Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM

Kaj E C Blokland, Habibie Habibie, Theo Borghuis, Greta J Teitsma, Michael Schuliga, Barbro N Melgert, Darryl A Knight, Corry-Anke Brandsma, Simon D Pouwels, Janette K Burgess*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article number1628
Pages (from-to)1-18
Number of pages18
JournalCells
Volume10
Issue number7
DOIs
Publication statusPublished - 29-Jun-2021

Keywords

  • extracellular matrix
  • idiopathic pulmonary fibrosis
  • profibrotic
  • proinflammatory
  • senescence

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