bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2025–10–19
eleven papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. Genetic architecture and phenotypic diversity of oocyte and early embryo competence defects in female infertility.
  2. A continuous totipotent-like cell-based embryo model recapitulates mouse embryogenesis from zygotic genome activation to gastrulation.
  3. Vitamin C conveys geroprotection on primate ovaries.
  4. Codon Composition in Human Oocytes Reveals Age-Associated Defects in mRNA Decay.
  5. Long-term Culture of Human Primordial Germ Cell-like Cells.
  6. Cross-species insemination reveals mouse sperm ability to enter and cross the fish micropyle.
  7. Maternal age and genome-wide failure of meiotic recombination are associated with triploid conceptions in humans.
  8. Parental noncoding RNA expression dynamics across sperm, oocyte, and zygote.
  9. Tailor-made 3D in vitro maturation of early antral follicles uncovers cumulus-cell transcriptomic driver signature to predict oocyte competence.
  10. HIF1A-mediated pathways promote euploid cell survival in chromosomally mosaic embryos.
  11. Posterior pole of dermapteran oocytes houses a single aggregate of organelles reminiscent of endolysosomal vesicular assemblies described in mouse oocytes.
  1. Nat Med. 2025 Oct 16.
    Genetic architecture and phenotypic diversity of oocyte and early embryo competence defects in female infertility.
    Changlong Zhang, Wei Zheng, Honghui Zhang, Shuai Zhao, Huiling Hu, Xilin Xu, Xian Wan, Jiaqi Sun, Wei Su, Yang Wang, Ying Cui, Bohan Yang, Changjian Yin, Xin Zhang, Cheng Li, Xin Zhang, Changming Zhang, Zhao Wang, Ying Yuan, Liu Liu, Fei Meng, Jiangtao Zhang, Yongzhi Cao, Yuan Gao, Shigang Zhao, Fei Gong, Keliang Wu, Feng Zhang, Shuyan Tang, Ge Lin, Han Zhao, Zi-Jiang Chen.
      Oocyte and early embryo competence defects (OECD) represent a recently recognized cause of female infertility with the application of assisted reproductive technology, characterized by impaired oocyte or early embryo development. To investigate the genetic landscape and subtypes of OECD, we performed whole-exome sequencing on 2,140 patients, classifying them into six distinct subtypes. We identified 183 pathogenic/likely pathogenic variants across 28 established genes. Notably, distinct genetic profiles and diagnostic rates emerged across subtypes, with a rate of 53% in the Empty Follicle subtype. Additionally, we identified and validated two potentially causative genes, MLH3 and CENPH. Gene burden analysis, using 2,424 fertile controls, suggested nine potential previously unreported associated genes and offered biological insights into the underlying pathogenic mechanisms of OECD. Collectively, these genetic findings accounted for 12.8-23.1% of OECD cases. This study delineates the genetic architecture of OECD, offering insights that may inform the development of diagnostic genetic screenings and provide a reference for standardized subtyping of patients with OECD.
    DOI:  https://doi.org/10.1038/s41591-025-04001-1
  2. Nat Cell Biol. 2025 Oct 15.
    A continuous totipotent-like cell-based embryo model recapitulates mouse embryogenesis from zygotic genome activation to gastrulation.
    Yixuan Ren, Xuyang Wang, Haiyin Liu, Yaxing Xu, Ruoqi Cheng, Shengnan Ren, Zining Li, Yunfei Huo, Bo Li, Jingyang Guan, Cheng Li, Hongkui Deng, Jun Xu.
      The development of stem-cell-derived models of mammalian embryogenesis has provided invaluable tools for investigating embryo development. However, constructing embryo models that can continuously recapitulate the developmental trajectory, from zygotic genome activation to gastrulation, remains challenging. Here we report the development of a chemical cocktail to induce totipotent-like cells with robust proliferative ability and leverage these cells to establish a stepwise protocol for generating a continuous embryo model. This model sequentially mimics mouse embryogenesis from embryonic day 1.5 to 7.5. It recapitulates key developmental milestones, including zygotic genome activation in 2-cell embryos, the diversification of embryonic and extraembryonic lineages from 4-cell to 64-cell stages, the formation of blastocysts and the subsequent development into post-implantation egg cylinders. Notably, these structures undergo gastrulation, as indicated by the formation of a primitive streak-like structure and the subsequent emergence of several early organogenesis hallmarks. Our study opens avenues for modelling mammalian embryogenesis in vitro.
