Cellular Senescence Affects ECM Regulation in COPD Lung Tissue

Woldhuis, R. R.; Bekker, N. J.; Nijnatten, J. L. L.; Meuleman, R. A.; Kooistra, W.; Wolters, K. J. C.; Horvatovich, P. L.; Guryev, V.; van den Berge, M.; Timens, W.; Brandsma, C.-A.

doi:10.1101/2023.08.02.551614

bioRxiv · 10.1101/2023.08.02.551614

Cellular Senescence Affects ECM Regulation in COPD Lung Tissue

Woldhuis, R. R.·Bekker, N. J.·Nijnatten, J. L. L.·Meuleman, R. A.·Kooistra, W.·Wolters, K. J. C.·Horvatovich, P. L.·Guryev, V.·van den Berge, M.·Timens, W.·Brandsma, C.-A.

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Abstract

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.

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Woldhuis, R. R., Bekker, N. J., Nijnatten, J. L. L., Meuleman, R. A., Kooistra, W., Wolters, K. J. C., Horvatovich, P. L., Guryev, V., van den Berge, M., Timens, W., Brandsma, C.-A.. 2023-08-05. Cellular Senescence Affects ECM Regulation in COPD Lung Tissue. https://doi.org/10.1101/2023.08.02.551614

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