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The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1

Serini, G.
Borsi, L.
Zardi, L.
Published in Journal of Cell Biology. 1998, vol. 142, no. 3, p. 873-881
Abstract 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.
Keywords Actins/metabolismAnimalsCell Differentiation/ physiologyExtracellular Matrix/physiologyFemaleFibroblasts/ cytologyFibronectins/chemistry/ physiologyHumansMuscle, Smooth/ cytologyPhenotypeRatsRats, WistarSignal TransductionTransforming Growth Factor beta/ physiology
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PMID: 9700173
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