Transforming growth factor-β1 (TGFβ1), a major promoter of myofibroblast differentiation, induces α-smooth muscle (sn) actin, modulates the expression of adhesive receptors, and enhances the synthesis of extracellular matrix (ECM) molecules including ED-A fibronectin (FN), an isoform de novo expressed during wound healing and fibrotic changes. We report here that ED-A FN deposition precedes α-SM actin expression by fibroblasts during granulation tissue evolution in vivo and after TGFβ1 stimulation in vitro. Moreover, there is a correlation between in vitro expression of α-SM actin and ED-A FN in different fibroblastic populations. Seeding fibroblasts on ED-A FN does not elicit per se α-SM actin expression; however, incubation of fibroblasts with the anti-ED-A monoclonal antibody IST-9 specifically blocks the TGFβ1-triggered enhancement of α-SM actin and collagen type I, but not that of plasminogen activator inhibitor-1 mRNA. Interestingly, the same inhibiting action is exerted by the soluble recombinant domain ED-A, but neither of these inhibitory agents alter FN matrix assembly. Our findings indicate that ED-A–containing polymerized FN is necessary for the induction of the myofibroblastic phenotype by TGFβ1 and identify a hitherto unknown mechanism of cytokine-determined gene stimulation based on the generation of an ECM-derived permissive outside in signaling, under the control of the cytokine itself.
The Fibronectin Domain ED-A Is Crucial for Myofibroblastic Phenotype Induction by Transforming Growth Factor-β1
A. Roberts (National Institutes of Health, Bethesda, MD), D.A. Cox (Novartis, Basel, Switzerland), F.E. Baralle (International Centre for Genetic Engineering and Biotechnology, Trieste, Italy), and M.S. Pepper (University of Geneva, Geneva, Switzerland) are gratefully acknowledged for providing recombinant human TGFβ1, recombinant human TGFβ2, full-length cellular FN cDNA clone and PAI-1 cDNA probe, respectively. We thank R.B. Low (University of Vermont, Burlington, VT) and L. Trusolino (University of Torino Medical School, Candiolo, Italy) for critically reading this manuscript, F. Gabbiani for skillful technical assistance, J.C. Rumbeli and E. Denkinger for photographic work, and M. Vitali for typing the manuscript (all four from University of Geneva).
This work was partially supported by grants from the Swiss National Science Foundation (31-40372.94 and 31-50568.97) and Associazione Italiana per la Ricerca sul Cancro (AIRC) funds. G. Serini was supported by the Fondation pour des Bourses d'Etudes Italo-Suisses (Lausanne, Switzerland).
Address all correspondence to Giulio Gabbiani, Department of Pathology, CMU, University of Geneva, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. Tel.: (41) 22-70-25-742. Fax: (41) 22-70-25-746. E-mail: [email protected]
G. Serini's present address is Molecular Histology Unit (2A1), Department of Biological and Technical Research (DIBIT), H San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
Guido Serini, Marie-Luce Bochaton-Piallat, Patricia Ropraz, Antoine Geinoz, Laura Borsi, Luciano Zardi, Giulio Gabbiani; The Fibronectin Domain ED-A Is Crucial for Myofibroblastic Phenotype Induction by Transforming Growth Factor-β1 . J Cell Biol 10 August 1998; 142 (3): 873–881. doi: https://doi.org/10.1083/jcb.142.3.873
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