bims-ovagas Biomed News
on Ovarian aging and cGAS
Issue of 2026–06–21
twelve papers selected by
Haiyuan Mu, University of California Berkeley
  1. The VCD legacy: Understanding ovarian cell death mechanisms, elucidating ovarian chemical biotransformation, and developing a physiologically-relevant model of menopause induction.
  2. Transitions in development - an interview with Chii Jou (Joe) Chan.
  3. Aging disrupts spatiotemporal coordination in the cycling murine ovary.
  4. An Asynchronous Production Line of Meiotic Prophase I in the Mouse Fetal Ovary.
  5. Mouse Oocyte In Vitro Maturation, Fertilization, and Culture of Preimplantation Embryos.
  6. Mechanisms of mitochondrial dysfunction in premature ovarian insufficiency.
  7. Reconstitution of germ cell and gonadal development for in vitro gamete production.
  8. Artificial intelligence-assisted controlled ovarian stimulation in in vitro fertilization: A critical narrative review.
  9. CACNA2D1 promotes ovulation by regulating ovarian immune cell infiltration.
  10. A need for pragmatism in preclinical aging and longevity research.
  11. Role of insulin in female reproduction.
  12. Eye tracking reveals expert gaze patterns during intracytoplasmic sperm injection.
  1. Biol Reprod. 2026 Jun 15. pii: ioag129. [Epub ahead of print]
    The VCD legacy: Understanding ovarian cell death mechanisms, elucidating ovarian chemical biotransformation, and developing a physiologically-relevant model of menopause induction.
    Zelieann R Craig, Aileen F Keating, Jodi A Flaws, Heddwen L Brooks.
      4-vinylcyclohexane (VCH) destroys primordial and primary ovarian follicles, leading to ovarian failure. Since loss of ovarian function is associated with increased health risks in women, understanding mechanisms of ovarian failure and appreciating the associated health deficits is tantamount. Use of VCH and the diepoxide metabolite, 4-vinylcyclohexane diepoxide (VCD), has led to transformative studies to: 1) develop a model to study how ovarian follicles are damaged and depleted, 2) understand how the ovary metabolizes chemicals to protect against chemical-induced ovarian damage, and 3) generate a model that decouples systemic from ovarian aging to examine physiological events that occur post-ovarian failure. This review summarizes those studies to pay tribute to the legacy of Dr. Patricia B. Hoyer, who led the foundational discoveries using VCH and VCD as model toxicants to understand basic ovarian physiology and the negative impacts that occur when the ovary ceases to function.
    Keywords:  4-vinylcyclohexane; 4-vinylcyclohexane diepoxide; cell death; menopause; ovary; primordial follicle
    DOI:  https://doi.org/10.1093/biolre/ioag129
  2. Development. 2026 Jun 15. pii: dev205844. [Epub ahead of print]153(12):
    Transitions in development - an interview with Chii Jou (Joe) Chan.
      Chii Jou (Joe) Chan is a Principal Investigator at the Mechanobiology Institute, National University of Singapore. Joe's group focuses on understanding the mechanobiological principles underlying oocyte maturation, follicle growth and collective dynamics during ovarian development and ageing, using ex vivo models and biophysical approaches. We spoke to Joe over Teams to learn more about his transition to becoming a group leader, his multidisciplinary interests spanning the physical sciences, psychology, spirituality and science communications, and his dedication to mentoring early-career researchers.
    DOI:  https://doi.org/10.1242/dev.205844
  3. Nat Aging. 2026 Jun;6(6): 1244-1266
    Aging disrupts spatiotemporal coordination in the cycling murine ovary.
    Tammy C T Lan, Alison Kochersberger, Ruth Raichur, Sophia Szady, Hien Tran, Radiana Simeonova, Ashley Helmuth, Andrew Minagar, Maria José Orozco Fuentes, Vipin Kumar, Giovanni Marrero, Irving Barrera, Sarah Mangiameli, Alex K Shalek, Pardis C Sabeti, Fei Chen, David S Fischer, Jennifer L Garrison, Hattie Chung.
      Throughout the female reproductive lifespan, the ovary undergoes hundreds of cycles of follicle development, ovulation and tissue regeneration. How aging disrupts the coordination of such precise, multicellular interactions across time and space is not well understood. Using Slide-seq, a near-cellular spatial transcriptomics method, here we profile 22 mouse ovaries across the reproductive cycle and chronological ages, capturing 610,620 spots across 69 spatial profiles. We develop a novel segmentation pipeline to examine the multicellular dynamics of 358 oocytes, 668 follicles and 236 corpora lutea to find that aging impairs the spatial and temporal coordination required for folliculogenesis even before reproductive cycles cease. These disruptions are characterized by altered immune cell dynamics, inflammatory signaling and global tissue disorganization, which impair the cyclic remodeling required for ovarian function. Our findings reveal how multicellular niches orchestrate ovarian function and demonstrate that age-related breakdown in tissue organization precedes the end of fertility.
