bims-ovagas Biomed News
on Ovarian aging and cGAS
Issue of 2026–06–07
twelve papers selected by
Haiyuan Mu, University of California Berkeley
  1. Activation of primordial follicles.
  2. Pyroptosis in Ovarian Aging, and Its Influence on Female Reproductive Health in Aged Ovaries.
  3. The ovarian stroma as a key regulator of follicular development and gamete quality across the reproductive lifespan.
  4. Building a resilient ovarian reserve: Early soma-oocyte interactions.
  5. Intercellular cyclic nucleotide dynamics mediate oocyte meiosis in mammalian preovulatory follicles.
  6. Establishment of human ovarioids: a novel matrix-free 3D ovarian model.
  7. Role of retinoic acid in meiosis.
  8. Impact of cancer immunotherapies on oocyte health and ovarian function.
  9. Conditional replacement of the mouse LH receptor with GFP, enabling imaging of cell migration during ovulation.
  10. Mechanisms of germ-soma communication during follicular growth.
  11. Conditional replacement of the mouse LH receptor with GFP, enabling imaging of cell migration during ovulation.
  12. Nucleolar Dynamics During Oogenesis.
  1. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00035-9. [Epub ahead of print]169 137-167
    Activation of primordial follicles.
    In-Won Lee, Deepak Adhikari.
      Primordial follicle activation represents the pivotal and rate-limiting transition that governs the size and longevity of the ovarian reserve, thereby shaping female reproductive lifespan. Although the vast majority of primordial follicles remain quiescent, a small fraction is periodically activated through tightly regulated signaling events. Emerging evidence reveals that dormancy is not a passive state, but an actively maintained program orchestrated by intrinsic oocyte pathways, surrounding pre-granulosa cells, and the ovarian microenvironment. Key intracellular regulator PI3K-Akt-FOXO3 signaling establishes the oocyte's threshold for activation, and pre-granulosa cell cues, including KITL-KIT interactions, mechanical constraints, and extracellular matrix dynamics, modulate this core signaling. Additionally, paracrine signals from stromal cells, local hypoxia, and biomechanical forces contribute to the spatial patterning of activation within the ovary. Integration of these inputs ensures both the lifelong preservation of a dormant pool and the continuous supply of follicles entering the growth phase. Recent advances in single-cell technologies, imaging, and lineage tracing systems have begun to redefine the temporal and spatial complexity of primordial follicle activation. Dysregulation of this system underlies a spectrum of reproductive disorders, from premature ovarian insufficiency to diminished ovarian reserve and aberrant follicle recruitment. Understanding the molecular logic of activation not only illuminates the biology of ovarian aging but also informs emerging therapeutic strategies, including targeted modulation of signaling pathways, ovarian tissue engineering, and fertility preservation interventions. This chapter describes current knowledge of the mechanisms governing primordial follicle activation and highlights key gaps that will shape future research in ovarian biology.
    Keywords:  Female fertility; Follicle activation; Oocyte; Ovarian reserve; Pre-granulosa cells; Primordial follicles; Signaling pathways
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.04.002
  2. Am J Reprod Immunol. 2026 Jun;95(6): e70265
    Pyroptosis in Ovarian Aging, and Its Influence on Female Reproductive Health in Aged Ovaries.
    Caglar Berkel.
      Pyroptosis is a lytic cell death mechanism mediated by the gasdermin family of proteins, resulting in the release of certain pro-inflammatory molecules to the extracellular space. Ovaries serve as the source of oocytes and main producer of steroid sex hormones, making them essential with respect to the maintenance of fertility and endocrine homeostasis during reproductive lifespan in females. Ovaries exhibit early-onset aging-associated dysfunction, compared to most other tissues, with dramatic functional declines after only 30 years of age in women. In this review, I covered studies reporting the age-dependent changes in pyroptotic cell death in ovaries, and the effects of increased pyroptotic events in aged ovaries on the female reproductive health. Increased pyroptosis of diverse cell types in the ovarian microenvironment might adversely influence ovarian function and composition in the course of ovarian aging, mostly by its effects on inflammation and cellular senescence. Novel strategies targeting pyroptotic cell death in aging ovaries might alleviate certain adverse outcomes in terms of fertility or female reproductive health in general. Considering that many molecules which are known to inhibit pyroptosis are currently available, a better molecular understanding and evaluation of these pyroptosis inhibitors in the clinic for the mitigation of aging-associated declines in ovarian function and female fertility is needed.
