Aberrant epithelial reprogramming can induce metaplastic differentiation at sites of tissue injury, culminating in transformed barriers composed of scar and metaplastic epithelium. While the plasticity of epithelial stem cells is well-characterized, the identity and role of the niche has not been delineated in metaplasia. Here we show that
Gli1
+ mesenchymal stromal cells (MSCs), previously shown to contribute to myofibroblasts during scarring, promote metaplastic differentiation of airway progenitors into KRT5+ basal cells. During fibrotic repair,
Gli1
+ MSCs integrate hedgehog activation to upregulate BMP antagonism in the progenitor niche that promotes metaplasia. Restoring the balance towards BMP activation attenuated metaplastic KRT5+ differentiation while promoting adaptive alveolar differentiation into SFTPC+ epithelium. Finally, fibrotic human lungs demonstrate altered BMP activation in the metaplastic epithelium. These findings show that
Gli1
+ MSCs integrate hedgehog signaling as a rheostat to control BMP activation in the progenitor niche to determine regenerative outcome in fibrosis.
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.
Senescent cells are recognized drivers of aging-related decline in organ function, but deciphering the biology of senescence in vivo has been hindered by the paucity of tools to track and isolate senescent cells in tissues1–4. Deleting senescent cells from transgenic murine models have demonstrated therapeutic benefits in numerous age-related diseases5–11, but the identity, behavior, and function of the senescent cells deleted in vivo remain elusive. We engineered an ultra-sensitive reporter of p16INK4a, a biomarker of senescence12, to isolate and track p16INK4a+ cells in vivo. Surprisingly, p16INK4a+ mesenchymal cells appear in the basement membrane adjacent to epithelial progenitors in the lung shortly after birth, and these cells demonstrate senescent characteristics in vivo and ex vivo. Transcriptomic analysis of p16INK4a+ mesenchymal cells from non-aged lungs demonstrates a transition to a secretory phenotype upon airway epithelial injury. Heterotypic 3D organoid assays show that injured p16INK4a+ mesenchymal cells enhance epithelial progenitor proliferation, and we identified EREG as a novel airway progenitor mitogen produced by the secretory p16INK4a+ mesenchymal cells. Mesenchymal-specific deletion of the p16INK4a gene abrogates features of senescence in vivo, but also attenuates normal epithelial repair. Thus, p16INK4a+ 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 in vivo 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.