    DOI:  https://doi.org/10.1038/s43587-026-01140-z
  4. Exp Cell Res. 2026 Jun 15. pii: S0014-4827(26)00216-8. [Epub ahead of print] 115099
    An Asynchronous Production Line of Meiotic Prophase I in the Mouse Fetal Ovary.
    Ziyi Jin, Chang Liu, Gan Liu, Guofeng Feng, Jie Li, Yiwei Wu, Hao Jia, David L Keefe, Lin Liu.
      The initiation of meiosis in the female germline of mammals is a gradual process, but there is currently no clear quantitative framework for determining the precise timing of its onset. Here, we attempt to standardize the description of meiotic entry timing through a systematic, quantitative analysis of meiotic entry and progression in the mouse fetal ovary. Using dynamic expression profiling of key regulators Stra8, Sycp1, and Sycp3 alongside proliferation markers, we demonstrate that germ cells enter meiosis asynchronously and continuously between embryonic days E12.5 and E16.5. During this extended period, mitotic proliferation persists, indicating that germ cells are progressively recruited into the meiotic pathway rather than halting division simultaneously. Homologous chromosome synapsis, marked by Sycp1/Sycp3 co-localization, initiates at E14.5 and is completed prenatally by E18.5. Using stage-composition data, we constructed a continuous-time Markov chain model to infer a population-level meiotic stage clock. This model estimates approximately conserved population-level effective intervals from the modeled early-prophase L compartment to pachytene-stage synapsis (∼72 h) and to the late-prophase/dictyate-associated D-state transition (∼91 h) across modeled cohort-start times. Our findings refine the conventional view by quantitatively defining the extended window of meiotic entry and subsequent progression through prophase I.
    Keywords:  Stra8; Sycp1; Sycp3; meiotic initiation; synapsis
    DOI:  https://doi.org/10.1016/j.yexcr.2026.115099
  5. J Vis Exp. 2026 May 29.
    Mouse Oocyte In Vitro Maturation, Fertilization, and Culture of Preimplantation Embryos.
    Debao Wang, Xueting Li, Haoran Sun, Yong Zhang, Jingcheng Zhang.
      Mouse oocyte in vitro maturation, combined with in vitro fertilization and subsequent embryo culture, enables the generation of preimplantation embryos under defined conditions. These procedures facilitate the investigation of the biological functions and molecular mechanisms underlying oocyte maturation, fertilization, and early embryo development. However, the successful application of this approach depends on careful handling of oocytes and sperm, appropriate culture conditions, and accurate assessment of developmental progression at each stage. Here, we describe methods for isolating immature cumulus-oocyte complexes (COCs) from mouse ovaries, in vitro maturation of oocytes, in vitro fertilization, and in vitro culture of embryos to the blastocyst stage. These procedures include preparing and equilibrating media and culture dishes, isolating and selecting COCs after ovarian dissection, collecting sperm and capacitating them, performing insemination under standardized conditions, and subsequently culturing embryos for developmental assessment. Developmental progression is evaluated using morphological criteria, including the formation of male and female pronuclei, cleavage to the two-cell stage, and blastocyst formation. This protocol can be integrated into studies of oocyte maturation and maternal factor function, providing a valuable tool for basic research in mammalian reproductive biology.
    DOI:  https://doi.org/10.3791/71053
  6. J Ovarian Res. 2026 Jun 17.
    Mechanisms of mitochondrial dysfunction in premature ovarian insufficiency.
    Chenyu Jia, Huihui Li, Ruotong Ju, Puhua Zhang, Li Peng, Tingting Xue, Xinyu Zhu, Shu Wang, Jiali Luo, Ruixiang Zhu, Xuan Jing, Xiangrong Cui.
      Premature ovarian insufficiency (POI) is a clinical syndrome characterized by the decline of ovarian function in women under the age of 40, and its core pathological feature is the irreversible depletion of the ovarian reserve. Mitochondria serve as the central hub for energy metabolism and signal integration in ovarian cells, and their dysfunction drives POI progression through multiple cell death pathways and signaling cascades. This review systematically examines the multidimensional mechanisms by which mitochondrial damage leads to follicle depletion and proposes, for the first time, an integrated regulatory model termed "mitochondrial damage - follicle fate decision." The review further identifies contradictory evidence, model limitations, and gaps in clinical translation within current research. Regarding therapeutic strategies, we evaluate the current status, safety risks, and ethical barriers of mitochondrial nutrients, stem cell therapy, gene editing, and mitochondrial replacement therapy. Finally, we propose a future research framework centered on mitochondrial dynamics and quality control, emphasizing the need for multi-omics integration and personalized interventions.
