Single-Cell Transcriptomic Atlas of Primate Ovarian Aging

Wang, Si; Zheng, Yuxuan; Li, Jingyi; Yu, Yang; Zhang, Weiqi; Song, Moshi; Liu, Zunpeng; Min, Zheying; Hu, Huifang; Jing, Ying; He, Xiaojuan; Sun, Liang; Ma, Lu; Esteban, Concepción Rodrı́guez; Chan, Piu; Qiao, Jie; Zhou, Qi; Belmonte, Juan Carlos Izpisúa; Qu, Jing; Tang, Fuchou; Liu, Guanghui

doi:10.1016/j.cell.2020.01.009

Cited by 405 publications

(376 citation statements)

References 99 publications

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“…Single cell gene expression analyses bridge the interface of cell biology, pathology and gene regulation. These analyses are transforming our understanding of intra-tissue heterogeneity in development, normal tissue homeostasis, and disease alike (Cao et al, 2019;Wang et al, 2020). Using single cell RNA-seq performed with the 10x Genomics platform, we generated a cellular atlas of the human fallopian tube in cancer-free women, and identified the transcriptional networks driving the expression programs of 13 major cell types.…”

Section: Discussionmentioning

confidence: 99%

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

Dinh

Lin

Abbasi

et al. 2020

Preprint

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The human fallopian tube harbors the cell-of-origin for the majority of high-grade serous 'ovarian' cancers (HGSCs), but its cellular composition, particularly the epithelial component, is poorly characterized. We performed single-cell transcriptomic profiling in 12 primary fallopian specimens from 8 patients, analyzing around 53,000 individual cells to map the major immune, fibroblastic and epithelial cell types present in this organ. We identified 10 epithelial sub-populations, characterized by diverse transcriptional programs including SOX17 (enriched in secretory epithelial cells), TTF3 and RFX3 (enriched in ciliated cells) and NR2F2 (enriched in early, partially differentiated secretory cells). Based on transcriptional signatures, we reconstructed a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3 high intermediate. Computational deconvolution of the cellular composition of advanced HGSCs based on epithelial subset signatures identified the 'early secretory' population as a likely precursor state for the majority of HGSCs. The signature of this rare population of cells comprised both epithelial (EPCAM, KRT) and mesenchymal (THY1, ACTA2) features, and was enriched in mesenchymal-type HGSCs (P = 6.7 x 10 -27 ), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia.

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Section: Discussionmentioning

confidence: 99%

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

Dinh

Lin

Abbasi

et al. 2020

Preprint

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“…In contrast, localization of CYP17A1 shifted from exclusively the theca interna in control mice to patches in the interstitial stroma in DHT-treated mice, supporting a potential role for the stroma in androgen production following certain perturbations (Candelaria et al 2019). Singlecell RNA sequencing studies have also demonstrated subpopulations of stromal cells expressing CYP17A1 and STAR (Wagner et al 2020, Wang et al 2020. Although stromal cells have demonstrated varied hormone production and responsiveness, definitive characterization of these dynamics and their functional significance remains to be established (Fig.…”

Section: R33mentioning

confidence: 95%

“…The stromal cell distribution is also likely to be affected by cyclic structural changes, as follicles grow and ovulate and corpora lutea develop. Changes are also evident over the reproductive lifespan, including increases in fibrotic collagen as demonstrated in aging murine and primate ovaries (Briley et al 2016, Wang et al 2020. Some possible cellular markers that have been identified include COUP-TFII and/or ARX (Hummitzsch et al 2013, Rotgers et al 2018.…”

Section: Incompletely Characterized Stromal Cellsmentioning

confidence: 99%

“…Higher expression in some of the human cells considered to be stroma was demonstrated for markers PDGFRA, DCN, COL1A1, COL6A1, STAR, and/or CYP17A1 (Wagner et al 2020). A different study delineated nonhuman primate ovarian stroma by expression of TCF21, COL1A2, and/ or STAR (Wang et al 2020). For these incompletely characterized stromal cell types, careful ontology, further marker identification, and attention to nuances of regionality and steroid production are critical next steps (Table 1).…”

Section: Incompletely Characterized Stromal Cellsmentioning

confidence: 99%

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The ovarian stroma as a new frontier

et al. 2020

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Historically, research in ovarian biology has focused on folliculogenesis, but recently the ovarian stroma has become an exciting new frontier for research, holding critical keys to understanding complex ovarian dynamics. Ovarian follicles, which are the functional units of the ovary, comprise the ovarian parenchyma, while the ovarian stroma thus refers to the inverse, or the components of the ovary that are not ovarian follicles. The ovarian stroma includes more general components such as immune cells, blood vessels, nerves, and lymphatic vessels, as well as ovary-specific components including ovarian surface epithelium, tunica albuginea, intraovarian rete ovarii, hilar cells, stem cells, and a majority of incompletely characterized stromal cells including the fibroblast-like, spindle-shaped, and interstitial cells. The stroma also includes ovarian extracellular matrix components. This review combines foundational and emerging scholarship regarding the structures and roles of the different components of the ovarian stroma in normal physiology. This is followed by a discussion of key areas for further research regarding the ovarian stroma, including elucidating theca cell origins, understanding stromal cell hormone production and responsiveness, investigating pathological conditions such as polycystic ovary syndrome (PCOS), developing artificial ovary technology, and using technological advances to further delineate the multiple stromal cell types.

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“…Inflammation is associated with numerous processes including mitochondrial, oxidative stress and uncontrolled inflammation can negatively affect female fertility (4).…”

mentioning

confidence: 99%

Inhibition of the NLRP3 inflammasome prevents ovarian aging

Navarro‐Pando

Alcocer-Gómez

Castejón-Vega

et al. 2020

Preprint

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Inflammation is a hallmark of many processes during aging and reproductive physiology, negatively affecting female fertility. The goal of this study was to evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in female WT mice during reproductive aging. High expression of NLRP3, caspase 1 and IL-1β was also observed in granulosa cells from patients with primary ovarian insufficiency. Ablation of the NLRP3 inflammasome improved the survival and pregnancy rates in mice, increased hormonal levels of AMH, a biochemical marker of ovarian reserve, and autophagy rates in ovarian tissue. Deficiency of the NLRP3 inflammasome also reduced serum FSH and estradiol levels. Consistent with these results, pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved fertility in female mice to levels comparable to those of Nlrp3−/− mice. These results suggest that the NLRP3 inflammasome is implicated in the age-dependent loss of female fertility and position this inflammasome as a potential new therapeutic target for the treatment of infertility.

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Single-Cell Transcriptomic Atlas of Primate Ovarian Aging

Abstract: Highlights d Single-cell transcriptomic roadmap of NHP ovarian aging d Molecular signatures revealed for NHP oocytes at stepwise developmental stages d Cell-type-specific inactivation of antioxidant genes in aged monkey and human ovaries

Cited by 405 publications

References 99 publications

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

The ovarian stroma as a new frontier

Inhibition of the NLRP3 inflammasome prevents ovarian aging

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