bims-cebooc 2026-09-20 papers

bims-cebooc

Biomed News

on Cell biology of oocytes

Issue of 2026–09–20
nine papers selected by
Gabriele Zaffagnini, Universität zu Köln

Interfollicular communication among preovulatory follicles after luteinizing hormone signaling.
In vivo labeling-based proteomic analysis of early follicle oocytes and cisplatin-induced alterations in mice.
Generation of eight-cell embryo-like cells from human pluripotent stem cells.
Highly efficient base editing at PCSK9 and normal human embryo development.
First cleavage signatures define a temporal trade-off and predict embryo fitness.
Critical Function of SIK3 in Androgen-Producing Ovarian Theca Cells for Female Reproductive Competence.
Dietary composition and metabolic stress differentially affect the ovarian microenvironment in mice.
Mitochondria-Associated Transcription Precedes Oxidative Phosphorylation in Human Embryos.
Cryopreservation of Rodent Ovarian Tissues and Oocytes.

Endocrinology. 2026 Sep 16. pii: bqag105. [Epub ahead of print]

Interfollicular communication among preovulatory follicles after luteinizing hormone signaling.

Corie M Owen, Siu-Pok Yee, Laurinda A Jaffe.

  Luteinizing hormone (LH) triggers the resumption of oocyte meiosis and ovulation in preovulatory ovarian follicles. These events have generally been viewed as autonomous responses occurring independently within each follicle. Here, however, we show that mouse preovulatory follicles can communicate with one another through an LH-induced paracrine signaling network. Isolated preovulatory follicles lacking LH receptors (Lhr-KO) resumed oocyte meiosis when co-cultured with LH-stimulated wildtype follicles, despite being unable to respond directly to LH. Oocytes within Lhr-KO follicles also resumed meiosis when exposed to conditioned medium from LH-treated wildtype follicles, demonstrating that diffusible factors mediate this interfollicular communication. Neutralizing antibodies against the epidermal growth factor receptor ligands epiregulin and amphiregulin inhibited the LH-induced interfollicular communication, identifying these LH-induced factors as key signaling molecules. Although epiregulin and amphiregulin are known to transmit LH signals within individual follicles, our findings indicate that they can also coordinate responses among neighboring follicles. Together, these results demonstrate that LH regulates a communication network between preovulatory follicles rather than acting solely at the level of individual follicles.

Keywords:  epidermal growth factor receptor; interfollicular communication; luteinizing hormone; mouse; oocyte meiosis; ovary

DOI:  https://doi.org/10.1210/endocr/bqag105
Nat Commun. 2026 Aug 15. pii: 9815. [Epub ahead of print]17(1):

In vivo labeling-based proteomic analysis of early follicle oocytes and cisplatin-induced alterations in mice.

Zhi-Yan Jiang, Meiyu Bi, Xuan Wu, Miaomiao Ban, Yuyao Lu, Jiangli Cao, Jie Li, Qilong Wang, Xin Zhu, Mo Li, Heng-Yu Fan, Bingteng Xie.

A systematic proteomic profile of oocytes from early-stage follicles, particularly primordial follicles, is critical to protect female reproductive capacity in the context of chemotherapy, yet progress has been hindered by the rarity of oocyte samples and technical challenges associated with oocyte isolation. In this study, we generated in vivo oocyte protein labeling APEX fluorescent mice. With these mice, we reconstructed the ovary in 3D, enabling precise quantification of follicles and identified 2772 proteins and 2878 gene transcripts in oocytes predominantly from primordial follicles. Proteomic shifts of short-time cisplatin treatment revealed that many altered proteins were involved in DNA damage repair and histone modification. Notably, simultaneous application of cisplatin and EZH2's inhibitor, GSK126, relieved cisplatin-induced oocyte developmental defects. Our study provides a systematic proteomic characterization of oocytes predominantly from primordial follicles in female mice, and reveals dynamic proteome shifts in response to chemotherapeutic agents, laying the foundation for targeted fertility-preserving strategies.

DOI: https://doi.org/10.1038/s41467-026-76665-3
Nat Protoc. 2026 Sep 11.

Generation of eight-cell embryo-like cells from human pluripotent stem cells.

