{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:26:34Z","timestamp":1790519194033,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T00:00:00Z","timestamp":1624579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005304","name":"Agence Nationale pour le D\u00e9veloppement de la Recherche en Sant\u00e9","doi-asserted-by":"publisher","award":["ANR-11-INSB-005"],"award-info":[{"award-number":["ANR-11-INSB-005"]}],"id":[{"id":"10.13039\/501100005304","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Association des Scl\u00e9rodermiques de France","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"Soci\u00e9t\u00e9 Nationale Fran\u00e7aise de M\u00e9decine Interne","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Systemic sclerosis (SSc) is a complex disorder resulting from dysregulated interactions between the three main pathophysiological axes: fibrosis, immune dysfunction, and vasculopathy, with no specific treatment available to date. Adipose tissue-derived mesenchymal stromal cells (ASCs) and their extracellular vesicles (EVs) have proved efficacy in pre-clinical murine models of SSc. However, their precise action mechanism is still not fully understood. Because of the lack of availability of fibroblasts isolated from SSc patients (SSc-Fb), our aim was to determine whether a TGF\u03b21-induced model of human myofibroblasts (T\u03b2-Fb) could reproduce the characteristics of SSc-Fb and be used to evaluate the anti-fibrotic function of ASCs and their EVs. We found out that T\u03b2-Fb displayed the main morphological and molecular features of SSc-Fb, including the enlarged hypertrophic morphology and expression of several markers associated with the myofibroblastic phenotype. Using this model, we showed that ASCs were able to regulate the expression of most myofibroblastic markers on T\u03b2-Fb and SSc-Fb, but only when pre-stimulated with TGF\u03b21. Of interest, ASC-derived EVs were more effective than parental cells for improving the myofibroblastic phenotype. In conclusion, we provided evidence that T\u03b2-Fb are a relevant model to mimic the main characteristics of SSc fibroblasts and investigate the mechanism of action of ASCs. We further reported that ASC-EVs are more effective than parental cells suggesting that the TGF\u03b21-induced pro-fibrotic environment may alter the function of ASCs.<\/jats:p>","DOI":"10.3390\/ijms22136837","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T11:07:40Z","timestamp":1624619260000},"page":"6837","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Extracellular Vesicles Are More Potent Than Adipose Mesenchymal Stromal Cells to Exert an Anti-Fibrotic Effect in an In Vitro Model of Systemic Sclerosis"],"prefix":"10.3390","volume":"22","author":[{"given":"Pauline","family":"Rozier","sequence":"first","affiliation":[{"name":"INSERM U1183, H\u00f4pital Saint-Eloi, IRMB, University of Montpellier, 80 Avenue Augustin Fliche, CEDEX 5, 34295 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Maumus","sequence":"additional","affiliation":[{"name":"INSERM U1183, H\u00f4pital Saint-Eloi, IRMB, University of Montpellier, 80 Avenue Augustin Fliche, CEDEX 5, 34295 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Bony","sequence":"additional","affiliation":[{"name":"INSERM U1183, H\u00f4pital Saint-Eloi, IRMB, University of Montpellier, 80 Avenue Augustin Fliche, CEDEX 5, 34295 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre Thibault Jacques","family":"Maria","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Multi-Organic Diseases, CHU, 34295 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Sabatier","sequence":"additional","affiliation":[{"name":"INSERM, INRA, C2VN, Aix Marseille University, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Jorgensen","sequence":"additional","affiliation":[{"name":"INSERM U1183, H\u00f4pital Saint-Eloi, IRMB, University of Montpellier, 80 Avenue Augustin Fliche, CEDEX 5, 34295 Montpellier, France"},{"name":"Clinical Immunology and Osteoarticular Disease Therapeutic Unit, Department of Rheumatology, CHU, 34295 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Guilpain","sequence":"additional","affiliation":[{"name":"INSERM U1183, H\u00f4pital Saint-Eloi, IRMB, University of Montpellier, 80 Avenue Augustin Fliche, CEDEX 5, 34295 Montpellier, France"},{"name":"Department of Internal Medicine, Multi-Organic Diseases, CHU, 34295 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3498-3776","authenticated-orcid":false,"given":"Dani\u00e8le","family":"No\u00ebl","sequence":"additional","affiliation":[{"name":"INSERM U1183, H\u00f4pital Saint-Eloi, IRMB, University of Montpellier, 80 Avenue Augustin Fliche, CEDEX 5, 34295 Montpellier, France"},{"name":"Clinical Immunology and Osteoarticular Disease Therapeutic Unit, Department of Rheumatology, CHU, 34295 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.22203\/eCM.v009a09","article-title":"The ultrastructure of mouse articular cartilage: Collagen orientation and implications for tissue functionality. A polarised light and scanning electron microscope study and review","volume":"9","author":"Hughes","year":"2005","journal-title":"Eur. Cells Mater."