The function and decline of the female reproductive tract at single-cell resolution

Abstract

The female reproductive tract (FRT) undergoes extensive remodeling during each reproductive cycle, regulated by systemic changes in sex hormones. Whether this recurrent remodeling influences a specific organ's aging trajectory is unknown. To address this, we systematically characterized at single-cell resolution the morphological and transcriptional changes that occur in ovary, oviduct, uterus, cervix, and vagina at each phase of the mouse estrus cycle, during decidualization, and into aging. Transcriptional and cell-to-cell communication networks in estrus cycle and aging are enriched for ECM reorganization and inflammation, two essential components of FRT remodeling. We directly link the organ-specific level of these two processes over reproductive lifespan with the gradual, age-related development of fibrosis and chronic inflammation. Our data represent a comprehensive atlas of the FRT lifespan, revealing pathological consequences of incomplete resolution of recurrent inflammation and tissue repair.

Systemic low-dose anti-fibrotic treatment attenuates ovarian aging in the mouse

“…Fibrosis and inflammation are hallmarks of many aging tissues, and this is also true of the ovary which ages earlier relative to most organs [5, 10, 11, 15, 20–22, 24–27]. In this study, we advanced the field by demonstrating that we could mitigate age-related ovarian fibrosis through a systemic and constant administration of low dose Pirfenidone, an anti-fibrotic drug, for 6 weeks beginning in mice at 7 months of age when fibrotic foci are first observed in the ovary [20].…”

Superovulation and aging perturb oocyte-granulosa cell communication

“…We asked whether aging may also increase cell-to-cell variability in oocytes, as has been previously reported for other cell types. [85][86][87][88] We first compared gene expression variability by Shannon entropy between young and old oocytes (Figure 5D), and found that aging increases cell-to-cell variability. Similar analyses revealed that superovulation also substantially increases oocyte cell-cell variability in gene expression (Figure 5D).…”

Mechanisms of Regeneration and Fibrosis in the Endometrium

“…Glandular offshoots (glandular epithelium) extending from the surface epithelium (luminal epithelium) project into the stroma and merge into a highly branched plexus running parallel to the myometrial border (Tempest et al 2020, Yamaguchi et al 2021. Recent single-cell transcriptomic approaches have revealed extensive heterogeneity among endometrial stromal and epithelial populations, illuminating the complexity of this important tissue (Garcia-Alonso et al 2021;Kirkwood et al 2021Kirkwood et al , 2022Wang et al 2020;Winkler et al 2022).…”