Single-Cell Atlas of Human Ovaries Reveals The Role Of The Pyroptotic Macrophage in Ovarian Aging

Adv Sci (Weinh). 2024 Jan;11(4):e2305175. doi: 10.1002/advs.202305175. Epub 2023 Nov 30.


Female fecundity declines in a nonlinear manner with age during the reproductive years, even as ovulatory cycles continue, which reduces female fertility, disrupts metabolic homeostasis, and eventually induces various chronic diseases. Despite this, the aging-related cellular and molecular changes in human ovaries that occur during these reproductive years have not been elucidated. Here, single-cell RNA sequencing (scRNA-seq) of human ovaries is performed from different childbearing ages and reveals that the activation of the pyroptosis pathway increased with age, mainly in macrophages. The enrichment of pyroptotic macrophages leads to a switch from a tissue-resident macrophage (TRM)-involve immunoregulatory microenvironment in young ovaries to a pyroptotic monocyte-derived macrophage (MDM)-involved proinflammatory microenvironment in middle-aged ovaries. This remolded ovarian immuno-microenvironment further promotes stromal cell senescence and accelerated reproductive decline. This hypothesis is validated in a series of cell and animal experiments using GSDMD-KO mice. In conclusion, the work expands the current understanding of the ovarian aging process by illustrating a pyroptotic macrophage-involved immune mechanism, which has important implications for the development of novel strategies to delay senescence and promote reproductive health.

Keywords: aging; cell death; developmental trajectory; immune cells; intercellular communication; macrophage; ovary; pyroptosis; senescence; single-cell RNA sequencing.

MeSH terms

  • Aging* / physiology
  • Animals
  • Cellular Senescence / physiology
  • Female
  • Humans
  • Macrophages / metabolism
  • Mice
  • Middle Aged
  • Ovary* / metabolism
  • Pyroptosis