Aging remodels progenitor and niche interactions in lung regeneration

Introduction 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. Methods To analyze aging modifications, we used aged wild-type mice of 18–24 months old, and Zmpste24 –/– deficient mice, which exhibit an accelerated phenotype. A three-dimensional organoid culture system was employed to assess in vitro regenerative capacity. Additionally, cells were isolated and characterized with senescence and autophagy markers. Results Our findings revealed that lung epithelial cells from aged mice and Zmpste24 –/– mice retain organoid forming potential, maintaining their phenotype and cellular homeostasis through increased autophagy-associated transcriptional response, particularly when co-cultured with young fibroblasts. Moreover, these progenitor cells may exhibit increased susceptibility to mechanical stress with aging potentially associated with reduced nuclear lamins and the Zmpste24 defect. This vulnerability is illustrated by FACS sorting, which can further compromise their regenerative potential. By contrast, cultured fibroblasts from Zmpste24 –/– mice show nuclear defects and acquire a senescent phenotype, characterized by the mechanistic target of rapamycin complex 1 (mTORC1) activation and reduced autophagy, which in turn impairs organoid formation. Discussion Our results indicate that, in aging, progenitor cells and their fibroblast niche integrate microenvironmental signals that shape cell-cell interactions essential for lung regeneration.