{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T14:07:05Z","timestamp":1793369225789,"version":"4.5.0"},"reference-count":89,"publisher":"American Society for Clinical Investigation","issue":"17","funder":[{"name":"NIH","award":["HL120947"],"award-info":[{"award-number":["HL120947"]}]},{"name":"NIH","award":["HL103868"],"award-info":[{"award-number":["HL103868"]}]},{"name":"NIH","award":["HL137076"],"award-info":[{"award-number":["HL137076"]}]},{"name":"NIH","award":["AI137111"],"award-info":[{"award-number":["AI137111"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["Grant-in-Aid"],"award-info":[{"award-number":["Grant-in-Aid"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100031217","name":"Samuel Oschin Comprehensive Cancer Institute","doi-asserted-by":"crossref","award":["Lung Cancer Research Award"],"award-info":[{"award-number":["Lung Cancer Research Award"]}],"id":[{"id":"10.13039\/100031217","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,5]]},"abstract":"<jats:p>Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal lung disease. A maladaptive epithelium due to chronic injury is a prominent feature and contributor to pathogenic cellular communication in IPF. Recent data highlight the concept of a \u201creprogrammed\u201d lung epithelium as critical in the development of lung fibrosis. Extracellular vesicles (EVs) are potent mediators of cellular crosstalk, and recent evidence supports their role in lung pathologies, such as IPF. Here, we demonstrate that syndecan-1 is overexpressed by the epithelium in the lungs of patients with IPF and in murine models after bleomycin injury. Moreover, we find that syndecan-1 is a profibrotic signal that alters alveolar type II cell phenotypes by augmenting TGF-\u03b2 and Wnt signaling among other profibrotic pathways. Importantly, we demonstrate that syndecan-1 controls the packaging of several antifibrotic microRNAs into EVs that have broad effects over several fibrogenic signaling networks as a mechanism of regulating epithelial plasticity and pulmonary fibrosis. Collectively, our work reveals new insight into how EVs orchestrate cellular signals that promote lung fibrosis and demonstrate the importance of syndecan-1 in coordinating these programs.<\/jats:p>","DOI":"10.1172\/jci.insight.129359","type":"journal-article","created":{"date-parts":[[2019,8,8]],"date-time":"2019-08-08T12:00:37Z","timestamp":1565265637000},"source":"Crossref","is-referenced-by-count":90,"title":["Syndecan-1 promotes lung fibrosis by regulating epithelial reprogramming through extracellular vesicles"],"prefix":"10.1172","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4790-0730","authenticated-orcid":true,"given":"Tanyalak","family":"Parimon","sequence":"first","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1357-5017","authenticated-orcid":true,"given":"Changfu","family":"Yao","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6117-343X","authenticated-orcid":true,"given":"David M.","family":"Habiel","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyin","family":"Ge","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie A.","family":"Bora","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rena","family":"Brauer","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5600-7314","authenticated-orcid":true,"given":"Christopher M.","family":"Evans","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Xie","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3429-5105","authenticated-orcid":true,"given":"Felix","family":"Alonso-Valenteen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9807-5523","authenticated-orcid":true,"given":"Lali K.","family":"Medina-Kauwe","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4508-3829","authenticated-orcid":true,"given":"Dianhua","family":"Jiang","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul W.","family":"Noble","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."},{"name":"Department of Biomedical Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory M.","family":"Hogaboam","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."},{"name":"Department of Biomedical Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0914-7220","authenticated-orcid":true,"given":"Nan","family":"Deng","sequence":"additional","affiliation":[{"name":"Samuel Oschin Comprehensive Cancer Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Burgy","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis J.","family":"Antes","sequence":"additional","affiliation":[{"name":"Smidt Heart Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"K\u00f6nigshoff","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry R.","family":"Stripp","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."},{"name":"Department of Biomedical Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sina A.","family":"Gharib","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5330-1718","authenticated-orcid":true,"given":"Peter","family":"Chen","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."},{"name":"Department of Biomedical Sciences,"},{"name":"Samuel Oschin Comprehensive Cancer Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2019,9,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201006-0894CI"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1705751"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2807"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200810-1615OC"},{"issue":"14","key":"B5","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.86704","article-title":"Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis","volume":"1","author":"Naikawadi","year":"2016","journal-title":"JCI Insight"},{"key":"B6","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.31299","article-title":"Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres","volume":"7","author":"Povedano","year":"2018","journal-title":"Elife"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.06.028"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02367-2016"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12643"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00163814"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201306-1141WS"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1513\/pats.201012-067CB"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201312-2221PP"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605669103"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.276311"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)62351-6"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI36940"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.019117"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI33950"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002142"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64282-4"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2018.08.004"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201211138"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.125"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2017.12.009"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20141675"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.792416"},{"key":"B28","doi-asserted-by":"crossref","DOI":"10.1038\/cddis.2015.282","article-title":"Lung