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"226","DOI":"10.2741\/s22","article-title":"Transforming growth factor-beta in systemic sclerosis (scleroderma)","volume":"1","author":"Varga","year":"2009","journal-title":"Front. Biosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1530\/rep.1.01072","article-title":"The structural basis of TGF-beta, bone morphogenetic protein, and activin ligand binding","volume":"132","author":"Lin","year":"2006","journal-title":"Reproduction"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1146\/annurev.biochem.67.1.753","article-title":"TGF-beta signal transduction","volume":"67","author":"Massague","year":"1998","journal-title":"Annu. Rev. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Milano, A., Pendergrass, S.A., Sargent, J.L., George, L.K., McCalmont, T.H., Connolly, M.K., and Whitfield, M.L. (2008). Molecular subsets in the gene expression signatures of scleroderma skin. PLoS ONE, 3.","DOI":"10.1371\/annotation\/05bed72c-c6f6-4685-a732-02c78e5f66c2"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"12319","DOI":"10.1073\/pnas.1635114100","article-title":"Systemic and cell type-specific gene expression patterns in scleroderma skin","volume":"100","author":"Whitfield","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","first-page":"69","article-title":"Altered expression of RXFP1 receptor contributes to the inefficacy of relaxin-based anti-fibrotic treatments in systemic sclerosis","volume":"37","author":"Corallo","year":"2019","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1124\/jpet.114.213520","article-title":"Targeting the myofibroblast genetic switch: Inhibitors of myocardin-related transcription factor\/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury","volume":"349","author":"Haak","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_9","first-page":"S86","article-title":"Imatinib mesylate causes genome-wide transcriptional changes in systemic sclerosis fibroblasts in vitro","volume":"30","author":"Hinchcliff","year":"2012","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Liu, T., Zhang, J., Zhang, J., Mu, X., Su, H., Hu, X., Liu, W., Zhao, E., and Li, W. (2013). RNA interference against platelet-derived growth factor receptor alpha mRNA inhibits fibroblast transdifferentiation in skin lesions of patients with systemic sclerosis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060414"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.autrev.2010.09.016","article-title":"Fibrosis and immune dysregulation in systemic sclerosis","volume":"10","author":"Chizzolini","year":"2011","journal-title":"Autoimmun. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1097\/BOR.0000000000000112","article-title":"Endothelial dysfunction in systemic sclerosis","volume":"26","author":"Altorok","year":"2014","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.3389\/fimmu.2018.02938","article-title":"Mesenchymal Stem Cells in Systemic Sclerosis: Allogenic or Autologous Approaches for Therapeutic Use?","volume":"9","author":"Rozier","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1002\/art.39477","article-title":"Antifibrotic, Antioxidant, and Immunomodulatory Effects of Mesenchymal Stem Cells in HOCl-Induced Systemic Sclerosis","volume":"68","author":"Maria","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jaut.2016.03.013","article-title":"Human adipose mesenchymal stem cells as potent anti-fibrosis therapy for systemic sclerosis","volume":"70","author":"Maria","year":"2016","journal-title":"J. Autoimmun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"997","DOI":"10.3389\/fbioe.2020.00997","article-title":"Mesenchymal Stem Cell-Derived Extracellular Vesicles: Opportunities and Challenges for Clinical Translation","volume":"8","author":"Maumus","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102660","DOI":"10.1016\/j.jaut.2021.102660","article-title":"Mesenchymal stromal cells-derived extracellular vesicles alleviate systemic sclerosis via miR-29a-3p","volume":"121","author":"Rozier","year":"2021","journal-title":"J. Autoimmun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1093\/rheumatology\/keq208","article-title":"Modulation of collagen type I, fibronectin and dermal fibroblast function and activity, in systemic sclerosis by the antioxidant epigallocatechin-3-gallate","volume":"49","author":"Dooley","year":"2010","journal-title":"Rheumatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4008","DOI":"10.1002\/art.20658","article-title":"Selective inhibition of activin receptor-like kinase 5 signaling blocks profibrotic transforming growth factor beta responses in skin fibroblasts","volume":"50","author":"Mori","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"519","DOI":"10.2353\/ajpath.2009.080574","article-title":"Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-gamma","volume":"174","author":"Wu","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1093\/rheumatology\/keq448","article-title":"Enhanced expression of ephrins and thrombospondins in the dermis of patients with early diffuse systemic sclerosis: Potential contribution to perturbed angiogenesis and fibrosis","volume":"50","author":"Avouac","year":"2011","journal-title":"Rheumatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.3389\/fimmu.2018.01865","article-title":"Interleukin-6 and Type-I Collagen Production by Systemic Sclerosis Fibroblasts Are Differentially Regulated by Interleukin-17A in the Presence of Transforming Growth Factor-Beta 1","volume":"9","author":"Dufour","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/1523-1747.ep12313452","article-title":"Growth regulation in scleroderma fibroblasts: Increased response to transforming growth factor-beta 1","volume":"105","author":"Kikuchi","year":"1995","journal-title":"J. Investig. