detect entire transcripts in human and mouse oocytes. Isoform diversity during oocyte maturation is systematically profiled, including 7154 and 4875 putative novel human and mouse transcripts, respectively. More than half of novel isoforms are categorized as novel-not-in-catalog (NNC) and may serve specific functions in oocytes. For example, ARHGAP18 mainly encoded by novel isoforms colocalizes with microtubules, and targeted knockdown of novel isoforms disrupts oocyte maturation. Moreover, approximately 30% of NNC isoforms are derived from transposable elements, and their incorporation within transcripts could enhance isoform stability during oocyte maturation. Altogether, our findings represent a valuable resource showcasing the complexity and diversity of RNA isoforms in oocytes, as well as transposable element co-option for novel isoform generation and isoform stability enhancement.
    DOI:  https://doi.org/10.1038/s41467-026-71425-9
  9. bioRxiv. 2026 Mar 11. pii: 2026.03.10.710713. [Epub ahead of print]
    SUMO mediates the coordinate regulation of meiotic chromosome length and crossover rate.
    Yan Yun, Huanyu Qiao, Martin White, Sumit Sandhu, Wendy Qiu, Sarah Bourne, Anusha Deshpande, Shubhang Bhatt, Ajay Sharma, Logan Bailey, Hung Tran, Ben Van, H B D Prasada Rao, Neil Hunter.
      Meiotic prophase-I chromosomes are organized into linear arrays of chromatin loops anchored to proteinaceous axes that define the interaction interfaces for the pairing and synapsis of homologous chromosomes. Chromatin loop size and axial chromosome length are inversely correlated and vary widely both between and within species, including between the sexes. The molecular basis of this variation remains unclear. Here, we provide evidence that the small ubiquitin-like modifier, SUMO, regulates loop-axis organization in mouse meiosis. Our analysis shows that the longer axes of oocyte chromosomes contain more SUMO per unit length than the shorter axes of spermatocyte chromosomes. In mouse models, the loss of SUMO1 results in shorter axes and longer chromatin loops. Conversely, increased SUMO1 conjugation, caused by mutation of the SENP1 isopeptidase, produces longer axes with shorter loops. Axis length positively correlates with meiotic recombination. Accordingly, Sumo1 and Senp1 mutations respectively decrease and increase crossover frequency. These findings identify SUMO as a key regulator of meiotic chromosome architecture and suggest a molecular basis for the physiological variation in chromosome length and recombination rates seen among species, sexes, individuals, and individual meiocytes.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.03.10.710713
  10. ArXiv. 2026 Apr 01. pii: arXiv:2604.01357v1. [Epub ahead of print]
    Cell Migration Boundary Motion in Drosophila Egg Chambers: A Combined Phase Field and Chemoattractant Model.
    Naghmeh Akhavan, Alexander George, Michelle Starz-Gaiano, Bradford E Peercy.
      In the Drosophila melanogaster egg chamber, the collective migration of border cells toward the oocyte is guided by spatial gradients of chemoattractants. While cellular responses to these cues are well characterized, the spatial distribution of chemoattractant within the tissue remains difficult to measure experimentally due to imaging limitations and extracellular complexity. In this study, we develop a spatially resolved mathematical framework to model local chemoattractant concentrations during border cell migration. We use a phase-field approach to represent the egg chamber geometry and define a diffusion-reaction system with spatially heterogeneous diffusivity that accounts for confinement by cellular domains. This framework allows chemoattractant diffusion to be restricted to extracellular space while remaining excluded from the interiors of nurse cells, the border cell cluster, and the oocyte, similar to what we observe in vivo. We simulate secretion from the oocyte and degradation throughout the domain, showing how geometry shapes the distribution of signaling molecules. We further couple this chemical field to a mechanical model of cluster migration that includes a tangential interface migration (TIM) force, allowing the cluster to respond to both chemoattractant gradients and cell-cell contact. Our results show that signal localization and tissue geometry jointly influence directional persistence and the speed of migration. Notably, geometric bottlenecks and intersections can flatten local gradients and slow migration, consistent with experimental observations. This modeling framework offers a tool to investigate how biophysical constraints shape signaling environments and guide collective cell movement in vivo.
  11. Nat Commun. 2026 Apr 08.
    Establishment of DNA methylation during primate germ cell development.
