A single-cell atlas of the aging murine ovary

Abstract

Ovarian aging leads to diminished fertility, dysregulated endocrine signaling, and increased chronic disease burden. These effects begin to emerge long before follicular exhaustion. Around 35 years old, women experience a sharp decline in fertility, corresponding to declines in oocyte quality. However, the field lacks a cellular map of the transcriptomic changes in the aging ovary to identify 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 T and B lymphocyte proportions increasing most. We also discovered an age-related upregulation of alternative macrophage and downregulation of collagenase pathways in stromal fibroblasts. Overall, follicular cells (especially granulosa and theca) display stress response, immunogenic, and fibrotic signaling pathway inductions with aging. These changes are more exaggerated in the atretic granulosa cells but are also observed in healthy antral and preantral granulosa cells. Moreover, we did not observe age-related changes in markers of cellular senescence in any cellular population with advancing age, despite specific immune cells expressing senescence-related genes across both timepoints. This report raises several new hypotheses that could be pursued to elucidate mechanisms responsible for ovarian aging phenotypes.

Mast cell tryptase is involved in the pathogenesis of POI by inducing ovarian fibrosis via protease-activated receptor-2 signaling.

“…Excessive amount of ECM, indicative of tissue brosis, is responsible for impaired ovarian function 32 . Increased in ammation and brosis occur before the exhaustion of follicles and probably lead to ovarian insu ciency 33 . Mast cells are mostly best known for their role in in ammation, and they are mainly located in ovarian stromal tissues 34 .…”

Analysis of cell–cell interaction between mural granulosa cells and cumulus granulosa cells during ovulation using single‐cell RNA sequencing data of mouse ovary

“…reported the role of progesterone receptor in ovulation after the LH surge using an scRNA‐seq approach. 8 Although there have been other reports of single‐cell RNA sequencing in mouse ovaries, 9 , 10 , 11 , 12 the changes in the interactions between MGCs and CGCs during ovulation remain unclear. In this study, we performed in silico analysis of the reported scRNA‐seq data of mouse ovary to investigate the interactions between MGCs and CGCs during ovulation after the LH surge.…”