Sentinel <i>p16</i> ^INK4a+ cells in the basement membrane form a reparative niche in the lung

Abstract

We engineered an ultrasensitive reporter of <i>p16</i>^INK4a, a biomarker of cellular senescence. Our reporter detected <i>p16</i>^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 <i>p16</i>^INK4a+ fibroblasts had enhanced capacity to sense tissue inflammation and respond through their increased secretory capacity to promote epithelial regeneration. In addition, <i>p16</i>^INK4a expression was required in fibroblasts to enhance epithelial regeneration. This study highlights a role for <i>p16</i>^INK4a+ fibroblasts as tissue-resident sentinels in the stem cell niche that monitor barrier integrity and rapidly respond to inflammation to promote tissue regeneration.