    DOI:  https://doi.org/10.1038/s41556-025-01793-9
  3. Cell Stem Cell. 2025 Oct 14. pii: S1934-5909(25)00339-X. [Epub ahead of print]
    Vitamin C conveys geroprotection on primate ovaries.
    Ying Jing, Huifen Lu, Jingyi Li, Zan He, Liyun Zhao, Chen Zhang, Ziqi Huang, Lixiao Liu, Shuhui Sun, Shuai Ma, Concepcion Rodriguez Esteban, Xiaobing Fu, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Si Wang, Guang-Hui Liu.
      Ovarian aging plays a pivotal role in female reproductive health, with implications for treatment strategies and quality of life. However, the potential of a single pharmaceutical agent to mitigate primate ovarian aging remains largely unexplored. Our 3.3-year study in monkeys demonstrates that oral vitamin C has geroprotective effects against ovarian aging. Vitamin C diminishes key aging biomarkers, including oxidative stress and follicular depletion. Using a single-cell transcriptomic clock, we show that vitamin C can reduce the biological age of oocytes by 1.35 years and somatic cells by 5.66 years. This effect is partly mediated by the NRF2 pathway, which alleviates ovarian cell senescence and inflammation. Our findings highlight the role of vitamin C in combating primate ovarian aging and provide insights for developing interventions against human ovarian aging.
    Keywords:  NRF2; aging; aging clock; antioxidant; inflammation; ovary; oxidative stress; primate; senescence; vitamin C
    DOI:  https://doi.org/10.1016/j.stem.2025.09.008
  4. Int J Mol Sci. 2025 Sep 26. pii: 9395. [Epub ahead of print]26(19):
    Codon Composition in Human Oocytes Reveals Age-Associated Defects in mRNA Decay.
    Pavla Brachova, Lane K Christenson, Nehemiah S Alvarez.
      Oocytes from women of advanced reproductive age exhibit diminished developmental potential, but the underlying mechanisms remain incompletely defined. Oocyte maturation depends on translational control of maternal mRNA synthesized during growth. We performed a computational analysis on human oocytes from women <30 versus ≥40 years and observed that mRNA GC content correlates negatively with half-life in oocytes from young (<30 yr) but positively with oocytes from aged (>40 yr) women. In young oocytes, longer mRNA half-life is associated with lower protein abundance, whereas in aged oocytes GC content correlates positively with protein abundance. During the GV-to-MII transition, codon composition stratifies stability: codons that support rapid translation (optimal) stabilize mRNA, while slow-translating codons (non-optimal) promote decay. With reproductive aging, GC-containing codons become more optimal and align with increased protein abundance. These findings indicate that reproductive aging remodels codon-optimality-linked, translation-coupled mRNA decay, stabilizing a subset of GC-rich maternal mRNA that may be prone to excess translation during maturation. Our analysis is explicitly within human reproductive aging; it does not revisit cross-species stability rules. Instead, it shows that sequence-stability relations are reprogrammed with age within human oocytes, including an inversion of the GC-stability association during GV-to-MII transition. Disruption of the normal mRNA clearance program in aged oocytes may compromise oocyte competence and alter maternal mRNA dosage, with downstream consequences for early embryonic development.
    Keywords:  GV-to-MII; codon optimality; maternal mRNA decay; oocyte; reproductive aging; translation
    DOI:  https://doi.org/10.3390/ijms26199395
  5. J Vis Exp. 2025 Sep 26.
    Long-term Culture of Human Primordial Germ Cell-like Cells.
    Keiko Shioda, Mutsumi Kobayashi, Misato Kobayashi, Junko Odajima, Hikari Hagihara, Yoko Hashimoto, Takuto Yamamoto, Toshihiro Shioda.
