{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:55:03Z","timestamp":1790315703717,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,7,2]],"date-time":"2022-07-02T00:00:00Z","timestamp":1656720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministerio de Ciencia e Innovaci\u00f3n (MCIN)\/Agencia Estatal de Investigaci\u00f3n (AEI)","award":["PID2020-120073GB-100"],"award-info":[{"award-number":["PID2020-120073GB-100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Skin is constantly exposed to injuries that are repaired with different outcomes, either regeneration or scarring. Scars result from fibrotic processes modulated by cellular physical forces transmitted by integrins. Fibronectin (FN) is a major component in the provisional matrix assembled to repair skin wounds. FN enables cell adhesion binding of \u03b15\u03b21\/\u03b1IIb\u03b23 and \u03b1v-class integrins to an RGD-motif. An additional linkage for \u03b15\/\u03b1IIb is the synergy site located in close proximity to the RGD motif. The mutation to impair the FN synergy region (Fn1syn\/syn) demonstrated that its absence permits complete development. However, only with the additional engagement to the FN synergy site do cells efficiently resist physical forces. To test how the synergy site-mediated adhesion affects the course of wound healing fibrosis, we used a mouse model of skin injury and in-vitro migration studies with keratinocytes and fibroblasts on FNsyn. The loss of FN synergy site led to normal re-epithelialization caused by two opposing migratory defects of activated keratinocytes and, in the dermis, induced reduced fibrotic responses, with lower contents of myofibroblasts and FN deposition and diminished TGF-\u03b21-mediated cell signalling. We demonstrate that weakened \u03b15\u03b21-mediated traction forces on FNsyn cause reduced TGF-\u03b21 release from its latent complex.<\/jats:p>","DOI":"10.3390\/cells11132100","type":"journal-article","created":{"date-parts":[[2022,7,2]],"date-time":"2022-07-02T11:12:35Z","timestamp":1656760355000},"page":"2100","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["The Role of the Fibronectin Synergy Site for Skin Wound Healing"],"prefix":"10.3390","volume":"11","author":[{"given":"Irene","family":"Gimeno-LLuch","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Universitat de Val\u00e8ncia, 46110 Burjassot, Spain"},{"name":"Institut Universitari de Biotecnologia i Biomedicina, Universitat de Val\u00e8ncia, 46110 Burjassot, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Benito-Jard\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Universitat de Val\u00e8ncia, 46110 Burjassot, Spain"},{"name":"Institut Universitari de Biotecnologia i Biomedicina, Universitat de Val\u00e8ncia, 46110 Burjassot, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Guerrero-Barber\u00e0","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Universitat de Val\u00e8ncia, 46110 Burjassot, Spain"},{"name":"Institut Universitari de Biotecnologia i Biomedicina, Universitat de Val\u00e8ncia, 46110 Burjassot, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Burday","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Universitat de Val\u00e8ncia, 46110 Burjassot, Spain"},{"name":"Institut Universitari de Biotecnologia i Biomedicina, Universitat de Val\u00e8ncia, 46110 Burjassot, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6146-996X","authenticated-orcid":false,"given":"Mercedes","family":"Costell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Universitat de Val\u00e8ncia, 46110 Burjassot, Spain"},{"name":"Institut Universitari de Biotecnologia i Biomedicina, Universitat de Val\u00e8ncia, 46110 Burjassot, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1089\/ten.teb.2018.0350","article-title":"Regenerative Scar-Free Skin Wound Healing","volume":"25","author":"Monavarian","year":"2019","journal-title":"Tissue Eng. Part B. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.ydbio.2017.09.025","article-title":"Learning from Regeneration Research Organisms: The Circuitous Road to Scar Free Wound Healing","volume":"433","author":"Erickson","year":"2018","journal-title":"Dev. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mam.2018.06.003","article-title":"Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications","volume":"65","author":"Weiskirchen","year":"2019","journal-title":"Mol. Asp. