{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:43:24Z","timestamp":1792457004109,"version":"4.5.0"},"reference-count":25,"publisher":"National Academy of Sciences","issue":"18","license":[{"start":{"date-parts":[[2017,10,19]],"date-time":"2017-10-19T00:00:00Z","timestamp":1508371200000},"content-version":"vor","delay-in-days":183,"URL":"http:\/\/www.pnas.org\/site\/misc\/userlicense.xhtml"}],"funder":[{"DOI":"10.13039\/100006352","name":"Virginia and D.K. Ludwig Fund for Cancer Research","doi-asserted-by":"publisher","award":["U01HL099999"],"award-info":[{"award-number":["U01HL099999"]}],"id":[{"id":"10.13039\/100006352","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA86017"],"award-info":[{"award-number":["R01CA86017"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2017,5,2]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Severe human fibrotic diseases are devastating and without effective treatments. We found that c-JUN expression is increased in many human fibrotic diseases and that systemic induction of c-Jun in mice resulted in development of fibrosis of multiple organs. These results suggest that many fibrotic diseases share a common pathomechanism that converges on c-Jun induction. Thus, common treatment strategies could potentially be developed for these seemingly different fibrotic disease entities. Moreover, the in vivo c-Jun induction represents a mouse model for these devastating diseases that could be used for preclinical evaluation of candidate antifibrotic treatments. Indeed, we show that blockade of the antiphagocytotic signal CD47 and the AKT and VEGF receptor pathways reverses tissue fibrosis in mice.<\/jats:p>","DOI":"10.1073\/pnas.1621375114","type":"journal-article","created":{"date-parts":[[2017,4,19]],"date-time":"2017-04-19T21:00:39Z","timestamp":1492635639000},"page":"4757-4762","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":203,"title":["Unifying mechanism for different fibrotic diseases"],"prefix":"10.1073","volume":"114","author":[{"given":"Gerlinde","family":"Wernig","sequence":"first","affiliation":[{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Baxter Laboratories Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Van Neste","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Tsai","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeraja","family":"Kambham","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannes","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaso","family":"Natkunam","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Gary","family":"Gilliland","sequence":"additional","affiliation":[{"name":"Fred Hutchinson\/University of Washington Cancer Consortium, Seattle, WA 98109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garry","family":"Nolan","sequence":"additional","affiliation":[{"name":"Baxter Laboratories Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irving L.","family":"Weissman","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Ludwig Center for Cancer Stem Cell Biology and Medicine, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2017,4,19]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1056\/NEJMe1403448","article-title":"A new hope for idiopathic pulmonary fibrosis","volume":"370","author":"Hunninghake GM","year":"2014","unstructured":"GM Hunninghake, A new hope for idiopathic pulmonary fibrosis. N Engl J Med 370, 2142\u20132143 (2014).","journal-title":"N Engl J Med"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/exd.12237","article-title":"Deciphering the pro-fibrotic phenotype of fibroblasts in systemic sclerosis","volume":"23","author":"Maier C","year":"2014","unstructured":"C Maier, JH Distler, C Beyer, Deciphering the pro-fibrotic phenotype of fibroblasts in systemic sclerosis. Exp Dermatol 23, 99\u2013100 (2014).","journal-title":"Exp Dermatol"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1111\/j.1365-2141.2007.06807.x","article-title":"Bone marrow fibrosis: Pathophysiology and clinical significance of increased bone marrow stromal fibres","volume":"139","author":"Kuter DJ","year":"2007","unstructured":"DJ Kuter, B Bain, G Mufti, A Bagg, RP Hasserjian, Bone marrow fibrosis: Pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol 139, 351\u2013362 (2007).","journal-title":"Br J Haematol"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/nature12614","article-title":"Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma","volume":"503","author":"Gerber EE","year":"2013","unstructured":"EE Gerber, , Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature 503, 126\u2013130 (2013).","journal-title":"Nature"},{"key":"e_1_3_4_5_2","first-page":"96","article-title":"Fibrosis: A common pathway to organ injury and failure","volume":"373","author":"Rockey DC","year":"2015","unstructured":"DC Rockey, PD Bell, JA Hill, Fibrosis: A common pathway to organ injury and failure. N Engl J Med 373, 96 (2015).","journal-title":"N Engl J Med"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/nm.2807","article-title":"Mechanisms of fibrosis: Therapeutic translation for fibrotic disease","volume":"18","author":"Wynn TA","year":"2012","unstructured":"TA Wynn, TR Ramalingam, Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat Med 18, 1028\u20131040 (2012).","journal-title":"Nat Med"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nm1685","article-title":"The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak","volume":"14","author":"Tager AM","year":"2008","unstructured":"AM Tager, , The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med 14, 45\u201354 (2008).","journal-title":"Nat Med"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"L344","DOI":"10.1152\/ajplung.00300.2014","article-title":"Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis","volume":"308","author":"Liu F","year":"2015","unstructured":"F Liu, , Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol 308, L344\u2013L357 (2015).","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/nature12783","article-title":"Distinct fibroblast lineages determine dermal architecture in skin development and repair","volume":"504","author":"Driskell RR","year":"2013","unstructured":"RR Driskell, , Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277\u2013281 (2013).","journal-title":"Nature"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s00403-005-0635-z","article-title":"The bleomycin-induced scleroderma model: What have we learned for scleroderma pathogenesis?","volume":"297","author":"Yamamoto T","year":"2006","unstructured":"T Yamamoto, The bleomycin-induced scleroderma model: What have we learned for scleroderma pathogenesis? Arch Dermatol Res 297, 333\u2013344 (2006).","journal-title":"Arch Dermatol Res"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"10525","DOI":"10.1073\/pnas.0801414105","article-title":"Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2\/AP-1","volume":"105","author":"Eferl R","year":"2008","unstructured":"R Eferl, , Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2\/AP-1. Proc Natl Acad Sci USA 105, 10525\u201310530 (2008).