      Primordial germ cells (PGCs) are common precursors of all male and female germline cells. PGCs arise in peri-implantation mammalian embryos and become gender-specific germ cell precursors upon sexual differentiation of the gonadal anlage. The in vitro model commonly known as PGC-Like Cells (PGCLCs), generated from human pluripotent stem cells, is a useful surrogate of the human embryonic PGCs, providing a unique opportunity to explore human gametogenesis in vitro. The protocol presented here supports long-term in vitro expansion of human PGCLCs. Freshly isolated PGCLCs are maintained initially on a STO feeder layer and then expanded in a feeder-free condition on basement membrane extract. The long-term culture PGCLCs (LTC-PGCLCs) can be Fluorescence-Activated Cell Sorting (FACS)-enriched as CD38-positive cells and are readily amplified to tens of millions of cells as pure, feeder-free, and serum-free monotonous culture without apparent limitations such as senescence. It is practically feasible to obtain a pure population of more than 1 million human PGCLCs from a few thousand freshly isolated PGCLCs. The human LTC-PGCLC cell culture is a useful and convenient in vitro model to study human germ cell biology and differentiation into the downstream germline cells.
    DOI:  https://doi.org/10.3791/68679
  6. Elife. 2025 Oct 16. pii: RP106303. [Epub ahead of print]14
    Cross-species insemination reveals mouse sperm ability to enter and cross the fish micropyle.
    Suma Garibova, Eva Stickler, Fatima AlAli, Maha A Abdulla, Abbirami Sathappan, Sahar I Da'as, Lillian Ghanem, Mohamed Nadhir Djekidel, Rick Portman, Matteo Avella.
      Extracellular matrices surrounding eggs in fish (chorion) and mammals (zona pellucida [ZP]) regulate gamete recognition before fertilization, though their mechanisms differ. Mouse sperm bind and cross the ZP at any site, while fish sperm cross the chorion through a funnel-shaped opening, the micropyle. To explore these divergent processes, we established cross-species insemination assays, mixing zebrafish eggs with mouse sperm. While mouse sperm could not bind to the chorion, a subpopulation successfully located and crossed the fish micropyle. Confocal and electron microscopy revealed that sperm entered the micropyle and accumulated in the zebrafish inter-chorion space. However, transgenic mouse sperm with mCherry-labeled acrosomes failed to undergo acrosome exocytosis efficiently in the micropyle, with both acrosome-intact and reacted sperm found in the inter-chorion space. Sperm entry and crossing were dependent on hyperactive motility, as sperm from CatSperdNull mice, which fail to undergo hyperactivation, did not interact with or cross the micropyle. These findings suggest a conserved mechanism for sperm entry into the micropyle, providing a novel platform to investigate cross-species gamete interactions and uncover novel steps in fertilization.
    Keywords:  cell biology; developmental biology; gamete interaction; mouse; oocyte; zebrafish; zona pellucida
    DOI:  https://doi.org/10.7554/eLife.106303
  7. Am J Hum Genet. 2025 Oct 14. pii: S0002-9297(25)00390-8. [Epub ahead of print]
    Maternal age and genome-wide failure of meiotic recombination are associated with triploid conceptions in humans.
    Ludovica Picchetta, Christian Simon Ottolini, Xin Tao, Yiping Zhan, Vaidehi Jobanputra, Carlos Marin Vallejo, Francesca Mulas, Elvezia Maria Paraboschi, Maria José Escribá Pérez, Thomas Molinaro, Christine Whitehead, Pavan Gill, Emily Mounts, Dhruti Babariya, Laura Francesca Rienzi, Filippo Maria Ubaldi, Juan Antonio Garcia-Velasco, Antonio Pellicer, Shai Carmi, Eva R Hoffmann, Antonio Capalbo.
      Triploid and haploid conceptions are not viable and are a common occurrence in humans, where they account for 10% of all pregnancy losses. Despite the parent of origin being important in the etiology of the pregnancy, our knowledge of their causes is limited, especially at the point of conception. Using a dataset of 96,660 biopsies and a validation dataset of 44,324 from human blastocyst embryos generated by intracytoplasmic sperm injection, we estimate that 1.1% of human conceptions (n = 1,063) contain extra or missing chromosome sets in zygotes. In our cohort of intracytoplasmic-sperm-injection-derived embryos, where the risk of polyspermy is inherently lower compared to natural conception, we identify for the first time a maternal age effect, with a 1.046-per-year increased risk in triploidy/haploidy (p < 0.001). In 0.03% of couples, we identified three or more triploid/haploid embryos, suggesting a personal risk effect (p = 0.03). Genotype analysis of 41 triploid embryo biopsies and their parents shows that around one-third of maternal triploid conceptions originate in meiosis I and two-thirds in meiosis II. Seven of these embryos are inferred to have entirely failed to initiate meiotic recombination genome wide, a surprising finding suggesting that human oocytes with pervasive meiotic recombination failure that are formed during fetal development are capable of ovulation in adult life. Finally, we identify a type of genome-wide maternal isodiploidy (two maternal chromosome sets) in 0.05% of embryos (41/74,009). Collectively, our findings shed light on the biology of meiosis and the formation of human oocytes with the number of chromosome sets.