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e1800069","DOI":"10.1002\/prca.201800069","article-title":"Proteomic Analysis of Human Scleroderma Fibroblasts Response to Transforming Growth Factor-ss","volume":"13","author":"Chaigne","year":"2019","journal-title":"Proteom. Clin. Appl."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1159\/000501499","article-title":"Platelet-Rich Plasma and Bone Marrow-Derived Mesenchymal Stromal Cells Prevent TGF-beta1-Induced Myofibroblast Generation but Are Not Synergistic when Combined: Morphological in vitro Analysis","volume":"206","author":"Chellini","year":"2018","journal-title":"Cells Tissues Organs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E35","DOI":"10.1002\/lary.26121","article-title":"Mesenchymal stem cells have antifibrotic effects on transforming growth factor-beta1-stimulated vocal fold fibroblasts","volume":"127","author":"Hiwatashi","year":"2017","journal-title":"Laryngoscope"},{"key":"ref_27","unstructured":"Li, X., Wang, H., and Xu, W. (2020). HGF and bFGF Secreted by Adipose-Derived Mesenchymal Stem Cells Revert the Fibroblast Phenotype Caused by Vocal Fold Injury in a Rat Model. J. Voice, in press."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2734","DOI":"10.1002\/stem.169","article-title":"Mesenchymal stem cells promote matrix metalloproteinase secretion by cardiac fibroblasts and reduce cardiac ventricular fibrosis after myocardial infarction","volume":"27","author":"Mias","year":"2009","journal-title":"Stem Cells"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1097\/PRS.0b013e3182a3bf2b","article-title":"Adipose-derived stem cells inhibit the contractile myofibroblast in Dupuytren\u2019s disease","volume":"132","author":"Verhoekx","year":"2013","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1258\/ebm.2011.010317","article-title":"Effects of mesenchymal stem cells on matrix metalloproteinase synthesis in cardiac fibroblasts","volume":"236","author":"Wang","year":"2011","journal-title":"Exp. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1111\/j.1582-4934.2012.01610.x","article-title":"Conditioned mesenchymal stem cells attenuate progression of chronic kidney disease through inhibition of epithelial-to-mesenchymal transition and immune modulation","volume":"16","author":"Chang","year":"2012","journal-title":"J. Cell. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s13238-015-0196-7","article-title":"Direct intercellular communications dominate the interaction between adipose-derived MSCs and myofibroblasts against cardiac fibrosis","volume":"6","author":"Li","year":"2015","journal-title":"Protein Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s13287-019-1224-y","article-title":"Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies","volume":"10","author":"Noronha","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.5966\/sctm.2015-0367","article-title":"Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomal MicroRNAs Suppress Myofibroblast Differentiation by Inhibiting the Transforming Growth Factor-beta\/SMAD2 Pathway During Wound Healing","volume":"5","author":"Fang","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4150705","DOI":"10.1155\/2017\/4150705","article-title":"MiRNA-Sequence Indicates That Mesenchymal Stem Cells and Exosomes Have Similar Mechanism to Enhance Cardiac Repair","volume":"2017","author":"Shao","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Velier, M., Simoncini, S., Abellan, M., Francois, P., Eap, S., Lagrange, A., Bertrand, B., Daumas, A., Granel, B., and Delorme, B. (2019). Adipose-Derived Stem Cells from Systemic Sclerosis Patients Maintain Pro-Angiogenic and Antifibrotic Paracrine Effects In Vitro. J. Clin. Med., 8.","DOI":"10.3390\/jcm8111979"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"655","DOI":"10.3389\/fimmu.2015.00655","article-title":"Adipose Mesenchymal Stem Cells Isolated after Manual or Water-jet-Assisted Liposuction Display Similar Properties","volume":"6","author":"Bony","year":"2016","journal-title":"Front. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6837\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:24:04Z","timestamp":1760163844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6837"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,25]]},"references-count":37,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22136837"],"URL":"https:\/\/doi.org\/10.3390\/ijms22136837","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,25]]}}}