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.12688\/f1000research.8081.1","article-title":"Recent advances in understanding myelofibrosis and essential thrombocythemia","volume":"5","author":"Vainchenker W","year":"2016","unstructured":"W Vainchenker, SN Constantinescu, I Plo, Recent advances in understanding myelofibrosis and essential thrombocythemia. F1000 Res 5, 5 (2016).","journal-title":"F1000 Res"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ccr.2008.02.009","article-title":"Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera","volume":"13","author":"Wernig G","year":"2008","unstructured":"G Wernig, , Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell 13, 311\u2013320 (2008).","journal-title":"Cancer Cell"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"4274","DOI":"10.1182\/blood-2005-12-4824","article-title":"Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model","volume":"107","author":"Wernig G","year":"2006","unstructured":"G Wernig, , Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 107, 4274\u20134281 (2006).","journal-title":"Blood"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1038\/sj.onc.1204389","article-title":"AP-1 in mouse development and tumorigenesis","volume":"20","author":"Jochum W","year":"2001","unstructured":"W Jochum, E Passegu\u00e9, EF Wagner, AP-1 in mouse development and tumorigenesis. Oncogene 20, 2401\u20132412 (2001).","journal-title":"Oncogene"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/nrc2681","article-title":"Emerging roles of ATF2 and the dynamic AP1 network in cancer","volume":"10","author":"Lopez-Bergami P","year":"2010","unstructured":"P Lopez-Bergami, E Lau, Z Ronai, Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nat Rev Cancer 10, 65\u201376 (2010).","journal-title":"Nat Rev Cancer"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/hep.26518","article-title":"Activator Protein 1 transcription factor Fos-related antigen 1 (Fra-1) is dispensable for murine liver fibrosis, but modulates xenobiotic metabolism","volume":"59","author":"Hasenfuss SC","year":"2014","unstructured":"SC Hasenfuss, L Bakiri, MK Thomsen, R Hamacher, EF Wagner, Activator Protein 1 transcription factor Fos-related antigen 1 (Fra-1) is dispensable for murine liver fibrosis, but modulates xenobiotic metabolism. Hepatology 59, 261\u2013273 (2014).","journal-title":"Hepatology"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"1250689","DOI":"10.1126\/science.1250689","article-title":"Systems biology: Conditional density-based analysis of T cell signaling in single-cell data","volume":"346","author":"Krishnaswamy S","year":"2014","unstructured":"S Krishnaswamy, , Systems biology: Conditional density-based analysis of T cell signaling in single-cell data. Science 346, 1250689 (2014).","journal-title":"Science"},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"16466","DOI":"10.1073\/pnas.1419337111","article-title":"Single-cell mass cytometry of TCR signaling: Amplification of small initial differences results in low ERK activation in NOD mice","volume":"111","author":"Mingueneau M","year":"2014","unstructured":"M Mingueneau, , Single-cell mass cytometry of TCR signaling: Amplification of small initial differences results in low ERK activation in NOD mice. Proc Natl Acad Sci USA 111, 16466\u201316471 (2014).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2009.05.046","article-title":"CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis","volume":"138","author":"Jaiswal S","year":"2009","unstructured":"S Jaiswal, , CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271\u2013285 (2009).","journal-title":"Cell"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.cell.2010.07.044","article-title":"Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma","volume":"142","author":"Chao MP","year":"2010","unstructured":"MP Chao, , Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699\u2013713 (2010).","journal-title":"Cell"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1101\/gad.13.5.607","article-title":"Control of cell cycle progression by c-Jun is p53 dependent","volume":"13","author":"Schreiber M","year":"1999","unstructured":"M Schreiber, , Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev 13, 607\u2013619 (1999).","journal-title":"Genes Dev"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"aaa2151","DOI":"10.1126\/science.aaa2151","article-title":"Skin fibrosis: Identification and isolation of a dermal lineage with intrinsic fibrogenic potential","volume":"348","author":"Rinkevich Y","year":"2015","unstructured":"Y Rinkevich, , Skin fibrosis: Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science 348, aaa2151 (2015).","journal-title":"Science"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/nature18935","article-title":"CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis","volume":"536","author":"Kojima Y","year":"2016","unstructured":"Y Kojima, , CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 536, 86\u201390 (2016).","journal-title":"Nature"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/gene.20180","article-title":"Efficient method to generate single-copy transgenic mice by site-specific integration in embryonic stem cells","volume":"44","author":"Beard C","year":"2006","unstructured":"C Beard, K Hochedlinger, K Plath, A Wutz, R Jaenisch, Efficient method to generate single-copy transgenic mice by site-specific integration in embryonic stem cells. Genesis 44, 23\u201328 (2006).","journal-title":"Genesis"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1621375114","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1621375114","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T11:38:55Z","timestamp":1654601935000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1621375114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,19]]},"references-count":25,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2017,5,2]]}},"alternative-id":["10.1073\/pnas.1621375114"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1621375114","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.727535500.793564986","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,19]]},"assertion":[{"value":"2017-04-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}