    Keywords:  embryos; genotyping; haploidy; human development; pregnancy loss; triploidy
    DOI:  https://doi.org/10.1016/j.ajhg.2025.09.014
  8. NAR Genom Bioinform. 2025 Dec;7(4): lqaf136
    Parental noncoding RNA expression dynamics across sperm, oocyte, and zygote.
    Arpana Verma, Byapti Ghosh, Troyee Das, Aritra Deb, Ayan Mukherjee, Pritha Sengupta, Arijita Sarkar, Kuladip Jana, Zhumur Ghosh.
      Fertilization ensures the flow of information from the parent to the progeny via fusion of male and female gametes orchestrated by a cascade of events guided by parental noncoding RNA (ncRNA) molecules. These parental ncRNAs play an essential role toward rewiring the germ cell profile to make them compatible for successful fertilization, thereby resulting in the formation of the zygote. They further modulate the zygotic profile to support the postfertilization events. In this work, an in-depth meta-analysis of small and long RNA-seq data corresponding to sperm, oocyte, and one-cell stage zygote of Mus musculus has been performed, followed by subsequent wet bench experiments. Our findings provide a comprehensive long noncoding RNA (lncRNA) and microRNA (miRNA) profile contributed by the parental gametes. Further, a set of novel lncRNAs have been identified, which have a potential role toward modulating sperm and oocyte fertility in the pre-fertilization stage. Moreover, a fine-tuned miRNA expression dynamics has been observed between the germ cells and the zygote to increase the competency of the germ cells for fertilization in the pre-fertilization stage. Its subsequent effects have been observed on early embryonic development in the postfertilization stage.
    DOI:  https://doi.org/10.1093/nargab/lqaf136
  9. Front Endocrinol (Lausanne). 2025 ;16 1629815
    Tailor-made 3D in vitro maturation of early antral follicles uncovers cumulus-cell transcriptomic driver signature to predict oocyte competence.
    Camila Rojo-Fleming, Fani Konstantinidou, Alessia Peserico, Chiara Di Berardino, Giulia Capacchietti, Delia Nardinocchi, Chiara Camerano Spelta Rapini, Valentina Russo, Nicola Bernabò, Antonio Capalbo, Liborio Stuppia, Valentina Gatta, Barbara Barboni.
       Background: Assisted reproductive technologies (ART) are constrained by the limited pool of medium antral follicles. Early antral follicles (EAfs) are an emerging additional source coming either from cryopreserved ovaries or from in vitro folliculogenesis protocols. The EAfs have the advantage of being gonadotropin sensitive follicles enclosing fully grown oocytes that can be enrolled in ART using advanced IVM techniques. The present research has been designed using the validated 3-D follicle-enclosed IVM protocol to insight into EAfs ART competence by profiling the transcriptome of the surrounding cumulus cells (CCs) to uncover non-invasive predictors of oocyte developmental competence.
    Results: Transcriptome analysis of 22-141 genes revealed 1-386 DEGs in CCs supporting metaphase-II (MII) oocytes and 1-420 in CCs enclosing germinal-vesicle (GV) oocytes. Network modelling pinpointed as signature of competent CCs three down-regulated outliers (EFHD1, HS6ST2, SLC35G1) and two hubs (CDC6, KIF11), while the unsuccessful ones revealed six outliers (HBA1, SLC39A8, ERO1A, TKDP5, CALCRL, ELOVL6) and the hub CASP3. The profile of EAfs enclosing competent oocyte converged towards cumulus expansion and controlled cell-cycle quiescence pathways whereas lipid dysregulation, oxidative stress and apoptosis characterized CC surrounding incompetent oocytes. The endpoint comparison yielded 11 markers, highlighted by SEMA3A up-regulation and IL1A, DDIT4 and VNN1 down-regulation. qPCR confirmed the transcriptome profile of the key genes (HS6ST2, CDC6, ERO1, CASP3 and SEMA3A) while immuno-assays corroborated the differential expression and localization of some related codified driver proteins (HAS2, CASP3 and SEMA3A).