    Keywords:  aging; cell death; fertility; inflammation; ovarian aging; ovary; pyroptosis; reproductive lifespan; senescence
    DOI:  https://doi.org/10.1111/aji.70265
  3. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00038-4. [Epub ahead of print]169 237-272
    The ovarian stroma as a key regulator of follicular development and gamete quality across the reproductive lifespan.
    Shweta S Dipali, Francesca E Duncan.
      The follicle is the functional unit of the ovary and has been the historical focus of ovarian biology research. However, recently a greater emphasis has been placed on the role of the ovarian microenvironment, or stroma, in supporting the follicle and germ cell within. The ovarian stroma is composed of the ovarian surface epithelium, blood and lymphatic vasculature, nerves, immune cells, fibroblasts, mesenchymal cells, and the extracellular matrix (ECM). The stroma provides structural, biomechanical, biochemical, and metabolic support for follicle activation and development, in turn impacting gamete quality. The ovary is one of the first organs to age characterized by a loss of gamete quantity and quality. In addition, the stroma exhibits significant age-related changes - becoming fibrotic, inflammatory, and stiff. This review summarizes the physiological functions of ovarian stromal cell populations and components in supporting ovarian function, alterations in the ovarian stroma that occur with advanced age, and the resulting reproductive consequences.
    Keywords:  Aging; Epithelium; Extracellular matrix; Fibroblasts; Immune cells; Nerves; Ovarian stroma; Ovary; Vasculature
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.04.005
  4. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00040-2. [Epub ahead of print]169 97-136
    Building a resilient ovarian reserve: Early soma-oocyte interactions.
    Cora Thompson, Alaina Houghton-Chamberlain, Joan S Jorgensen.
      Soma-oocyte interactions are a key component in female fertility. First the ovary must adopt a female fate and become populated with supporting somatic cells. We discuss the origins of each somatic cell type with a particular focus on pre-granulosa cell origins and differentiation. Upon germ cell arrival into the ovary, the oogonia develop into cysts and begin their interactions with neighboring pre-granulosa cells. Cell to cell contacts change over time as the germline cysts form and then break down to facilitate primordial follicle formation. These changes do not happen in isolation, rather, they are mediated by signaling cascades and changes in the physical structures. The processes and developmental changes explored in this chapter are crucial for the longevity and success of the primordial follicle and thus, an essential part of female fertility.
    Keywords:  Balbiani body; Development; Follicle; Germline cyst; Meiosis; Mitosis; Oocyte; Ovary; Pre-granulosa cell
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.04.007
  5. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00041-4. [Epub ahead of print]169 193-235
    Intercellular cyclic nucleotide dynamics mediate oocyte meiosis in mammalian preovulatory follicles.
    Jeremy R Egbert.
      The cell cycle of the mammalian oocyte arrests in prophase around the time of birth and remains in meiotic arrest as it grows interdependently with increasing layers of surrounding somatic cells as a structure called an ovarian follicle. Within preovulatory follicles, gap junction communication between somatic cells and the oocyte allow cyclic nucleotides to maintain equilibrium concentrations that prevent premature meiotic resumption. Intercellular communication is also required for the mid-cycle surge in luteinizing hormone to alter cyclic nucleotide dynamics and cause the oocyte cell cycle to resume. In this review, the increasingly well-understood mechanisms by which meiotic arrest and meiotic resumption occur will be summarized, along with recent developments made possible by an improved cyclic nucleotide sensor and imaging techniques. These studies have uncovered new aspects of this process and helped clarify the required role of epidermal growth factor receptor signaling in meiotic resumption. Growing evidence that the cyclic nucleotide-associated participants in oocyte cell cycle regulation, first described in rodents, appear to be universal across mammals will also be summarized. This understanding has fostered new approaches to assisted reproductive technologies (ARTs) in domesticated animals and humans.
    Keywords:  Functional syncytium; Gap junction; Guanylyl cyclase; Intercellular signaling; Live imaging; Meiotic arrest; Meiotic resumption; Ovarian follicle; Regulatory phosphorylation
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.04.008
  6. Fertil Steril. 2026 Jun 01. pii: S0015-0282(26)00476-0. [Epub ahead of print]
    Establishment of human ovarioids: a novel matrix-free 3D ovarian model.