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1002\/wdev.309","article-title":"Scarless wound healing: Transitioning from fetal to regenerative healing","volume":"7","author":"Moore","year":"2018","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1089\/wound.2021.0040","article-title":"Modulating Cellular Responses to Mechanical Forces to Promote Wound Regeneration","volume":"11","author":"Mascharak","year":"2022","journal-title":"Adv. Wound Care"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/s41556-018-0073-8","article-title":"Two Succeeding Fibroblastic Lineages Drive Dermal Development and the Transition from Regeneration to Scarring","volume":"20","author":"Jiang","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/cshperspect.a004994","article-title":"Integrin Structure, Activation, and Interactions","volume":"3","author":"Campbell","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"C1934","DOI":"10.1152\/ajpcell.00130.2007","article-title":"Fibronectin-Dependent Collagen I Deposition Modulates the Cell Response to Fibronectin","volume":"293","author":"Sottile","year":"2007","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1091\/mbc.e08-08-0830","article-title":"Fibrillin Assembly Requires Fibronectin","volume":"20","author":"Sabatier","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.gde.2021.04.005","article-title":"Distinct Fibroblasts in Scars and Regeneration","volume":"70","author":"Jiang","year":"2021","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41586-019-1794-y","article-title":"Patch Repair of Deep Wounds by Mobilized Fascia","volume":"576","author":"Jiang","year":"2019","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2017.04.003","article-title":"The Provisional Matrix: Setting the Stage for Tissue Repair Outcomes","volume":"60\u201361","author":"Barker","year":"2017","journal-title":"Matrix Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ceb.2008.06.001","article-title":"The Role of Integrin Binding Sites in Fibronectin Matrix Assembly In Vivo","volume":"20","author":"Leiss","year":"2008","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"21612","DOI":"10.1074\/jbc.270.37.21612","article-title":"Requirement for the Synergy Site for Cell Adhesion to Fibronectin Depends on the Activation State of Integrin Alpha 5 Beta 1","volume":"270","author":"Danen","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10856","DOI":"10.1016\/S0021-9258(17)34137-6","article-title":"Identification of a Novel Integrin Binding Site in Fibronectin. Differential Utilization by Beta 3 Integrins","volume":"269","author":"Bowditch","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/ncb3336","article-title":"Mechanical Regulation of a Molecular Clutch Defines Force Transmission and Transduction in Response to Matrix Rigidity","volume":"18","author":"Oria","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e22264","DOI":"10.7554\/eLife.22264","article-title":"The Fibronectin Synergy Site Re-Enforces Cell Adhesion and Mediates a Crosstalk between Integrin Classes","volume":"6","author":"Klapproth","year":"2017","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms14684","article-title":"Defining Stem Cell Dynamics and Migration during Wound Healing in Mouse Skin Epidermis","volume":"8","author":"Aragona","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rippa, A.L., Kalabusheva, E.P., and Vorotelyak, E.A. (2019). Regeneration of Dermis: Scarring and Cells Involved. Cells, 8.","DOI":"10.3390\/cells8060607"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Haydont, V., Neiveyans, V., Perez, P., Busson, \u00c9., Lataillade, J.J., Asselineau, D., and Fortunel, N.O. (2020). Fibroblasts from the Human Skin Dermo-Hypodermal Junction Are Distinct from Dermal Papillary and Reticular Fibroblasts and from Mesenchymal Stem Cells and Exhibit a Specific Molecular Profile Related to Extracellular Matrix Organization and Modeling. Cells, 9.","DOI":"10.3390\/cells9020368"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.matbio.2018.02.020","article-title":"Therapeutic Approaches to Control Tissue Repair and Fibrosis: Extracellular Matrix as a Game Changer","volume":"71\u201372","author":"Walraven","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1083\/jcb.201402006","article-title":"Prestress in the Extracellular Matrix Sensitizes Latent TGF-\u03921 for Activation","volume":"207","author":"Klingberg","year":"2014","journal-title":"J. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/nm.3490","article-title":"Kindlin-1 controls Wnt and TGF-\u03b2 availability to regulate cutaneous epithelial stem cell proliferation","volume":"20","author":"Rognoni","year":"2014","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/978-1-4939-9698-8_19","article-title":"Quantification of Extracellular Matrix Fiber Systems Related to ADAMTS Proteins","volume":"2043","author":"Zhang","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_25","first-page":"1","article-title":"\u03b1v-Class integrin binding to fibronectin is solely mediated by RGD and unaffected by an RGE mutation","volume":"219","author":"Strohmeyer","year":"2020","journal-title":"J. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1006\/abio.1994.1042","article-title":"An Assay for Transforming Growth Factor-Beta Using Cells Transfected with a Plasminogen Activator Inhibitor-1 Promoter-Luciferase Construct","volume":"216","author":"Abe","year":"1994","journal-title":"Anal. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7656","DOI":"10.1038\/srep07656","article-title":"Leader cells regulate collective cell migration via Rac activation in the downstream signaling of integrin \u03b21 and PI3K","volume":"5","author":"Yamaguchi","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.retram.2016.09.003","article-title":"The Role of Myofibroblasts in Wound Healing","volume":"64","author":"Hinz","year":"2016","journal-title":"Curr. Res. Transl. Med."