Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM
Open Access
- 29 June 2021
- Vol. 10 (7), 1628
- https://doi.org/10.3390/cells10071628
Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor survival. Age is a major risk factor, and both alveolar epithelial cells and lung fibroblasts in this disease exhibit features of cellular senescence, a hallmark of ageing. Accumulation of fibrotic extracellular matrix (ECM) is a core feature of IPF and is likely to affect cell function. We hypothesize that aberrant ECM deposition augments fibroblast senescence, creating a perpetuating cycle favouring disease progression. In this study, primary lung fibroblasts were cultured on control and IPF-derived ECM from fibroblasts pretreated with or without profibrotic and prosenescent stimuli, and markers of senescence, fibrosis-associated gene expression and secretion of cytokines were measured. Untreated ECM derived from control or IPF fibroblasts had no effect on the main marker of senescence p16Ink4a and p21Waf1/Cip1. However, the expression of alpha smooth muscle actin (ACTA2) and proteoglycan decorin (DCN) increased in response to IPF-derived ECM. Production of the proinflammatory cytokines C-X-C Motif Chemokine Ligand 8 (CXCL8) by lung fibroblasts was upregulated in response to senescent and profibrotic-derived ECM. Finally, the profibrotic cytokines transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) were upregulated in response to both senescent- and profibrotic-derived ECM. In summary, ECM deposited by IPF fibroblasts does not induce cellular senescence, while there is upregulation of proinflammatory and profibrotic cytokines and differentiation into a myofibroblast phenotype in response to senescent- and profibrotic-derived ECM, which may contribute to progression of fibrosis in IPF.Funding Information
- Jan Kornelis de Cock Stichting (2020-48)
- Rosalind Franklin Fellowship (0)
This publication has 42 references indexed in Scilit:
- Fibronectin at Select Sites Binds Multiple Growth Factors and Enhances their Activity: Expansion of the Collaborative ECM-GF ParadigmJournal of Investigative Dermatology, 2014
- Fibrotic extracellular matrix activates a profibrotic positive feedback loopJCI Insight, 2014
- Extracellular matrix proteins: A positive feedback loop in lung fibrosis?Matrix Biology, 2014
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- CTGF drives autophagy, glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growthCell Cycle, 2012
- Comparison of decellularization techniques for preparation of extracellular matrix scaffolds derived from three‐dimensional cell cultureJournal of Biomedical Materials Research Part A, 2012
- Smoking and Idiopathic Pulmonary FibrosisPulmonary Medicine, 2012
- Matrix Proteins from Smoke-Exposed Fibroblasts Are Pro-proliferativeAmerican Journal of Respiratory Cell and Molecular Biology, 2012
- Detection of mycoplasma in leukemia–lymphoma cell lines using polymerase chain reactionLeukemia, 2002
- A biomarker that identifies senescent human cells in culture and in aging skin in vivo.Proceedings of the National Academy of Sciences of the United States of America, 1995