{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:13:21Z","timestamp":1790172801476,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,7,14]],"date-time":"2020-07-14T00:00:00Z","timestamp":1594684800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000833","name":"Rosetrees Trust","doi-asserted-by":"publisher","award":["A18\/14 UCL"],"award-info":[{"award-number":["A18\/14 UCL"]}],"id":[{"id":"10.13039\/501100000833","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>In systemic sclerosis (<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c), a persistent tissue repair process leads to progressive fibrosis of the skin and internal organs. The role of mesenchymal stem cells (<jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content>s), which characteristically initiate and regulate tissue repair, has not been fully evaluated. We undertook this study to investigate whether dividing metakaryotic <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content>s are present in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c skin and to examine whether exposure to the disease microenvironment activates <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content>s and leads to transdifferentiation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Skin biopsy material from patients with recent\u2010onset diffuse <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c was examined by collagenase spread of 1\u2010mm\u2013thick surface\u2010parallel sections, in order to identify dividing metakaryotic stem cells in each tissue plane. Adipose\u2010derived <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content>s from healthy controls were treated with dermal blister fluid (<jats:styled-content style=\"fixed-case\">BF<\/jats:styled-content>) from patients with diffuse <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c and profiled by next\u2010generation sequencing, or they were evaluated for phenotypic changes relevant to <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c. Differential responses of dermal fibroblasts were studied in parallel.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content>\u2010like cells undergoing active metakaryotic division were identified in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c sections (but not control sections) most prominently in the deep dermis and adjacent to damaged microvessels, in both clinically involved and uninvolved skin. Furthermore, exposure to <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c <jats:styled-content style=\"fixed-case\">BF<\/jats:styled-content> caused selective <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content> activation, inducing a myofibroblast signature, while reducing signatures of vascular repair and adipogenesis and enhancing migration and contractility. Microenvironmental factors implicated in inducing transdifferentiation included the profibrotic transforming growth factor \u03b2, the presence of lactate, and mechanosensing, while the microenvironment Th2 cytokine, interleukin\u201031, enhanced osteogenic commitment (calcinosis).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Dividing <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content>\u2010like cells are present in the <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c disease microenvironment where multiple factors, likely acting in concert, promote transdifferentiation and lead to a complex and resistant disease state.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41267","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T02:01:15Z","timestamp":1585706475000},"page":"1361-1374","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Pathogenic Activation of Mesenchymal Stem Cells Is Induced by the Disease Microenvironment in Systemic Sclerosis"],"prefix":"10.1002","volume":"72","author":[{"given":"Zeinab","family":"Taki","sequence":"first","affiliation":[{"name":"Royal Free Hospital Campus and University College London Medical School  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Gostjeva","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of Technology  Cambridge"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Thilly","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of 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