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Senescence-Linked Fibrosis in the Aging Human Ovary Revealed by p16-Based Histological Profiling and Spatial Transcriptomics

Watson, M. A.; Devrukhkar, P. R.; Murad, N. F.; Wu, F.; Kim, M. J.; Anvari, H.; Tran, U.; Martin, N.; Tran, T.; Zaza, G.; Schneider, K.; Soygur, B.; Shanes, E. D.; Wirtz, D.; Pavone, M. G.; Melov, S.; Wu, P.-H.; Furman, D.; Duncan, F. E.; Schilling, B.

2025-12-08 cell biology
10.64898/2025.12.03.692228 bioRxiv
Show abstract

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.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.