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- Title
Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM.
- Authors
Blokland, Kaj E. C.; Habibie, Habibie; Borghuis, Theo; Teitsma, Greta J.; Schuliga, Michael; Melgert, Barbro N.; Knight, Darryl A.; Brandsma, Corry-Anke; Pouwels, Simon D.; Burgess, Janette K.
- 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.
- Subjects
MYOFIBROBLASTS; CELLULAR aging; CONNECTIVE tissue growth factor; IDIOPATHIC pulmonary fibrosis; TRANSFORMING growth factors; EXTRACELLULAR matrix
- Publication
Cells (2073-4409), 2021, Vol 10, Issue 7, p1628
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells10071628