},{"key":"ref_29","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","year":"2013","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"27687","DOI":"10.1074\/jbc.M111.261677","article-title":"Fibronectin and \u03b2-Catenin Act in a Regulatory Loop in Dermal Fibroblasts to Modulate Cutaneous Healing","volume":"286","author":"Bielefeld","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1755-1536-4-21","article-title":"Plasma and Cellular Fibronectin: Distinct and Independent Functions during Tissue Repair","volume":"4","author":"To","year":"2011","journal-title":"Fibrogenesis Tissue Repair"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e8174","DOI":"10.15252\/msb.20178174","article-title":"Fibroblast state switching orchestrates dermal maturation and wound healing","volume":"14","author":"Rognoni","year":"2018","journal-title":"Mol. Syst. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1038\/jid.2014.90","article-title":"The Nano-Scale Mechanical Properties of the Extracellular Matrix Regulate Dermal Fibroblast Function","volume":"134","author":"Achterberg","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1242\/jcs.114.1.187","article-title":"Latent TGF-Beta Binding Protein LTBP-1 Contains Three Potential Extracellular Matrix Interacting Domains","volume":"114","year":"2001","journal-title":"J. Cell Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1242\/jcs.00229","article-title":"Making Sense of Latent TGFbeta Activation","volume":"116","author":"Annes","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1080\/10408360490460933","article-title":"Latent TGF-Beta Binding Proteins: Extracellular Matrix Association and Roles in TGF-Beta Activation","volume":"41","author":"Penttinen","year":"2004","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1083\/jcb.200403067","article-title":"Disruption of LTBP-4 Function Reduces TGF-Beta Activation and Enhances BMP-4 Signaling in the Lung","volume":"167","author":"Koli","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1160\/TH08-05-0273","article-title":"Integration of non-SMAD and SMAD signaling in TGF-\u03b21-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells","volume":"100","author":"Samarakoon","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/0955-0674(89)90072-0","article-title":"Wound Repair","volume":"1","author":"Clark","year":"1989","journal-title":"Curr. Opin. Cell. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/85471","article-title":"Plasma Fibronectin Supports Neuronal Survival and Reduces Brain Injury Following Transient Focal Cerebral Ischemia but Is Not Essential for Skin-Wound Healing and Hemostasis","volume":"7","author":"Sakai","year":"2001","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/s41556-017-0030-y","article-title":"Nanopillar Force Measurements Reveal Actin-Cap-Mediated YAP Mechanotransduction","volume":"20","author":"Shiu","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/ncb2747","article-title":"\u03921- and Av-Class Integrins Cooperate to Regulate Myosin II during Rigidity Sensing of Fibronectin-Based Microenvironments","volume":"15","author":"Schiller","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nrm.2017.98","article-title":"Mechanobiology of Collective Cell Behaviours","volume":"18","author":"Ladoux","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"12974","DOI":"10.1073\/pnas.1119313109","article-title":"Emerging Modes of Collective Cell Migration Induced by Geometrical Constraints","volume":"109","author":"Vedula","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/nm.2574","article-title":"Focal Adhesion Kinase Links Mechanical Force to Skin Fibrosis via Inflammatory Signaling","volume":"18","author":"Wong","year":"2012","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jmbbm.2016.12.004","article-title":"Factors affecting the mechanical behavior of collagen hydrogels for skin tissue engineering","volume":"69","author":"Pensalfini","year":"2017","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nrm809","article-title":"Myofibroblasts and Mechano-Regulation of Connective Tissue Remodelling","volume":"3","author":"Tomasek","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1083\/jcb.200704042","article-title":"Myofibroblast Contraction Activates Latent TGF-\u03921 from the Extracellular Matrix","volume":"179","author":"Wipff","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1002\/j.1460-2075.1991.tb08049.x","article-title":"A Role of the Latent TGF-Beta 1-Binding Protein in the Assembly and Secretion of TGF-Beta 1","volume":"10","author":"Miyazono","year":"1991","journal-title":"EMBO J."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/13\/2100\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:42:08Z","timestamp":1760139728000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/13\/2100"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,2]]},"references-count":49,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["cells11132100"],"URL":"https:\/\/doi.org\/10.3390\/cells11132100","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,2]]}}}