The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1.
Transforming growth factor-beta1 (TGFbeta1), a major promoter of myofibroblast differentiation, induces alpha-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 alpha-SM actin expression by fibroblasts during granulation tissue evolution in vivo and after TGFbeta1 stimulation in vitro. Moreover, there is a correlation between in vitro expression of alpha-SM actin and ED-A FN in different fibroblastic populations. Seeding fibroblasts on ED-A FN does not elicit per se alpha-SM actin expression; however, incubation of fibroblasts with the anti-ED-A monoclonal antibody IST-9 specifically blocks the TGFbeta1-triggered enhancement of alpha-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 TGFbeta1 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.
Department of Pathology, University of Geneva, 1211 Geneva 4, Switzerland.
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Serini
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Gabbiani
D000199:Actins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology*; D005353:Fibronectins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D009130:Muscle, Smooth / Q000166:cytology*; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*
D000199:Actins; D005353:Fibronectins; D016212:Transforming Growth Factor beta