    Keywords:  Follicular atresia; Granulosa cell death; Mitochondrial dysfunction; Premature ovarian insufficiency
    DOI:  https://doi.org/10.1186/s13048-026-02170-2
  7. J Reprod Dev. 2026 ;72(3): 115-120
    Reconstitution of germ cell and gonadal development for in vitro gamete production.
    Katsuhiko Hayashi, Takashi Yosihno, Kenjiro Shirane.
      Germ cell formation involves a unique developmental trajectory in which diploid pluripotent cells are transformed into haploid gametes through a series of tightly regulated processes. This trajectory encompasses fundamental biological events, including extensive epigenetic remodeling, sexual fate determination, and meiotic division. Understanding the molecular and cellular mechanisms governing these processes is a fundamental challenge in reproductive biology and medicine, yet many aspects remain elusive. One long-standing strategy to overcome this limitation has been the establishment of in vitro gametogenesis that recapitulates germ cell development under defined culture conditions. In recent years, advances in stem cell biology have dramatically accelerated the development of such systems, opening new experimental platforms to dissect germ cell development. Beyond their value as research tools, these technologies also hold potential as alternative sources of gametes for animal reproduction and, perhaps, for human applications. In this review, we discuss the historical evolution of in vitro gametogenesis, highlight recent progress in the field, and outline the remaining technical and conceptual challenges.
    Keywords:  Gonadogenesis; In vitro gametogenesis; Sex determination
    DOI:  https://doi.org/10.1262/jrd.2026-009
  8. Int J Gynaecol Obstet. 2026 Jun 19.
    Artificial intelligence-assisted controlled ovarian stimulation in in vitro fertilization: A critical narrative review.
    E Deligeoroglou, G Makrakis, E Makrakis.
      Artificial intelligence (AI) is increasingly being investigated as a decision-support tool in controlled ovarian stimulation (COS) during in vitro fertilization. Machine learning and deep learning algorithms have demonstrated promising predictive performance for outcomes including ovarian response, mature oocyte yield, premature luteinizing hormone rise, gonadotropin dose adjustment, and optimization of trigger timing. Convolutional neural networks applied to three-dimensional ultrasound imaging have also enabled automated follicular monitoring and more standardized assessment of follicular development. This narrative review summarizes current AI applications in COS and critically evaluates the methodological quality, validation status, and clinical relevance of available models. Most published studies are retrospective and based on single-center data sets, with limited external validation and scarce prospective randomized evidence. Furthermore, many reported improvements relate primarily to surrogate laboratory outcomes rather than clinically meaningful endpoints such as live birth rates. Although AI-assisted COS demonstrates considerable potential for individualized treatment and workflow optimization, important barriers remain, including model interpretability, generalizability, ethical considerations, data privacy, and regulatory oversight. Future progress will require multicenter collaborations, prospective clinical validation, explainable AI frameworks, and careful integration of AI tools into clinician-guided reproductive care.
    Keywords:  artificial intelligence; gonadotropins; in vitro fertilization; machine learning; ovarian stimulation; reproductive medicine
    DOI:  https://doi.org/10.1002/ijgo.71163
  9. BMC Vet Res. 2026 Jun 13.
    CACNA2D1 promotes ovulation by regulating ovarian immune cell infiltration.
    Conghui Guo, Jie Liu, Kaihao Chen, Guangbin Liu, Dewu Liu, Yaokun Li.
       BACKGROUND: In the previous single-cell transcriptome analysis of goat ovulation, we identified that CACNA2D1 may play a critical role in immune cell infiltration during the ovulation process. Therefore, this study aimed to investigate the function of CACNA2D1 in ovulation.
    METHODS: CACNA2D1-associated signaling was pharmacologically inhibited in a mouse ovulation model to evaluate ovarian immune cell infiltration, ovulatory output, and transcriptomic changes. In vitro, CACNA2D1 knockdown and overexpression were performed in ovarian granulosa cells to assess chemokine production, intracellular calcium signaling, CaMKII activation, and cell proliferation. Granulosa cell-mediated macrophage recruitment was functionally examined using a RAW264.7 transwell migration assay.