    Manyu Zhang, Christina Anna Stratopoulou, Alessandra Camboni, Farima Rahimi Mansour, Delphine Lemaire, Chloé Beaussart, Pascale Jadoul, Mathieu Luyckx, Jacques Donnez, Marie-Madeleine Dolmans.
      
    Keywords:  3D culture; Ovarioid; follicle culture; human ovary; ovarian organoid
    DOI:  https://doi.org/10.1016/j.fertnstert.2026.05.168
  7. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00036-0. [Epub ahead of print]169 29-49
    Role of retinoic acid in meiosis.
    Emma A Gilbert, Christopher B Geyer.
      To produce haploid gametes, mitotic germ cells in both sexes must transition to the specialized meiotic program. The molecular details underlying this transition - termed meiotic initiation - are poorly defined in higher eukaryotes, especially mammals. In mammals, the current mechanistic dogma is the signal, or 'meiosis inducing substance' (MIS), triggering germ cell meiotic initiation is provided by retinoic acid (RA). However, over the past twenty years a considerable number of reports using both genetic and pharmacologic approaches have been published that alternatively support or challenge RA's role as the mammalian MIS. Here, we attempt to fairly describe this conflicting evidence in the hopes that it will stimulate future conversations and design of studies to elucidate the molecular and cellular mechanisms driving meiotic initiation in the mammalian germline.
    Keywords:  Meiosis; Oocyte; Oogonia; Ovary; Retinoic acid; Spermatocyte; Spermatogonia; Testis
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.04.003
  8. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00039-6. [Epub ahead of print]169 273-305
    Impact of cancer immunotherapies on oocyte health and ovarian function.
    Yasmin Lewis, Yujie Cao, Jordan Higgins, Lauren R Alesi, Amy L Winship, Karla J Hutt.
      The ovary is an immunologically active organ in which tightly regulated interactions between immune cells, cytokines, and reproductive hormones are essential for follicle and oocyte development, ovulation, luteal function, and maintenance of the ovarian reserve. Immune checkpoints such as PD-1, PD-L1, and CTLA-4 are increasingly recognized as key regulators of immune tolerance beyond classical lymphoid tissues, yet their roles within the ovary remain poorly defined. Immune checkpoint inhibitors (ICIs), which target these pathways to enhance anti-tumor immunity, have transformed cancer treatment and are increasingly administered to women of reproductive age. While traditional cancer therapies are well known to compromise ovarian function and fertility, the reproductive consequences of ICIs are only beginning to emerge. Here we synthesize current knowledge of ovarian immune biology, with a focus on T cells and immune checkpoint signaling, and integrate clinical, preclinical, and mechanistic evidence linking immune checkpoint blockade to ovarian dysfunction. We discuss immune-related adverse events (irAEs), their management, and emerging evidence that the ovary may be uniquely sensitive to immune checkpoint perturbation. Collectively, this review highlights emerging knowledge of T cells and immune checkpoints in the ovary, highlights critical gaps in our understanding of immune - ovarian crosstalk, and discusses the urgent need to define the reproductive risks of ICIs to inform fertility preservation strategies and clinical decision-making for women with cancer.
    Keywords:  Cancer; Fertility; Immune cells; Immune checkpoints; Ovary
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.04.006
  9. bioRxiv. 2026 May 25. pii: 2026.05.21.726840. [Epub ahead of print]
    Conditional replacement of the mouse LH receptor with GFP, enabling imaging of cell migration during ovulation.
    Corie M Owen, Katie M Lowther, Deborah Kaback, Laurinda A Jaffe, Siu-Pok Yee.
      To facilitate the investigation of signaling by the luteinizing hormone receptor (LHR), we created a mouse line called Lhr -COIN. This line allows for the conditional replacement of the Lhr coding sequence with enhanced green fluorescent protein (eGFP), resulting in both a conditional knockout line and a reporter line. By breeding these mice with mice expressing Cre recombinase, we generated mice in which either one or both Lhr alleles were replaced with eGFP. Notably, mice in which one Lhr allele in the granulosa cells was replaced with eGFP exhibited normal LH responsiveness. This enabled live imaging of LH-induced migration of LH-receptor-expressing granulosa cells within preovulatory ovarian follicles. The Lhr -COIN mouse line holds significant potential for future research on LHR function and localization in the ovary and other tissues.
    DOI:  https://doi.org/10.64898/2026.05.21.726840
  10. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00042-6. [Epub ahead of print]169 169-191
    Mechanisms of germ-soma communication during follicular growth.