    Kazuaki Kojima, Yi Li, Shin-Ichi Tomizawa, Miho Kohara, Yuta Kuze, Takuya Sato, Toshinobu Ebata, Musashi Kubiura-Ichimaru, Mei Cao, Tatsuya Hattori, So Maezawa, Sofia B Winge, Kristian Almstrup, Ryo Nakaki, Shinya Sato, Yohei Miyagi, Yataro Daigo, Takako Yoshioka, Yuichi Hasegawa, Yoshiaki Kinoshita, Taiju Hyuga, Kimihiko Moriya, Hideyuki Kobayashi, Laurence Baskin, Tadashi Sankai, Toshiaki Watanabe.
      DNA methylation is almost completely erased throughout the genome in primordial germ cells, and then reestablished during mammalian germ cell development. In this study, we demonstrate that in three primate species-marmosets, macaques, and humans-de novo methylation occurs postnatally in prospermatogonia in males and growing oocytes in females. In monkey prospermatogonia, de novo methylation is a prolonged process spanning 6 months to 1 year, primarily occurring within the first year after birth. In human testes, this process may occur more slowly over an extended period. Single-cell bisulfite sequencing analyses in spermatogonia of three species revealed that all genomic regions acquire DNA methylation gradually. However, DNA methylation levels increase faster in genic regions compared to intergenic regions. Unlike in mice, mitotic divisions occur during the establishment of methylation in prospermatogonia. The established methylation is likely maintained because maintenance methyltransferase DNMT1 is specifically expressed during the mitotic stage. Our findings show notable differences in the de novo DNA methylation processes in male germ cells between mice and primates.
    DOI:  https://doi.org/10.1038/s41467-026-71405-z
  12. NPJ Aging. 2026 Apr 04.
    Extracellular matrix: new insights into its role in female reproductive aging and potential therapeutic strategies.
    Ning Lu, Jing Wang, Yi-Hui Li, Xu-Hui Fang, Yu-Ting Peng, Qing-Peng Luo, Ai-Hua Liao.
      Extracellular matrix (ECM), once regarded as a passive structural scaffold, is now recognized as a key hallmark of aging. In the context of female reproductive aging, ECM remodeling acts as a pivotal driver of functional deterioration. This review outlines how age-associated ECM alterations, including collagen cross-linking, elastin degradation, and perturbed biomechanics, orchestrate ovarian aging through the mechanical activation of Hippo signaling, compromise endometrial receptivity via dysregulated matrix metalloproteinase activity, and impair embryo invasion by altering ligand presentation. We also discuss emerging ECM-targeted strategies, such as decellularized scaffolds, engineered hydrogels, and 3D-bioprinted matrices, which have demonstrated potential for rejuvenating reproductive function in preclinical models. Furthermore, matrisome-based biomarkers provide novel prognostic insights into reproductive outcomes. Collectively, these advances identify the ECM as a promising target for innovative, non-hormonal interventions aimed at extending female reproductive longevity.
    DOI:  https://doi.org/10.1038/s41514-026-00371-z
  13. Nat Commun. 2026 Apr 09. pii: 3186. [Epub ahead of print]17(1):
    A single-nucleotide enhancer mutation overrides chromosomal sex to drive XX male development.
    Elisheva Abberbock, Meshi Ridnik, Isabelle Stévant, Roni Weiss, Carmel Bamberger, Shelly Ziv Lhermann, Maor Lubman, Yumi Minyi Yao, Ariel Afek, Francis Poulat, Nitzan Gonen.
      Mammalian sex determination is governed by two mutually antagonistic genetic programs that must be precisely balanced. Activation of Sox9 initiates testis development, while its repression is essential for ovarian fate. The distal enhancer, Enh13, is essential for testicular Sox9 expression, with its deletion or inactivation resulting in complete XY sex reversal. Here, we show that subtle mutations within Enh13, including a single-nucleotide insertion, produce the reciprocal phenotype: complete XX female-to-male sex reversal. Pro-female factors can strongly repress Enh13, suggesting they mediate Sox9 silencing in ovaries. The small enhancer alterations facilitate inappropriate Sox9 upregulation in the absence of Sry, triggering the testicular transcriptome and repressing ovarian gene expression. Mechanistically, these mutations disrupt the repressive effect of RUNX1, NR5A1 and GATA4, thereby reprogramming enhancer activity. Our findings identify Enh13 as a central regulatory hub, integrating opposing sex-specific cues, hence acting as a binary switch for gonadal fate.
