Sentinel p16 INK4a + cells in the basement membrane form a reparative niche in the lung

Senescent cells are recognized drivers of aging-related decline in organ function, but deciphering the biology of senescence has been hindered by the paucity of tools to track and isolate senescent cells in tissues. Deleting senescent cells from transgenic murine models have demonstrated therapeutic benefits in numerous age-related diseases, but the identity, behavior, and function of the senescent cells deleted remain elusive. We engineered an ultra-sensitive reporter of , a biomarker of senescence, to isolate and track + cells . Surprisingly, + mesenchymal cells appear in the basement membrane adjacent to epithelial progenitors in the lung shortly after birth, and these cells demonstrate senescent characteristics and . Transcriptomic analysis of + mesenchymal cells from non-aged lungs demonstrates a transition to a secretory phenotype upon airway epithelial injury. Heterotypic 3D organoid assays show that injured + mesenchymal cells enhance epithelial progenitor proliferation, and we identified EREG as a novel airway progenitor mitogen produced by the secretory + mesenchymal cells. Mesenchymal-specific deletion of the gene abrogates features of senescence , but also attenuates normal epithelial repair. Thus, + mesenchymal cells can act as sentinels for the airway epithelial stem cell niche, poised to transition to a senescence-associated secretory phenotype to support barrier repair. Our data identify possible cellular targets for a rapidly growing list of senolytic therapies, but also raises important questions about the hidden cost of targeting senescent cells present in normal organs.