Biology subjects

Soygur, B.

Publications and source records attributed to Soygur, B..

8 recordsLinked to original sources

bioRxiv2026

Single-nucleus profiling reveals age-associated remodeling opposed by parity in the postmenopausal human ovary

The postmenopausal ovary is commonly viewed as a passive organ, and its biology and cell composition remain incompletely characterized. Here, we generated a single-nucleus atlas of the aging postmenopausal human ovary comprising 439,011 nuclei across 64 ovarian samples from 28 donors. We resolved 37 fine cell states, revealing extensive stromal, vascular, and immune heterogeneity in the postmenopausal ovary. Aging was associated with stromal stress-state expansion, vascular and immune depletion, and enrichment of steroidogenic programs consistent with ovarian androgenization. Several major age-associated compositional shifts were supported in an independent GTEx ovary bulk RNA-seq cohort. Notably, the number of live births broadly opposed age-associated transcriptional and compositional remodeling. Together, our findings show that the postmenopausal ovary remains an actively remodeled aging tissue and that reproductive history leaves durable molecular and cellular imprints on ovarian aging.

genomics↗

bioRxiv2026

The human ovary exhibits dynamic molecular remodeling in the decades post-menopause

The human ovary is among the first organs to show age-related functional decline, resulting in menopause. Beyond this transition, the postmenopausal ovary is often regarded as quiescent and remains poorly characterized. We analyzed the proteomes of healthy, non-pathological ovaries using mass spectrometry (data-independent acquisition) from 28 postmenopausal women (50-75 years old), stratified into three age groups (50-59, 60-69, [≥]70). We quantified 5,812 protein groups and observed progressive age-associated shifts, with 117 proteins significantly altered in the [≥]70 vs 50-59 age comparison. Multivariate analysis demonstrated clear separation between 50-59 and [≥]70-year-old age cohorts, with protein signatures shifting from RNA/gene-regulatory functions in younger ovaries to metabolic, trafficking, and innate immune/complement pathways in older ovaries. Across differential abundance, multivariate modelling, and covariate-adjusted linear modelling, we identified a convergent set of age-associated proteins that were integrated into the 26-protein Buck Postmenopausal Ovary Molecular Signature (BuckPOMS), a consensus molecular signature capturing progressive extracellular matrix remodeling, inflammatory signaling, and loss of structural and keratin-associated proteins with age. Representative BuckPOMS proteins, including the secreted matrisome proteins WNT4 and Fibromodulin (FMOD), were validated by immunohistochemistry. Pathway enrichment further identified an increase in inflammatory and matrisome pathways, and increased abundance of damage-associated secretory factors decades following menopause. These data fundamentally shift the notion of the postmenopausal ovary as an inert organ and instead demonstrate active and continuous molecular remodeling that has potential relevance to tissue signaling and implications for womens health.

biochemistry↗

bioRxiv2026

Proteogenomic Profiling Reveals a Distinct Endogenous p16INK4a-Associated Senescence Signature in the Human Ovary.

The tumor suppressor and cell cycle regulator, p16INK4a (p16), has been extensively linked to cellular senescence, and its accumulation can reflect endogenous senescence within ovarian tissue. However, gene and protein signatures associated with p16 have not been well defined in human tissue. We utilized immunohistochemical (IHC) staining for P16 to identify distinct positive (P16+) and negative (P16-) regions within the ovarian cortex and employed the GeoMx Digital Spatial Profiler for simultaneous proteomic and transcriptomic analyses on cortical tissue cores. Differential expression and translation between p16-positive and p16-negative cores identified genes and proteins that are cellular senescence related (e.g., CDKN1A, GADD45B, GADD45G, and MYC) or key regulators of the extracellular matrix (e.g., collagen I, ADAMTS4, and MMP11). Additionally, the transcriptomic signature identified here was significantly enriched for the spatially derived ovarian p16-associated signature, BuckSenOvary, but not for other senescence gene sets. Lastly, given the association between changes to the extracellular matrix in aged ovaries and ovarian cancer, we compared genes upregulated and downregulated in p16-positive regions relative to p16-negative regions against multiple ovarian cancer transcriptomic datasets. These findings provide new insight into the molecular landscape of naturally occurring ovarian senescence and its possible relationship to age-associated disease processes, including cancer development.

cell biology↗

bioRxiv2025

Senescence-Linked Fibrosis in the Aging Human Ovary Revealed by p16-Based Histological Profiling and Spatial Transcriptomics

Cellular senescence is implicated as a driver of ovarian aging, but senescent cells in the human postmenopausal ovary remain poorly defined. Using spatially resolved p16INK4a protein expression, a canonical senescence marker, we identified and mapped senescent cells in postmenopausal ovaries. We integrated p16 immunohistochemistry, multiplexed immunofluorescence, spatial transcriptomics, and AI-guided digital pathology to map senescent microenvironments. p16-positive cells formed discrete stromal, vascular, and cyst-associated clusters that increased with age and were enriched for macrophages and myofibroblast-like cells. Wholetranscriptome profiling of 92 spatial regions uncovered a 32-gene p16-associated signature, BuckSenOvary, that distinguished p16-positive regions across cortex and medulla. BuckSenOvary is characterized by suppression of cell-cycle regulators and activation of inflammatory and extracellular-matrix remodelling genes. AI-based collagen matrix analysis confirmed that p16-positive regions exhibit more architecturally complex collagen, demonstrating that focal senescent microenvironments are fibro-inflammatory. These findings position senescent ovarian niches as therapeutic targets to preserve ovarian function.

