{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:09:39Z","timestamp":1790611779928,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2011,2,21]],"date-time":"2011-02-21T00:00:00Z","timestamp":1298246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2011,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Fibrosis can occur in many organs, where it is a debilitating and preneoplastic condition. The senescence of activated fibroblasts has been proposed to ameliorate fibrosis via the innate immune system but its role in humans has not been investigated. The availability of oral submucous fibrosis (OSMF) biopsies at different stages of disease progression allowed us to test the hypothesis that senescent fibroblasts accumulate with the progression of human fibrosis <jats:italic>in vivo<\/jats:italic>, and also to examine the mechanism of senescence. We tested the hypothesis that senescent cells may ameliorate fibrosis by increasing the secretion of matrix metalloproteinases (MMPs). We have used a combination of <jats:italic>in situ<\/jats:italic> immunodetection techniques, drug treatments, fluorescence\u2010activated cell sorting and enzyme\u2010linked absorbance assays on tissue samples and fibroblast cultures. We report a novel panning technique, based on fibronectin adhesion rates, to enrich and deplete senescent cells from fibroblast populations. Senescent fibroblasts, as determined by the presence of senescence\u2010associated heterochromatic foci, accumulated with OSMF progression (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup> = 0.98) and possessed a reduced replicative lifespan <jats:italic>in vitro<\/jats:italic>. Unlike wounds, however, OSMF fibroblasts were quiescent <jats:italic>in vivo<\/jats:italic> and consistent with this observation, possessed functional telomeres of normal length. Senescence was associated <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> with oxidative damage, DNA damage foci and p16<jats:sup>INK4A<\/jats:sup> accumulation and required the production of reactive oxygen species (ROS), perhaps from damaged mitochondria, but not the continuous presence of the disease stimulus (areca nut and tobacco), the tissue environment or other cell types. Depletion of OSMF fibroblasts of senescent cells showed that these cells accounted for 25\u201383 times more MMP\u20101 and \u20102 than their presenescent counterparts. The results show that the accumulation of senescent fibroblasts in human fibrosis occurs by a telomere\u2010independent mechanism involving ROS and may locally ameliorate the condition by the increased expression of MMPs prior to clearance by the immune system. Copyright \u00a9 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.2839","type":"journal-article","created":{"date-parts":[[2010,12,7]],"date-time":"2010-12-07T08:41:12Z","timestamp":1291711272000},"page":"604-617","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["Senescent mesenchymal cells accumulate in human fibrosis by a telomere\u2010independent mechanism and ameliorate fibrosis through matrix metalloproteinases"],"prefix":"10.1002","volume":"223","author":[{"given":"Gayani Nadika","family":"Pitiyage","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Predrag","family":"Slijepcevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliya","family":"Gabrani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaghoub 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