    Conclusions: CC transcriptomics defines a concise 12-gene driver panel plus 11 endpoint markers that accurately predict the maturation fate of individual EAfs by providing actionable targets and a practical basis for rapid, non-invasive selection of high-quality follicles, with potential to enhance fertility preservation, livestock breeding and clinical ART outcomes. In addition, the analysis point on new gene/protein mediating CCs maturation mechanism is to be considered.
    Keywords:  cumulus cells; differentially expressed genes (DEGs); early antral follicles; follicle – enclosed oocyte in vitro maturation (FEO-IVM); highly interconnected genes (HUBs); ovine oocyte competence; transcriptome
    DOI:  https://doi.org/10.3389/fendo.2025.1629815
  10. Elife. 2025 Oct 14. pii: RP101912. [Epub ahead of print]13
    HIF1A-mediated pathways promote euploid cell survival in chromosomally mosaic embryos.
    Estefania Sanchez-Vasquez, Marianne E Bronner, Magdalena Zernicka-Goetz.
      Human fertility is suboptimal in part by error-prone divisions during early cleavage stages, which frequently result in chromosomal aneuploidy. Most human pre-implantation embryos are mosaics of euploid and aneuploid cells, yet those with a low proportion of aneuploid cells can develop to term at rates similar to fully euploid embryos. How embryos manage aneuploidy during early development remains poorly understood - yet this knowledge is crucial for improving fertility outcomes and reducing developmental defects. To investigate these mechanisms, we established a new mouse model of chromosome mosaicism to trace the fate of aneuploid cells during pre-implantation development. We previously used the Mps1 inhibitor reversine to induce aneuploidy. Here, we demonstrate that the more specific Mps1 inhibitor AZ3146 similarly disrupts chromosome segregation but supports higher developmental potential than reversine. AZ3146-treated embryos transiently upregulate hypoxia-inducible factor-1A (HIF1A) without triggering Trp53 activation. Given that pre-implantation embryos develop in a hypoxic environment in vivo, we further explored the role of oxygen tension. Hypoxia exposure in vitro reduced DNA damage in response to Mps1 inhibition and increased the proportion of euploid cells in mosaic epiblast. Conversely, HIF1A inhibition decreased the proportion of aneuploid cells. Together, these findings uncover a role for hypoxia signaling in modulating the response to chromosomal errors and suggest new strategies to improve the developmental potential of mosaic human embryos.
    Keywords:  aneuploidy; chromosomes; developmental biology; gene expression; hypoxia; mosaicism; mouse
    DOI:  https://doi.org/10.7554/eLife.101912
  11. Dev Biol. 2025 Oct 11. pii: S0012-1606(25)00295-7. [Epub ahead of print]529 121-129
    Posterior pole of dermapteran oocytes houses a single aggregate of organelles reminiscent of endolysosomal vesicular assemblies described in mouse oocytes.
    Magda Sochaczewska, Malgorzata Sekula, Waclaw Tworzydlo, Szczepan M Bilinski.
      Oocytes of derived dermapterans (the Eudermaptera), in addition to "conventional" organelles, i.e. mitochondria, elements of endoplasmic reticulum, Golgi complexes, lysosome-like bodies and reserve materials (yolk spheres, lipid droplets), contain unexpectedly rich set of noncanonical organelles. It includes assemblies of endoplasmic reticulum and fine granular "nuage" material, ribosome-associated vesicles, and extensive arrays of parallel arranged endoplasmic reticulum cisternae. During vitellogenesis (yolk formation), all lysosome-like bodies are gradually translocated towards the posterior oocyte pole, where they form relatively large, morphologically distinct compartment that we termed the posterior pole lysosomal compartment. This compartment is not surrounded by a limiting membrane and stains positively with Proteostat, a dye used to detect proteins implicated in the formation of biomolecular condensates. In the light of these results, we hypothesize that posterior pole lysosomal compartment is reminiscent of endolysosomal vesicular assembly/ies participating in the sequestration/degradation of aggregated proteins in mammalian oocytes.
    Keywords:  Biomolecular condensates; Endolysosomal vesicular assemblies (ELVAs); Germ plasm; Nuage; Oogenesis; Ribosome-associated vesicles
    DOI:  https://doi.org/10.1016/j.ydbio.2025.10.009
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