Kavli Affiliate: Denis Wirtz
| Authors: Mark A Watson, Pooja Raj Devrukhkar, Natalia F Murad, Fan Wu, Moo J Kim, Hannah Anvari, Uyen Tran, Nicolas Martin, Tommy Tran, Giuliana Zaza, Kevin Schneider, Bikem Soygur, Elisheva D Shanes, Denis Wirtz, MaryEllen G Pavone, Simon Melov, Pei-Hsun Wu, David Furman, Francesca E Duncan and Birgit Schilling
| Summary:
Cellular senescence is implicated as a driver of ovarian aging, but senescent cells in the human postmenopausal ovary remain poorly defined. Using spatially resolved p16INK4a protein expression, a canonical senescence marker, we identified and mapped senescent cells in postmenopausal ovaries. We integrated p16 immunohistochemistry, multiplexed immunofluorescence, spatial transcriptomics, and AI-guided digital pathology to map senescent microenvironments. p16-positive cells formed discrete stromal, vascular, and cyst-associated clusters that increased with age and were enriched for macrophages and myofibroblast-like cells. Wholetranscriptome profiling of 92 spatial regions uncovered a 32-gene p16-associated signature, BuckSenOvary, that distinguished p16-positive regions across cortex and medulla. BuckSenOvary is characterized by suppression of cell-cycle regulators and activation of inflammatory and extracellular-matrix remodelling genes. AI-based collagen matrix analysis confirmed that p16-positive regions exhibit more architecturally complex collagen, demonstrating that focal senescent microenvironments are fibro-inflammatory. These findings position senescent ovarian niches as therapeutic targets to preserve ovarian function.