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.
Aging is the final stage of development with stereotyped changes in tissue morphology. These age-related changes are risk factors for a multitude of chronic lung diseases, transcending the diverse pathogenic mechanisms that have been studied in disease-specific contexts. Two of the hallmarks of aging include inflammation and cellular senescence, which have been attributed as drivers of age-related organ decline. While these two age-related processes are often studied independently in the same tissue, there appears to be a reciprocal relationship between inflammation and senescence, which remodels the aging tissue architecture to increase susceptibility to chronic diseases. This review will attempt to address the “chicken or the egg” question as to whether senescence drives inflammation in the aging lung, or vice versa, and whether the causality of this relationship has therapeutic implications for age-related lung diseases.
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