Md Abdul Mazid, Yunpan Li, Mindie Zhao, Lixin Fu, Hao Liu, Yu Jiang, Wenqi Jia, Junjian Lai, Jinxiu Li, Haiwei Li, Babangida Jabir Saeed, Amash Manzoor, Zhiwei Luo, Yiwei Lai, Liang Wu, Yi Zou, Chaiyaboot Ariyachet, Carl Ward, Chuanyu Liu, Longqi Liu, Miguel A Esteban, Wenjuan Li.

Mammalian embryonic development is a highly orchestrated process initiated by the fusion of the oocyte with sperm to generate the zygote. In humans, the zygote remains transcriptionally quiescent until the major wave of zygotic genome activation (ZGA) occurs around the eight-cell (8C) stage (day 3 after fertilization). These cells and the derived morula cells are totipotent: they have the capacity to form a whole individual. Our understanding of human totipotency is very limited because of ethical concerns using embryos and the scarcity of material available for research. Recently, we established a controllable transgene-free methodology to generate totipotent eight-cell embryo-like cells (8CLCs) from human pluripotent stem cells (PSCs) in vitro. These 8CLCs are produced using a novel medium, formulated by us, containing specific chemical compounds and cytokines. Here, we provide a detailed protocol for inducing, isolating and characterizing 8CLCs generated with this medium. The induction process can be done either in a stepwise manner (primed-naive-8CLC) that requires only 5 d starting from naive PSCs or directly from primed PSCs, which takes ~7 d. The resulting 8CLCs exhibit transcriptional and epigenetic features resembling those of human 8C embryo cells. On the basis of our experience, we expect that an individual with ~1 year of experience working with human PSC culture would be able to carry out this protocol. Our approach provides a valuable model for studying human early embryogenesis, particularly the molecular events surrounding ZGA.

DOI: https://doi.org/10.1038/s41596-026-01414-1
Nature. 2026 Sep 09.

Highly efficient base editing at PCSK9 and normal human embryo development.

Stepan Jerabek, Chanju Jung, Michelle Kappy, Qiaojin Zhao, Julie Sung, Ning Wang, Euihyun Kim, Jimin Kim, Marcos Iuri Roos Kulmann, Madeleine Bliss King, Mitchell John McAndrew, Meng Li, Sakshi Bhatele, Melisa Isado, Hong-Su Jang, Michal Dolezal, Robert Prosser, Shuangyi Xu, Gue-Ho Hwang, Iva Pichova, Jia Xu, Diego Marin, Jae-Sung Woo, Sangsu Bae, Nathan Treff, Audrone Lapinaite, Dieter Egli.

Cas9-based tools enable programmable DNA lesions for studying repair outcomes, gene function, and genome correction. In human embryos, Cas9-induced DNA double-strand breaks are genotoxic, causing frequent aneuploidy and large deletions1,2. Here, we evaluate DNA repair outcomes at nicks and mismatches introduced by base editors at the PCSK9 and HBG loci in human embryos. Delivering ABE8e-V106W as a protein at fertilization achieved editing at all PCSK9 alleles, supporting development to the blastocyst stage and the derivation of homozygous edited stem cell lines. No insertions or deletions were detected, although rare on-target chromosome breakage and chromosomal abnormalities occurred. Nevertheless, editing at bystander and off-target sites was mosaic, and the introduction of the editor as mRNA caused frequent embryo arrest due to guide-independent deaminase activity. Thus, unlike Cas9-induced DNA breaks, base editor-induced lesions are efficiently repaired. However, undesirable consequences for the genome and development can occur, currently precluding clinical use in reproduction.

DOI: https://doi.org/10.1038/s41586-026-11118-x
Sci Rep. 2026 09 15. pii: 28752. [Epub ahead of print]16(1):

First cleavage signatures define a temporal trade-off and predict embryo fitness.

Daphne Norma Crasta, Si Won Lee, Jolene Fredrickson, Theodore Trejo, Nadeem Ghani Khan, Shama Prasada Kabekkodu, Satish Kumar Adiga, Yulian Zhao, Guruprasad Kalthur, Nagarajan Kannan.