epithelial cell-derived extracellular vesicles activate macrophage-mediated inflammatory responses via ROCK1 pathway","volume":"6","author":"Moon","year":"2015","journal-title":"Cell Death Dis"},{"key":"B29","article-title":"Epithelial cell-derived microvesicles activate macrophages and promote inflammation via microvesicle-containing microRNAs","volume":"6","author":"Lee","year":"2016","journal-title":"Sci Rep"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nature15756"},{"issue":"1\u20132","key":"B31","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.cell.2018.12.002","article-title":"Activated PMN exosomes: pathogenic entities causing matrix destruction and disease in the lung","volume":"176","author":"Genschmer","year":"2019","journal-title":"Cell"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2018-211897"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-016-0427-3"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1164\/rccm"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2018-0062OC"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2017-0248OC"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.02.001"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201509-1878OC"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.376814"},{"issue":"pt 21","key":"B40","first-page":"5188","article-title":"Syndecan-1 controls cell migration by activating Rap1 to regulate focal adhesion disassembly","volume":"125","author":"Altemeier","year":"2012","journal-title":"J Cell Sci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006565"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2015-0193OC"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)01079-6"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2011.10.001"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2502"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2015.29"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1713433114"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201712-2410OC"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt703"},{"issue":"20","key":"B50","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.90558","article-title":"Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis","volume":"1","author":"Xu","year":"2016","journal-title":"JCI Insight"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2018.12.008"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1013660"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1596"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/nature07488"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119590"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80545-0"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/77108"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1242\/dev.113266"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-07-797050"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12240"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1126\/science.1143578"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1216076"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801562"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07768-9"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.01.002"},{"issue":"20","key":"B66","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.90301","article-title":"miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways","volume":"1","author":"Ge","year":"2016","journal-title":"JCI Insight"},{"key":"B67","article-title":"MicroRNA-188 suppresses G1\/S transition by targeting multiple cyclin\/CDK complexes","volume":"12","author":"Wu","year":"2014","journal-title":"Cell Commun Signal"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.08.033"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201103097"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.10.028"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1712108114"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.08.027"},{"key":"B73","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.19276","article-title":"Y-box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction","volume":"5","author":"Shurtleff","year":"2016","journal-title":"Elife"},{"key":"B74","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2164-13-357","article-title":"Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types","volume":"13","author":"Guduric-Fuchs","year":"2012","journal-title":"BMC Genomics"},{"key":"B75","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms3980","article-title":"Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs","volume":"4","author":"Villarroya-Beltri","year":"2013","journal-title":"Nat Commun"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.09.031"},{"key":"B77","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms14448","article-title":"MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression","volume":"8","author":"Teng","year":"2017","journal-title":"Nat Commun"},{"key":"B78","doi-asserted-by":"crossref","DOI":"10.1038\/mtna.2011.2","article-title":"miR-1289 and \u201cZipcode\u201d-like sequence enrich mRNAs in microvesicles","volume":"1","author":"Bolukbasi","year":"2012","journal-title":"Mol Ther Nucleic Acids"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/nm1685"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.070891"},{"issue":"141","key":"B81","doi-asserted-by":"crossref","DOI":"10.3791\/58310","article-title":"Isolation of extracellular vesicles from murine bronchoalveolar lavage fluid using an ultrafiltration centrifugation technique","author":"Parimon","year":"2018","journal-title":"J Vis Exp"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.03.010"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2013-14-4-r36"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1186\/1751-0473-6-2"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"issue":"1","key":"B86","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J R Stat Soc Ser B (Methodological)"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4380"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.07.007"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/129359\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:24:45Z","timestamp":1779193485000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/129359"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,5]]},"references-count":89,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2019,9,5]]},"published-print":{"date-parts":[[2019,9,5]]}},"alternative-id":["10.1172\/jci.insight.129359"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.129359","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.736402056.793563840","asserted-by":"object"}]},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,5]]},"article-number":"e129359"}}