    DOI:  https://doi.org/10.1038/s41467-026-71328-9
  14. PLoS Biol. 2026 Apr;24(4): e3003692
    Dietary restriction shapes intergenerational ribosome abundance and early growth of Caenorhabditis elegans offspring.
    Sigma Pradhan, Klement Stojanovski, Ferdinand Dellemann, Sacha Psalmon, Joel Tuomaala, Nicholas E Stroustrup, Benjamin D Towbin.
      Cells adjust their proteome to their environment. Most prominently, ribosome expression often scales near linearly with the cellular growth rate to provide sufficient translational capacity while preventing metabolically wasteful ribosomal excess. In microbes, such proteome adjustments can passively perpetuate through symmetric cell division. However, in animals, a passive propagation is hindered by the separation between soma and germline. This separation raises the question whether the proteome of animals is reset at every generation or can be propagated from parent to offspring across this barrier. We addressed this question for the intergenerational effects of dietary restriction in Caenorhabditis elegans, combining proteomics and live imaging. Under ad libitum feeding, the offspring of dietarily restricted mothers grew more slowly than progeny of well-fed mothers. However, this growth disparity was attenuated when mTORC1 signaling in the progeny was inhibited, creating conditions in which the protein-synthesis capacity at hatching is less limiting. Maternal inhibition of mTORC1 signaling, either ubiquitously or specifically in the pharynx, similarly reduced growth and ribosomal protein levels in offspring, whereas other growth-reducing perturbations, such as reduced insulin signaling or mTORC1 inhibition in the epidermis, did not reduce progeny ribosomal protein levels. We conclude that maternal physiology shapes ribosomal protein provisioning across the soma-germline boundary, thereby modulating early offspring growth in accordance with post-hatching ribosome demand.
    DOI:  https://doi.org/10.1371/journal.pbio.3003692
  15. Nature. 2026 Apr 08.
    Single-cell spatiotemporal dissection of the human maternal-fetal interface.
    Cheng Wang, Yan Zhou, Yuejun Wang, Tuhin Kumar Guha, Zhida Luo, Anxhela Mustafaraj, Tara I McIntyre, Marisa E Schwab, Brittany R Davidson, Gabriella C Reeder, Ronald J Wong, Sarah K England, Juan M Gonzalez, Robert Blelloch, Alexis J Combes, Linda C Giudice, Adrian Erlebacher, Tippi C MacKenzie, David K Stevenson, Gary M Shaw, Michael P Snyder, Xiaofei Sun, Virginia D Winn, Susan J Fisher, Jingjing Li.
      The human maternal-fetal interface is characterized by mosaic intermingling of maternal and fetal cells1. Yet the underlying cellular, molecular and spatial programmes remain incompletely defined. Here we generate a comprehensive atlas of the human maternal-fetal interface across normal pregnancies from early gestation to term by integrating large-scale paired single-nucleus transcriptomic and chromatin accessibility profiling with submicrometre-resolution spatial transcriptomics and CODEX multiplex protein imaging2, substantially boosting the spatiotemporal resolution of prior research3. This framework delineates common and transient cell types, states and spatial niches across the fetal and maternal compartments, reconstructs transcriptional programmes that guide cytotrophoblast and decidual stromal cell differentiation, and resolves recurrent architecture structural units that build this interface. We identify previously unrecognized arterial endothelial state transitions during cytotrophoblast-mediated spiral artery remodelling and develop a machine learning model that predicts cytotrophoblast invasiveness from transcriptomic signatures. We further discover a decidual stromal cell subtype that suppresses cytotrophoblast invasion via endocannabinoid signalling at the human maternal-fetal interface. By integrating the atlas with genome-wide association data, we pinpoint maternal and fetal cells that are most vulnerable to pre-eclampsia, preterm birth or miscarriage. This resource provides a comprehensive spatially resolved single-cell multiomic reference of the human placenta and decidua and offers a framework for decoding their normal and disordered development.
    DOI:  https://doi.org/10.1038/s41586-026-10316-x
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