cell biology↗

bioRxiv2025

Comparative analysis of human and mouse ovaries across age

Mouse is a tractable model for human ovarian biology, however its utility is limited by incomplete understanding of how transcription and signaling differ interspecifically and with age. We compared ovaries between species using 3D-imaging, single-cell transcriptomics, and functional studies. In mice, we mapped declining follicle numbers and oocyte competence during aging; in human ovaries, we identified cortical follicle pockets and density changes. Oocytes had species-specific gene expression patterns during growth that converged toward maturity. Age-related transcriptional changes were greater in oocytes than granulosa cells across species, although mature oocytes change more in humans. We identified ovarian sympathetic nerves and glia; nerve density increased in aged human ovaries and, when ablated in mice, perturbed folliculogenesis. This comparative atlas defines shared and species-specific hallmarks of ovarian biology.

genomics↗

bioRxiv2024

A comprehensive multi-omics signature of doxorubicin-induced cellular senescence in the postmenopausal human ovary.

A major aging hallmark is the accumulation of cellular senescence burden. Over time senescent cells contribute to tissue deterioration through chronic inflammation and fibrosis driven by the Senescence-Associated Secretory Phenotype (SASP). The human ovary is one of the first organs to age, and prominent age-related fibroinflammation within the ovarian microenvironment is consistent with the presence of senescent cells, but these cells have not been characterized in the human ovary. We thus established a doxorubicin-induced model of cellular senescence to establish a "senotype" (gene/protein signature of a senescence cell state) for ovarian senescent cells. Explants of human postmenopausal ovarian cortex and medulla were treated with doxorubicin for 24 hours followed by culture for up to 10 days in a doxorubicin-free medium. Tissue viability was confirmed by histology, lack of apoptosis, and continued glucose consumption by explants. Single nuclei sequencing and proteomics revealed an unbiased signature of ovarian senescence. We identified distinct senescence profiles for the cortex and medulla, driven predominantly by epithelial and stromal cells. Proteomics uncovered subregional differences in addition to 120 proteins common to the cortex and medulla SASP. Integration of transcriptomic and proteomic analyses revealed 26 shared markers, defining a senotype of doxorubicin-induced senescence unique to the postmenopausal ovary. A subset of these proteins: Lumican, SOD2, MYH9, and Periostin were mapped onto native tissue to reveal compartment-specific localization. This senotype will help determine the role of cellular senescence in ovarian aging, inform biomarker development to identify, and therapeutic applications to slow or reverse ovarian aging, senescence, and cancer.

molecular biology↗

bioRxiv2024

Sustained fertility from first-wave follicle oocytes that pause their growth

Ovulation results from the cyclical recruitment of non-renewing, quiescent oocytes for growth. Therefore, the primordial follicles that are established during development from an oocyte encapsulated by granulosa cells are thought to comprise the lifelong ovarian reserve 1-4. However, using oocyte lineage tracing in mice, we observed that a subset of oocytes recruited for growth in the first juvenile wave remain paused for many months before continuing growth, ovulation, fertilization and development into healthy offspring. This small subset of genetically-labeled fetal oocytes, labeled with Sycp3-CreERT2, is distinguished by earlier entry and slower dynamics of meiotic prophase I. While labeled oocytes were initially found in both primordial follicles and growing follicles of the first wave, they disappeared from primordial follicles by puberty. Unexpectedly, these first-wave labeled growing oocytes persisted throughout reproductive lifespan and contributed to offspring at a steady rate beyond 12 months of age, suggesting that follicles can pause mid-growth for extended periods then successfully resume. These results challenge the conclusion from lineage tracing of granulosa cells that first-wave follicles make a limited contribution to fertility5 and furthermore suggest that growth-paused oocytes comprise a second and previously unrecognized ovarian reserve.

developmental biology↗

bioRxiv2022

Evidence for intercellular bridges and radial patterning of meiotic initiation in the human fetal ovary

Meiosis is the hallmark of reproduction. Our understanding of early oocyte development was improved by studying the spatiotemporal dynamics and mechanisms governing meiosis in mice, however, our knowledge of the meiotic initiation process in humans remains limited. Here, we utilized three-dimensional (3D) analysis to determine spatiotemporal dynamics of meiotic initiation in fetal human ovaries. Similar to mice, we found that the first meiotic cells appear in clusters in the center of human fetal ovaries as early at 9 weeks and that the initiation of meiosis propagates as a radial wave. Between developing germ cells in fetal human ovaries, we detected a component of the intercellular bridge, TEX14 protein. 3D quantification of germ cells in ovaries collected at the end of first trimester revealed, for the first time, considerable variation in the number of meiotic cells between individuals and asynchronous mitotic-meiotic transition. In addition to illustrating the geography of meiotic initiation in ovaries from the first trimester, we extended our 3D analysis approach to second trimester and showed heterogeneous spatial distribution of meiotic and non-meiotic germ cells in human fetal ovaries. This study is an important step towards better understanding of 3D structure of developing ovary and early stages of meiosis in humans. Highlights- Organic solvent-based clearing methods and confocal microscopy can be implemented to visualize and quantify germ cells in the intact human fetal ovary. - Identification of a new, radial, pattern of meiotic initiation in the ovaries from the first trimester. - Immunolocalization of the intercellular bridge component TEX14 between developing germ cells in the fetal ovary - Maintenance of pre-meiotic germ cells in second trimester ovaries suggests less synchronous mitotic-meiotic stage transition.

developmental biology↗