Primary human lung fibroblasts exhibit trigger- but not disease-specific cellular senescence and impair alveolar epithelial cell progenitor function

Abstract

Aging is the main risk factor for chronic lung diseases including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging such as cellular senescence are increased in different cell types such as fibroblasts in the lungs of these patients. However, whether the senescent phenotype of fibroblasts derived from IPF or COPD 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. H2O2and bleomycin treatment induced a senescent phenotype in phLF whereas TGF-β1 only had a pro-fibrotic effect. Interestingly, we did not observe any differences in susceptibility to senescence induction in phLF based on disease origin. However, exposure to different stimuli resulted in different senescent programs in phLF. Moreover, senescent phLF reduced colony formation efficiency of alveolar epithelial progenitor cells. In conclusion, the senescent phenotype of phLF is mainly determined by the senescence inducer and impairs alveolar epithelial progenitor capacityin vitro.

E-cigarette vapour induces cellular senescence in primary lung fibroblasts and may contribute to lung pathology

“…(31) In mice models, p16-positive senescent murine lung fibroblasts promote epithelial stem cell regeneration after injury, (32) while a recent study demonstrated that senescence-induced human lung fibroblasts impaired murine alveolar epithelial cell progenitor function. (33) These studies suggest that there might be a tight balance, where transient senescence is supportive for tissue repair and persistent senescence is detrimental for tissue repair. (34) This balance may be tissue and (micro-) environment-dependent.…”