    Claude Robert, Ricardo Perecin Nociti.
      Communication between cells is essential for orchestrating tissue, organ, and whole-body cohesion. The communication can occur within the same cell (autocrine signaling), between neighboring cells (paracrine signaling), from distant cells (endocrine signaling), and between adjacent cells (juxtacrine signaling). Extracellular vesicle secretions, where messaging molecules like proteins, RNAs, and lipids are embedded in a membrane-enclosed particle released by the signaling cell, allow signaling to occur upon uptake and release of the cargo. Intercellular communications in synchrony between folliculogenesis and oogenesis involve both long-distance and short-distance messaging within the ovarian follicle, which is segmented into different cell types, with the oocyte lying at the center. Cells can generate extensions to increase the range of messaging by reaching out to more distant cells the so-called protrusion-based intercellular communication exemplified by tunneling nanotubes (TNTs), MT-nanotubes (MTNTs), microvilli, filopodia, and cytonemes. In mammalian oocytes, the filopodia from follicular cells that grow towards the oocyte is known as transzonal projections (TZPs). They accumulate large cargos, such as EVs, proteins and RNAs, at the tip creating the gametic synapses. These projections keep the oocyte and follicular cells connected and exchanging cytoplasmic content despite the apparent physical separation caused by the oocyte's zona pellucida. The protective and nurturing nature of follicular cells towards the oocyte, due to the presence of cellular interconnectivity within follicular cells and the oocyte, is conserved between species and is essential for communication, playing a crucial role in the development of a high-quality oocyte.
    Keywords:  Filopodia; Intercellular communications; Oocyte; Ovarian follicle; Tran szonal projections
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.04.009
  11. Endocrinology. 2026 Jun 02. pii: bqag065. [Epub ahead of print]
    Conditional replacement of the mouse LH receptor with GFP, enabling imaging of cell migration during ovulation.
    Corie M Owen, Katie M Lowther, Deborah Kaback, Laurinda A Jaffe, Siu-Pok Yee.
      To facilitate the investigation of signaling by the luteinizing hormone receptor (LHR), we created a mouse line called Lhr-COIN. This line allows for the conditional replacement of the Lhr coding sequence with enhanced green fluorescent protein (eGFP), resulting in both a conditional knockout line and a reporter line. By breeding these mice with mice expressing Cre recombinase, we generated mice in which either one or both Lhr alleles were replaced with eGFP. Notably, mice in which one Lhr allele in the granulosa cells was replaced with eGFP exhibited normal LH responsiveness. This enabled live imaging of LH-induced migration of LH-receptor-expressing granulosa cells within preovulatory ovarian follicles. The Lhr-COIN mouse line holds significant potential for future research on LHR function and localization in the ovary and other tissues.
    Keywords:  granulosa cell migration; luteinizing hormone receptor; mouse; ovary; ovulation
    DOI:  https://doi.org/10.1210/endocr/bqag065
  12. bioRxiv. 2026 May 20. pii: 2026.05.19.726235. [Epub ahead of print]
    Nucleolar Dynamics During Oogenesis.
    Ruoyu Li, Grace McKown, Dai Tsuchiya, Mark Mattingly, Anna Galligos, Michay Diez, Jui Feng Lu, Mary C McKinney, Sean McKinney, Boris Rubinstein, Timothy J Corbin, Melainia McClain, Carrie Carmichael, Victoria A Hassebroek, Stephanie H Nowotarski, Jennifer L Gerton, Kamena K Kostova.
      Ribosome biogenesis is a conserved and highly regulated process that starts in the nucleolus, a membrane-less multi-phase organelle. Although the architecture of the nucleolus is known to change due to perturbations, how nucleolar organization is modulated during physiological processes to meet changing translational demands remains unclear. Here, we use zebrafish oogenesis as a developmental context requiring a rapid expansion of translational capacity to investigate the regulation of nucleolar architecture. We show nucleoli undergo coordinated changes in number, size, subnuclear localization, and layering throughout oogenesis. We further demonstrate that nucleoli form around extrachromosomal DNA circles that contain the rDNA locus. Notably, mouse oocytes undergo similar developmental changes in nucleolar layering and phase organization, indicating that remodeling of nucleolar condensates is a conserved feature of oogenesis. These findings reveal previously unexplored regulation of nucleolar architecture as developmental adaptations to changing biosynthetic needs.
    DOI:  https://doi.org/10.64898/2026.05.19.726235
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