  Early embryonic development is marked by substantial variability in cleavage dynamics, yet the extent to which first cleavage (FC) features relate to subsequent developmental progression remains incompletely defined. Using parthenogenetic (haploid and diploid) and fertilized embryos from Swiss albino mice, we combined time-lapse imaging with mechanistic analyses to define a novel FC-state grading system (FC-I to FC-IV) based on cleavage symmetry, fragmentation, and correction of the cleavage axis. Aberrant FCs arose from cytoskeletal instability, persistent cytoplasmic bridges, chromosome lagging, and transient nuclear mispositioning. We identified a reproducible inverse relationship between FC duration and subsequent cleavage interval, that predicts blastocyst quality and termed it as 'first cleavage-associated compensatory timing (FACT) relationship'. Haploid parthenogenetic embryos lacked this compensatory timing relationship, which was observed in fertilized embryos and diploid parthenotes, coinciding with markedly reduced developmental progression and competence. Analysis of > 1,100 human embryos revealed analogous FC-states and an inverse relationship between consecutive cleavage intervals that was associated with blastocyst morphology and developmental progression, with no clear association with aneuploidy. These findings position FC-state grading and the FACT relationship as potential non-invasive indicators of early embryo fitness.

Keywords:  Blastocyst; Cleavage timing compensation; Cytoskeletal defects; Fertilization; First cleavage; Inner cell mass; Irregular cleavage; Oocyte; Parthenogenesis ; Time-lapse imaging; Totipotency; Trophectoderm

DOI:  https://doi.org/10.1038/s41598-026-68288-x
Endocrinology. 2026 Sep 18. pii: bqag108. [Epub ahead of print]

Critical Function of SIK3 in Androgen-Producing Ovarian Theca Cells for Female Reproductive Competence.

Emily T Hayes, Mariam Hassan, James Boyett, Julia Kipp, Lauren Leung, Kaya Tarchichi, Oliwia Lakomy, Hiroshi Takemori, Carlos Stocco.

Infertility affects over 10% of women of reproductive age, with ovulatory dysfunction being the leading cause. Despite its widespread prevalence, the mechanisms behind infertility and anovulation are not fully understood. Recently, we reported infertility, ovulation failure, and severe ovarian abnormalities in mice lacking salt-inducible kinase 3 (SIK3). However, this phenotype was not fully replicated in mice in which SIK3 was deleted in granulosa cells. Since SIK3 is also expressed in theca cells, we generated SIK3 knockout mice specifically targeting SIK3 loss in androgen-producing theca cells (SIK3C17TCKO). These mice are infertile, have irregular estrous cycles, and produce fewer oocytes after gonadotropin treatment compared to controls. Histological examination revealed enlarged, cystic ovaries with hemorrhagic follicles and a significant increase in multinucleated giant cells, indicating inflammation and ovarian aging. Additionally, SIK3C17TCKO ovaries exhibited increased CYP17A1 expression, an enzyme crucial for androgen synthesis, resulting in higher serum testosterone levels. Consistent with in vivo results, knocking down SIK3 in primary mouse theca-interstitial cells in vitro significantly raised Cyp17a1 expression and testosterone production. This suggests that androgen excess may contribute to the severe ovarian dysfunction observed in SIK3C17TCKO mice. Overall, this study further highlights the vital role of SIK3 in ovarian function and identifies theca cells as key targets of this kinase. The phenotype of SIK3C17TCKO mice closely resembles many features of polycystic ovary syndrome (PCOS), making it a valuable model for studying PCOS pathophysiology and potential treatments for ovulatory disorders.

DOI: https://doi.org/10.1210/endocr/bqag108
Geroscience. 2026 Sep 15.

Dietary composition and metabolic stress differentially affect the ovarian microenvironment in mice.

Giulia da Cunha Pereira, Tarcísio H L Pereira, Juliane B Prosczek, Larissa S Magalhães, César A Pinzón-Osorio, Ândrea G A Nogueira, Jéssica D Hense, Bianka M Zanini, Driele N Garcia, Rafael G Mondadori, Rodrigo A Vaucher, Augusto Schneider.

