Spatiotemporal analysis of human ovarian aging at single-cell resolution

Wang, Shixuan; Wu, Meng; Tang, Weicheng; Chen, Ying; Wu, Chuqing; Zhu, Xiaoran; Sun, Chaoyang; Li, Yan; Zhang, Jinjin; Dai, Jun; Zhou, Su; Xue, Liru; Chen, Dan; Xiong, Jiaqiang; Yu, Jihong; Li, Hongyi; Zhao, Yongtao; Guo, Yican; Huang, Yibao; Zhu, Qingqing; Wei, Simin; Gao, Junbao; Wu, Mingfu; Li, Ya; Tang, Xiang

doi:10.21203/rs.3.rs-1624864/v1

Cited by 8 publications

(6 citation statements)

References 40 publications

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“…Wang et al [5] reported aging in monkey ovaries is associated with oxidative damage in oocytes and granulosa cells. Wang et al [7] also used scRNAseq studies to understand age-related changes in human ovaries. They detected several cellular senescence and inflammatory changes in aged ovaries and identified FOXP1 as a central protective factor for ovarian aging.…”

Section: Main Textmentioning

confidence: 99%

VSELs and OSCs together sustain oogenesis in adult ovaries and their dysfunction results in age-related senescence, PCOS, POI and cancer

Bhartiya

Sharma

2023

J Ovarian Res

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Multiple studies using single-cell RNA sequencing (scRNAseq) have failed to detect stem cells in adult ovaries. We have maintained that two populations of ovarian stem cells including pluripotent, very small embryonic-like stem cells (VSELs) and tissue-committed ‘progenitors’ termed ovarian stem cells (OSCs) can easily be detected in Hematoxylin and Eosin-stained ovary surface epithelial (OSE) cells smears prepared from both mice and human ovaries. Most likely the stem cells never get subjected to scRNAseq since they pellet down only by centrifuging cells suspension at 1000 g while cells for scRNAseq were invariably prepared by centrifuging at 200-400 g. A recent article provided further explanation for the failure of scRNAseq to detect ovarian stem cells. Extensive reanalysis of data (generated by scRNAseq) using an advanced software successfully detected OSCs and meiotic markers supporting neo-oogenesis in adult human ovaries. But this article remained critical on the biological relevance of VSELs and their relationship with OSCs. By carefully studying the OSE cells smears (which hold VSELs, OSCs and germ cell nests GCNs), prepared by partial trypsin digestion of intact mice ovaries during different stages of estrus cycle, we have successfully delineated novel functions of VSELs/OSCs in vivo under physiological conditions. VSELs undergo asymmetrical divisions to self-renew and give rise to slightly bigger OSCs which in turn undergo symmetrical divisions and clonal expansion to form GCNs, regular neo-oogenesis and follicle assembly. GCNs have been earlier described in fetal ovaries and during OSE cells culture (from adult ovaries) in response to FSH treatment. Dysfunction of VSELs/OSCs (which express ERα, ERβ, FSHR) due to neonatal exposure to endocrine disruption results in ovarian insufficiency and polycystic ovaries. VSELs have also been implicated in ovarian cancer. Age-related ovarian senescence/menopause is also due to dysfunction and blocked differentiation of VSELs/OSCs. These novel findings in vivo along with abundant in vitro and lineage tracing studies data in published literature provides huge scope for further research, offers novel avenues to manage ovarian pathologies and calls for re-writing of textbooks.

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Section: Main Textmentioning

confidence: 99%

VSELs and OSCs together sustain oogenesis in adult ovaries and their dysfunction results in age-related senescence, PCOS, POI and cancer

Bhartiya

Sharma

2023

J Ovarian Res

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“…Single-cell analyses of ovarian aging in nonhuman primates identified downregulation of antioxidant programs in aged oocytes and increased apoptosis in aged granulosa cells (GCs) 18 . In addition, single-cell analyses of human ovarian tissue are currently in progress 19 . However, mice represent the model organism most utilized for ovarian aging studies 20 due to their short lifespan and ease of genetic manipulation for mechanistic studies.…”

Section: Ovarian Immune Cell Changes With Agingmentioning

confidence: 99%

A single-cell atlas of the aging mouse ovary

Isola,

Ocañas,

Hubbart

et al. 2024

Nat Aging

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Ovarian aging leads to diminished fertility, dysregulated endocrine signaling and increased chronic disease burden. These effects begin to emerge long before follicular exhaustion. Female humans experience a sharp decline in fertility around 35 years of age, which corresponds to declines in oocyte quality. Despite a growing body of work, the field lacks a comprehensive cellular map of the transcriptomic changes in the aging mouse ovary to identify early drivers of ovarian decline. To fill this gap we performed single-cell RNA sequencing on ovarian tissue from young (3-month-old) and reproductively aged (9-month-old) mice. Our analysis revealed a doubling of immune cells in the aged ovary, with lymphocyte proportions increasing the most, which was confirmed by flow cytometry. We also found an age-related downregulation of collagenase pathways in stromal fibroblasts, which corresponds to rises in ovarian fibrosis. Follicular cells displayed stress-response, immunogenic and fibrotic signaling pathway inductions with aging. This report provides critical insights into mechanisms responsible for ovarian aging phenotypes. The data can be explored interactively via a Shiny-based web application.

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“…However, the sequencing depth of spatial transcriptomics is still limited compared to single-cell transcriptomics, making it less powerful in identifying the relatively confined changes in transcriptomes from young and old organisms. Therefore, the combination of spatial transcriptomics and single-cell transcriptomics is a trend in current analysis, such as in a recent preprint study of human ovarian aging (48). Nevertheless, technological advancements in spatial transcriptomics for higher resolution and more accurate incorporation of multimodal data with imaging will undoubtedly provide more insight into aging-associated molecular remodeling with the anatomical organization of cells.…”

Section: Spatial Omicsmentioning

confidence: 99%

Decoding Aging Hallmarks at the Single-Cell Level

Cai

et al. 2023

Annu. Rev. Biomed. Data Sci.

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Organismal aging exhibits wide-ranging hallmarks in divergent cell types across tissues, organs, and systems. The advancement of single-cell technologies and generation of rich datasets have afforded the scientific community the opportunity to decode these hallmarks of aging at an unprecedented scope and resolution. In this review, we describe the technological advancements and bioinformatic methodologies enabling data interpretation at the cellular level. Then, we outline the application of such technologies for decoding aging hallmarks and potential intervention targets and summarize common themes and context-specific molecular features in representative organ systems across the body. Finally, we provide a brief summary of available databases relevant for aging research and present an outlook on the opportunities in this emerging field. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Spatiotemporal analysis of human ovarian aging at single-cell resolution

Cited by 8 publications

References 40 publications

VSELs and OSCs together sustain oogenesis in adult ovaries and their dysfunction results in age-related senescence, PCOS, POI and cancer

VSELs and OSCs together sustain oogenesis in adult ovaries and their dysfunction results in age-related senescence, PCOS, POI and cancer

A single-cell atlas of the aging mouse ovary

Decoding Aging Hallmarks at the Single-Cell Level

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