{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T20:15:10Z","timestamp":1781813710122,"version":"3.54.5"},"reference-count":45,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T00:00:00Z","timestamp":1624924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016401","name":"Jan Kornelis de Cock Stichting","doi-asserted-by":"publisher","award":["2020-48"],"award-info":[{"award-number":["2020-48"]}],"id":[{"id":"10.13039\/100016401","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Rosalind Franklin Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 \u03b21 (TGF-\u03b21) 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.<\/jats:p>","DOI":"10.3390\/cells10071628","type":"journal-article","created":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T10:52:46Z","timestamp":1624963966000},"page":"1628","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1807-6359","authenticated-orcid":false,"given":"Kaj E. C.","family":"Blokland","sequence":"first","affiliation":[{"name":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands"},{"name":"University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, 9713 GZ Groningen, The Netherlands"},{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia"},{"name":"National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis, Sydney, NSW 2050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habibie","family":"Habibie","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, 9713 GZ Groningen, The Netherlands"},{"name":"University of Groningen, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, 9713 GZ Groningen, The Netherlands"},{"name":"Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo","family":"Borghuis","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands"},{"name":"University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greta J.","family":"Teitsma","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands"},{"name":"University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6742-5028","authenticated-orcid":false,"given":"Michael","family":"Schuliga","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7091-907X","authenticated-orcid":false,"given":"Barbro N.","family":"Melgert","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands"},{"name":"University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, 9713 GZ Groningen, The Netherlands"},{"name":"University of Groningen, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darryl A.","family":"Knight","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia"},{"name":"National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis, Sydney, NSW 2050, Australia"},{"name":"Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Providence Health Care Research Institute, Vancouver, BC V6Z 1Y6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corry-Anke","family":"Brandsma","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands"},{"name":"University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7345-8061","authenticated-orcid":false,"given":"Simon D.","family":"Pouwels","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands"},{"name":"University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, 9713 GZ Groningen, The Netherlands"},{"name":"Department of Pulmonology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9868-9966","authenticated-orcid":false,"given":"Janette K.","family":"Burgess","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands"},{"name":"University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1164\/rccm.201506-1063ST","article-title":"An Official ATS\/ERS\/JRS\/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. 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