Treffer: Comparative analysis of human and mouse ovaries across age.

The 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 three-dimensional 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 decreases in density. Oocytes had species-specific gene expression patterns during growth that converged toward maturity. Age-related transcriptional changes were greater in oocytes than in granulosa cells across species, although mature oocytes change more in humans. We identified ovarian sympathetic nerves and glia; axon density increased in aged ovaries and, when ablated in mice, perturbed folliculogenesis. This comparative atlas defines shared and species-specific hallmarks of ovarian biology. Editor's summary: Mice are frequently used in biomedical research as a model of human biology and disease, but there are many differences between the two, and it is helpful to know what exactly those differences are when interpreting data from mouse models of disease. An atlas of ovarian aging compiled by Gaylord et al. facilitates this task and provides insights into both species by characterizing transcriptomic changes and physical structure and function of the ovaries at different ages and life stages. In addition to providing a resource with side-by-side species comparisons, the authors also identified neurons and glia within the ovaries and examined their role in folliculogenesis in mice, which may be relevant for human fertility as well. —Yevgeniya Nusinovich INTRODUCTION: The ovary governs fertility and reproductive aging by coordinating interactions between germline and somatic cells. In mammals, oocytes are formed before birth and do not renew; their decrease through ovulation and cell death determines the onset of menopause. Ovarian function declines long before age-related degeneration of all other organs, with pregnancy at 35 clinically considered "geriatric." Improved understanding of ovarian biology and hallmarks of ovarian aging is needed to devise therapies for prolonging fertility and delaying menopause. RATIONALE: Laboratory mice share many reproductive features with humans and are widely used to study ovarian biology. However, their utility is limited by incomplete understanding of how cellular composition and molecular programs compare with those of human ovaries, especially during aging. RESULTS: We performed a multimodal analysis of human and C57BL6/J mouse ovaries at young and advanced reproductive ages. We combined three-dimensional tissue imaging, single-cell RNA sequencing (scRNA-seq), and functional assays to define shared and species-specific features of oocyte follicle distribution, follicle growth and maturation, cellular composition and signaling, and age-associated changes. High-resolution imaging of optically cleared intact mouse ovaries and human ovary fragments revealed discrete cortical "pockets" of human oocytes that shrink with age. Follicle density decreased with age in both species, and early decline of secondary-stage follicles in mice suggests vulnerability specific to stages of growth. scRNA-seq captured all major ovarian cell types and revealed both conserved and species-specific subtypes. Mature oocytes from both species shared enriched pathways, whereas immature oocytes diverged more substantially. Aging altered the transcriptome of oocytes in humans and mice more compared with that of surrounding granulosa cells, although early-stage oocytes were more changed in mice, and late-stage oocytes were more changed in humans. Subtype analysis revealed that granulosa, fibroblast, and endothelial cells shared conserved transcriptional programs, whereas species-specific subtypes emerged in theca, pericyte, and epithelial compartments. Ovarian glial cells were identified in both species, frequently in association with sympathetic nerves. Innervation was implicated in the growth of follicles by genetically ablating sympathetic nerves in mice, and pericytes were shown as the major source of nerve growth factor. Networks of ovarian nerves became more dense with age in mouse and human samples. In ovarian fibroblasts, age-related transcriptional changes included down-regulation of collagen genes, despite increased deposition of collagen protein in aged human ovaries, suggesting a conserved compensatory mechanism for fibrosis. Functionally, the competence and developmental potential of mouse oocytes declined markedly by 9 months of age, recapitulating the age dependence of human in vitro fertilization. Intercellular signaling between oocytes, granulosa, and theca cells was altered with age, revealing species-shared and -specific changes in pathways regulating oocyte support and maturation. CONCLUSION: This work provides a comprehensive reference of ovarian aging across mouse and human populations, revealing conserved cellular specialization, including sympathetic nerves and glia, alongside species-specific dynamics of follicle depletion, oocyte maturation, and stromal remodeling. Our findings enhance the interpretability of mouse models for human reproductive aging and establish a foundational resource for cross-species analysis of ovarian function and decline. Schematic of whole-mount imaging, scRNA-seq, and functional assays used to compare human and mouse ovaries.: Key findings include conserved and species-specific changes in follicle density and distribution, cellular composition, and innervation across reproductive aging in mouse and human ovaries. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR]

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