Biology subjects

Kooistra, W.

Publications and source records attributed to Kooistra, W..

2 recordsLinked to original sources

bioRxiv2023

Strong paracrine effects of SASP from senescence-induced severe early-onset COPD-derived fibroblasts

BackgroundLung fibroblasts from Severe Early-Onset (SEO-)COPD patients exhibit increased cellular senescence with higher levels of senescence-associated secretory phenotype (SASP) protein secretion. Yet, the impact of senescent fibroblasts, and their SASP, on surrounding fibroblasts in SEO-COPD lungs remains unclear. AimTo identify the effect of the SASP secreted by senescent SEO-COPD-derived fibroblasts on surrounding lung fibroblasts. MethodsCellular senescence was induced in lung fibroblasts derived from seven SEO-COPD patients (age[≤]53 years, FEV1<40% predicted), and conditioned medium (CM) containing the SASP, was collected (senescent CM). CM from untreated fibroblasts was used as control. Fibroblasts were stimulated with senescent and control CM, and with tissue plasminogen activator (t-PA), a previously identified COPD-associated SASP protein. Effects on paracrine senescence, inflammation, and extracellular matrix (ECM) regulation were assessed. ResultsStimulation with senescent CM increased the percentage of Senescence-associated beta-galactosidase positive fibroblasts and decreased p16, p21 & LMNB1 expression (p<0.05). T-PA did not affect these markers. Senescent CM increased IL-8 gene expression, increased IL-6 secretion, and strongly increased IL-8 secretion compared to control CM. T-PA slightly decreased IL-6 and IL-8 secretion. Additionally, senescent CM and t-PA stimulation both reduced decorin secretion. Senescent CM reduced FN1 gene expression, while DCN and MMP2 expression remained unaffected. T-PA did not affect ECM gene expression. ConclusionThe SASP from senescence-induced SEO-COPD-derived fibroblasts has a strong paracrine effect on untreated fibroblasts, suggesting that senescent lung fibroblasts contribute to chronic inflammation and ECM dysregulation. These findings imply involvement of senescent fibroblasts in abnormal lung ageing and possibly disease pathology in COPD.

cell biology↗

bioRxiv2023

Cellular Senescence Affects ECM Regulation in COPD Lung Tissue

IntroductionHigher levels of cellular senescence have been demonstrated in COPD patients, including severe early-onset (SEO)-COPD. Recently, we demonstrated that senescence induces extracellular matrix (ECM) dysregulation in lung fibroblasts. However, this in vitro observation has not been demonstrated in vivo yet. Therefore, we investigated whether cellular senescence can contribute to COPD-associated ECM changes in parenchymal lung tissue. MethodsTranscriptomic and proteomic analyses were performed on parenchymal lung tissue from 60 COPD patients (including 18 SEO-COPD patients) and 32 controls. Differential expression of ECM-related genes and proteins was compared between (SEO-)COPD and controls, followed by correlations with six senescence markers and four senescence signature scores. Significant ECM-senescence correlations were verified using histology and primary lung fibroblasts. ResultsWe identified 12 COPD- and 57 SEO-COPD-associated ECM genes and 4 COPD- and 9 SEO-COPD-associated ECM proteins of which the majority, 45 genes and 5 proteins, correlated with senescence. The correlations for COL6A1, COL6A2 and FBLN5 were confirmed in situ and correlations for 21 ECM genes were confirmed in primary lung fibroblasts at baseline. Four genes were successfully functionally validated in our senescence-induced lung fibroblast model, including increased protein levels of ADAMST1 and a non-functional FBLN5 protein. ConclusionsWe confirm a strong link between (SEO-)COPD-associated ECM changes and senescence in vivo in peripheral lung tissue from COPD patients. The strongest and most consistent senescence-associated ECM components include proteases, elastogenesis genes, and collagens 6. These results indicate a contributing role for senescence in disturbed ECM and elastic fiber organization, and protease-antiprotease imbalance in COPD.

pathology↗