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Journal Article Epublish 20 citations

PubMed: 34572347 DOI: 10.3390/biomedicines9091162

A Senescence Bystander Effect in Human Lung Fibroblasts.

Biomedicines 9(9)

Authors: David W Waters, Michael Schuliga, Prabuddha S Pathinayake, Lan Wei, Hui-Ying Tan, Kaj E C Blokland, Jade Jaffar, Glen P Westall, Janette K Burgess, Cecilia M Prêle, Steven E Mutsaers, Christopher L Grainge, Darryl A Knight

Affiliations

  • School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia.
  • National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis, New Lambton Heights, NSW 2308, Australia.
  • School of Medicine and Public Health, University of Newcastle, Callaghan, NSW 2308, Australia.
  • University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, 9713 GZ Groningen, The Netherlands.
  • Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Melbourne, VIC 3004, Australia.
  • Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, University of Western Australia, Nedlands, WA 6009, Australia.
  • Institute for Respiratory Health, University of Western Australia, Nedlands, WA 6009, Australia.
  • Providence Health Care Research Institute, Vancouver, BC V6Z 1Y5, Canada.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by a dense fibrosing of the lung parenchyma. An association between IPF and cellular senescence is well established and several studies now describe a higher abundance of senescent fibroblasts and epithelial cells in the lungs of IPF patients compared with age-matched controls. The cause of this abnormal accumulation of senescent cells is unknown but evidence suggests that, once established, senescence can be transferred from senescent to non-senescent cells. In this study, we investigated whether senescent human lung fibroblasts (LFs) and alveolar epithelial cells (AECs) could induce a senescent-like phenotype in "naïve" non-senescent LFs in vitro. Primary cultures of LFs from adult control donors (Ctrl-LFs) with a low baseline of senescence were exposed to conditioned medium (CM) from: (i) Ctrl-LFs induced to become senescent using HO or etoposide; (ii) LFs derived from IPF patients (IPF-LFs) with a high baseline of senescence; or (iii) senescence-induced A549 cells, an AEC line. Additionally, ratios of non-senescent Ctrl-LFs and senescence-induced Ctrl-LFs (100:0, 0:100, 50:50, 90:10, 99:1) were co-cultured and their effect on induction of senescence measured. We demonstrated that exposure of naïve non-senescent Ctrl-LFs to CM from senescence-induced Ctrl-LFs and AECs and IPF-LFs increased the markers of senescence including nuclear localisation of phosphorylated-H2A histone family member X (H2AXγ) and expression of p21, IL-6 and IL-8 in Ctrl-LFs. Additionally, co-cultures of non-senescent and senescence-induced Ctrl-LFs induced a senescent-like phenotype in the non-senescent cells. These data suggest that the phenomenon of "senescence-induced senescence" can occur in vitro in primary cultures of human LFs, and provides a possible explanation for the abnormal abundance of senescent cells in the lungs of IPF patients.

MeSH

Collagen, Cellular Senescence, Epithelial Cells, Lung, Fibroblasts, Phenotype, Bystander Effect

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