Lung progenitors exhaustion in response to microenvironment stress during aging

Progenitor cells in aged tissues undergo changes in their microenvironment that may impact their functionality during regeneration. Despite recent advances in understanding the role of adult lung progenitors, the impact of aging on these cells remains unclear. To analyze aging modifications, we used aged wild-type mice of 18-24 months old, and Zmpste24-/- deficient mice, which exhibit an accelerated aging phenotype. A three-dimensional organoid culture system was employed to assess the lung regeneration capacity. Additionally, mouse epithelial cells and fibroblasts were isolated and characterized with senescence and autophagy markers. Our findings revealed that lung epithelial cells from aged mice and Zmpste24-/- mice hold their regeneration capacity, maintaining their phenotype and a healthy cellular state through an increase in autophagy, particularly when co-cultured with healthy fibroblasts. Conversely, cultured fibroblasts from Zmpste24-/- mice show nuclear defects and acquire a senescent phenotype, characterized by mTORC1 activation and reduced autophagy, which in turn impairs organoid formation. Moreover, these progenitor cells become increasingly susceptible to mechanical stress with aging due to reduced nuclear lamins and the Zmpste24 defect. This vulnerability is illustrated by FACS sorting, which can further compromise their regenerative potential. Our results indicate that, in aging, progenitor cells and their fibroblast niche integrate microenvironmental signals that shape cell-cell interactions essential for lung regeneration.