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J. Cell Biol.,
Volume 142, Number 3, August 10, 1998 873-881
1
* Department of Pathology, University of Geneva, 1211 Geneva 4, Switzerland; and Transforming growth factor- Cell Biology Laboratory,
Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy
1 (TGF1), a
major promoter of myofibroblast differentiation, induces 
-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 -SM actin expression by fibroblasts during granulation tissue evolution
in vivo and after TGF1 stimulation in vitro. Moreover, there is a correlation between in vitro expression of
-SM actin and ED-A FN in different fibroblastic populations. Seeding fibroblasts on ED-A FN does not elicit
per se -SM actin expression; however, incubation of fibroblasts with the anti-ED-A monoclonal antibody IST-9 specifically blocks the TGF1-triggered enhancement of -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 TGF1 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.
-SM actin;
extracellular
matrix;
wound healing;
fibrosis
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