  The ovarian microenvironment is a dynamic target of aging and highly responsive to metabolic and dietary stressors. Western diets (WD) and high-fat diets (HFD) promote obesity and systemic metabolic dysfunction. However, whether these diets induce remodeling of the ovarian microenvironment remains unclear. In this study, we investigated how distinct dietary patterns influence metabolic homeostasis, estrous cyclicity, ovarian reserve, and stromal remodeling in female mice. Three-month-old C57BL/6 mice (n = 48) were fed a control diet (CTL), low-calorie Western diet (LcWD), WD, or HFD for 17 weeks. WD and HFD were associated with greater progressive weight gain, increased intra-abdominal adiposity, impaired insulin and glucose tolerance, and hepatocellular alterations, whereas LcWD also produced metabolic alterations despite its lower caloric density. WD mice exhibited shorter estrous cycles compared with CTL mice. Despite relatively preserved follicle numbers and no detectable differences in the number of oocytes ovulated, ovarian stromal collagen deposition was increased in WD and HFD mice compared with CTL mice and was intermediate in LcWD mice. Lipofuscin accumulation was higher in WD mice. Collectively, these findings indicate that distinct dietary patterns can promote ovarian stromal remodeling through potentially different metabolic and nutritional contexts, with collagen deposition emerging as a sensitive tissue-level alteration before broad depletion of the ovarian reserve or detectable changes in oocyte-associated parameters. These findings support ovarian stromal fibrosis as a potential early feature of diet-associated ovarian remodeling and reproductive aging.

Keywords:  High-fat diet; Ovarian aging; Reproductive function; Stromal fibrosis; Western diet

DOI:  https://doi.org/10.1007/s11357-026-02530-2
Reproduction. 2026 Sep 17. pii: xaag117. [Epub ahead of print]

Mitochondria-Associated Transcription Precedes Oxidative Phosphorylation in Human Embryos.

Andrew J Piasecki, Melissa Franco, Fausto Capelluto, Konstantin Khrapko, Jonathan L Tilly, Dori C Woods.

  Mitochondria undergo significant structural and functional changes during human pre-implantation embryogenesis, yet the transcriptional activity of both nuclear-encoded mitochondria-associated genes and mitochondrially transcribed genes across this developmental window remains poorly characterized. While mitochondria are established as the primary energy source for the early embryo, emerging evidence suggests they may also influence lineage specification through epigenetic regulation and metabolite availability. To investigate this, we applied a focused organelle-specific transcriptomic analysis framework, filtering expression data from two publicly available human single-cell RNA sequencing datasets against the MitoCarta 3.0 reference database. The first dataset spanned individual cells from the oocyte through blastocyst stage, and the second compared trophectoderm and inner cell mass cells isolated from blastocysts. Mitochondria-associated gene expression was sufficient to cluster human embryos by developmental stage. A pronounced shift in expression was identified at the 4-cell to 8-cell transition, with 115 unique differentially expressed genes across the two stages immediately following this transition compared to only 5 across the two prior stages. This transcriptional upregulation precedes the known onset of oxidative phosphorylation at approximately the 32-cell stage, suggesting mitochondrial roles in early embryogenesis beyond energy production. Mitochondrially transcribed genes were the primary drivers of clustering in earlier developmental stages, while nuclear-encoded genes drove clustering at the blastocyst stage, and mitochondrial gene expression profiles partially distinguished trophectoderm from inner cell mass lineages. These findings reframe mitochondria as active participants in early human developmental programming, with implications for lineage specification, epigenetic regulation, and the optimization of in vitro embryo culture conditions.

Keywords:  Differentiation; Embryogenesis; Mitochondria; Retrograde Signaling; Specification

DOI:  https://doi.org/10.1093/reprod/xaag117
Methods Mol Biol. 2026 ;3060 457-482

Cryopreservation of Rodent Ovarian Tissues and Oocytes.

Yuksel Agca, Cansu Agca.

  Germplasm cryobanking of rodents is a valuable tool for protecting scientifically important human disease models from genetic drift, genetic contamination, and loss of breeding colonies due to disease or catastrophic disasters to the housing facilities, as well as avoiding stress associated with domestic and international live animal shipment. Furthermore, germplasm cryopreservation enhances management efficiency by saving vivarium space, reducing workload for staff, financial burden of maintaining live animals, reducing the number of animals used to maintain a breeding colony, facilitating transportation of genetics by allowing distribution of frozen germplasm rather than live animals, which also reduces the risk of transfer of pathogens between facilities. In addition to spermatozoa and preimplantation embryos, effective long-term preservation of female germplasm within the ovarian tissues containing primordial follicles and mature oocytes via superovulation is critical for future reconstitution of scientifically important rodent strains for biomedical research. They also serve as a model to investigate and develop optimized oocyte and ovarian tissue cryopreservation and transplantation strategies for human infertility patients and family planning.

Keywords:  Cryopreservation; Mouse, rat; Oocytes, ovary; Vitrification

DOI:  https://doi.org/10.1007/978-1-0716-5416-3_19