Stimuli-specific senescence of primary human lung fibroblasts modulates alveolar stem cell function

Abstract

Aging is the main risk factor for chronic lung diseases (CLDs) including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging such as cellular senescence are present in different lung cell types such as fibroblasts in these patients. However, whether the senescent phenotype of fibroblasts derived from IPF or COPD patients differs is still unknown. Therefore, we characterized senescence at baseline and after exposure to disease-relevant insults (H2O2, bleomycin, and TGF-β1) in cultured primary human lung fibroblasts (phLF) from control donors, IPF, or COPD patients. We found that phLF from different disease-origins have a low baseline senescence. H2O2 and bleomycin treatment induced a senescent phenotype in phLF, whereas TGF-β1 had primarily a pro-fibrotic effect. Notably, we did not observe any differences in susceptibility to senescence induction in phLF based on disease origin, while exposure to different stimuli resulted in distinct senescence programs in phLF. Moreover, senescent phLF reduced colony formation efficiency of distal alveolar epithelial progenitor cells in a stimuli-dependent manner. In conclusion, the senescent phenotype of phLF is mainly determined by the senescence inducer and impairs alveolar epithelial progenitor capacity in vitro.