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

Abstract

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.

Multiparametric senescent cell phenotyping reveals CD24 osteolineage cells as targets of senolytic therapy in the aged murine skeleton

“…2C). Similar to recent findings using highly sensitive p16 Ink4a -reporter mice (INKBRITE) 37 , we found an inverse relationship between Ki67 and p16 expression (Extended Data Fig. 3B), which also revealed that clusters both high in p16 and low in Ki67 were defined by expression of BCL-2, a major regulator of apoptosis resistance 41 (Fig.…”

“…Although long-established as a marker of senescence, we found that p16 expression labels a diverse set of cells with both senescent and non-senescent properties. This finding is entirely consistent with recent findings using highly sensitive p16 Ink4a reporter mice (INKBRITE) 37 , although we provide important complementary data at the protein level to the transcriptional data in the previous study. Specifically, similar to our finding of p16 protein expression in both Ki67 negative and positive bone and marrow mesenchymal cells, in the INKBRITE p16 Ink4a reporter mice, p16 Ink4a was also expressed in both proliferating and non-proliferating lung fibroblasts.…”

“…2D-F; Extended Data Fig. 3B), high p16 Ink4a -expressing fibroblasts from the INKBRITE mice had lower proliferative capacity than low p16 Ink4a -expressing cells 37 . Collectively, these findings indicate that there is a spectrum of p16 Ink4a RNA and protein expression in vivo , with high expression associated with growth arrest and the full senescent phenotype.…”

“…Although found to be associated with age, p16 positivity can also be a characteristic of non-senescent cells 37–40 , and thus in isolation may not identify a pure population of truly senescent cells. Therefore, to define additional markers uniquely associated with age-induced senescent cells, we performed multidimensional clustering of p16+ mesenchymal cells from young and aged mice using all markers in our senescence panel (Fig.…”

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells

“…However, the use of senolytic drugs to treat cancers is complicated by the fact that our understanding of how senescent fibroblasts can impact normal (non-cancerous) cells remains quite limited. For example, recent evidence suggests that senescent fibroblasts in the lung can sense injury-induced tissue inflammation, alter the stem cell niche, and facilitate the regeneration of epithelial barrier integrity (30). Therefore, additional studies that better clarify the relationship between senescent fibroblasts and non-cancerous epithelial cells are critically important to better understand the efficacy of this therapeutic strategy.…”