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

We engineered an ultrasensitive reporter of p16^INK4a, a biomarker of cellular senescence. Our reporter detected p16^INK4a-expressing fibroblasts with certain senescent characteristics that appeared shortly after birth in the basement membrane adjacent to epithelial stem cells in the lung. Furthermore, these p16^INK4a+ fibroblasts had enhanced capacity to sense tissue inflammation and respond through their increased secretory capacity to promote epithelial regeneration. In addition, p16^INK4a expression was required in fibroblasts to enhance epithelial regeneration. This study highlights a role for p16^INK4a+ fibroblasts as tissue-resident sentinels in the stem cell niche that monitor barrier integrity and rapidly respond to inflammation to promote tissue regeneration.