    RESULTS: CACNA2D1 showed increased expression during the periovulatory period, and pharmacological inhibition of CACNA2D1-associated signaling in mice significantly reduced ovarian immune cell infiltration, particularly macrophages, accompanied by decreased ovulatory output. Ovarian transcriptomic analysis after inhibition revealed broad alterations in genes related to immune regulation, signal transduction, and cellular functional states. In granulosa cells, CACNA2D1 knockdown significantly reduced intracellular Ca2+ levels, decreased CaMKII phosphorylation, and suppressed the expression and secretion of immune recruitment-related factors, including IL6, CCL2, and CXCL12. Restoration of calcium signaling with A-23,187 rescued the reduced expression of these chemokines. Functionally, CACNA2D1 knockdown impaired granulosa cell-mediated RAW264.7 macrophage migration in a transwell co-culture system. CACNA2D1 also influenced granulosa cell proliferative activity, whereas its effect on macrophage-related responses appeared to be more closely associated with chemotactic signaling than with macrophage proliferation.
    CONCLUSIONS: This study identifies CACNA2D1 as a periovulatory granulosa cell-associated regulator involved in calcium-dependent chemokine production and macrophage recruitment. These findings provide new insight into ovarian immune remodeling during ovulation and offer a potential molecular basis for future studies of follicular development, ovulation efficiency, and fertility regulation in livestock species.
    Keywords:   CACNA2D1 ; Granulosa cells; Immune infiltration; Ovulation
    DOI:  https://doi.org/10.1186/s12917-026-05617-2
  10. Nat Aging. 2026 Jun 15.
    A need for pragmatism in preclinical aging and longevity research.
    Steven N Austad.
      
    DOI:  https://doi.org/10.1038/s43587-026-01151-w
  11. Curr Opin Obstet Gynecol. 2026 Jun 17.
    Role of insulin in female reproduction.
    Kamilah S Tebeau, Alex J Polotsky.
       PURPOSE OF REVIEW: Insulin resistance and related metabolic disorders are becoming increasingly common among women of reproductive age. However, the mechanisms by which insulin signaling influences female fertility remain only partially understood. Currently, there is rapid growth in the use of new insulin-sensitizing medications, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, prescribed to women who may want to conceive, raising concerns about reproductive safety and benefits.
    RECENT FINDINGS: Insulin acts at multiple points along the hypothalamic-pituitary-gonadal axis, including ovulatory function, oocyte maturation, and endometrial receptivity. Conditions such as polycystic ovary syndrome, diabetes, or obesity may impair oocyte development, modify IVF success rates, and compromise embryo implantation. Emerging evidence suggests that both SGLT2 inhibitors and GLP-1 receptor agonists improve factors such as ovulatory function and androgen balance, though both carry safety concerns during the periconception period.
    SUMMARY: Clinicians managing women of reproductive age with insulin-related metabolic disorders should incorporate reproductive counseling into treatment planning. Ultimately, fertility-focused trials of newer insulin modifiers may be beneficial.
    Keywords:  diabetes; fertility; insulin; obesity; polycystic ovary syndrome
    DOI:  https://doi.org/10.1097/GCO.0000000000001121
  12. Sci Rep. 2026 Jun 19.
    Eye tracking reveals expert gaze patterns during intracytoplasmic sperm injection.
    Azusa Asai, Hayato Hagiwara, Kazuki Hano, Tsubasa Kasui, Tatsuya Yoshimi, Masaki Takasu, Tadayoshi Aoyama, Kenji Kato.
      Intracytoplasmic sperm injection (ICSI) is a highly complex procedure that involves injecting a single sperm into an oocyte, requiring extensive training and advanced technical expertise, making it a task performed by specialists. Acquiring specialized microinjection skills alone often requires several years of training. ICSI performance has been primarily evaluated based on developmental outcomes, with little detailed assessment of operators' intrinsic skills. We analyzed expertise during microinjection using eye-tracking technology, which was recently employed in surgical and sports domains to evaluate expert performance. Eye tracking was used to compare the fixation patterns and eye-gaze behaviors of experts and novices during microinjection. Our results showed that the experts had shorter and more consistent procedural times than the novices did. In contrast, the novices initially took longer times; although their time gradually decreased, they remained unstable. This difference was particularly noticeable during oocyte rotation. Similar patterns were observed for fixation duration and the number of saccades. The heat maps and gaze plots revealed interesting distinctions between experts and novices. The experts exhibited efficient and highly consistent eye gaze patterns. Their eye-gaze data may contribute to developing AI-driven automated ICSI skill evaluation systems and AI- and robotics-based ICSI technical support and automation methods.
    DOI:  https://doi.org/10.1038/s41598-026-57054-8
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒13 at 18:28.