The Fibronectin Domain ED-A Is Crucial for Myofibroblastic Phenotype Induction by Transforming Growth Factor-β1

• Published in: The Journal of cell biology Vol. 142; no. 3; pp. 873 - 881
• Main Authors: Serini, Guido, Bochaton-Piallat, Marie-Luce, Ropraz, Patricia, Geinoz, Antoine, Borsi, Laura, Zardi, Luciano, Gabbiani, Giulio
• Format: Journal Article
• Language: English
• Published: Rockefeller University Press 10.08.1998; The Rockefeller University Press
• Subjects: Actins; Antibodies; Cells; Collagens; Fibroblasts; Gelatins; Granulation tissue; Messenger RNA; Myofibroblasts; Receptors; Regular
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.142.3.873

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.