EXTRACELLULAR-MATRIX ALTERS PDGF REGULATION OF FIBROBLAST INTEGRINS

Extracellular matrix (ECM) and growth factors are potent regulators of cell phenotype. These biological mediators of cellular responses are potentially interactive and as such could drive cells through progress ive phenotypes to create new tissue as in morphogenesis and wound repa ir, In fact, ECM composition changes during tissue formation accompani ed by alterations in cell growth and migration, How alterations in the ECM regulate cell activities is poorly defined. To address this quest ion in wound repair, we cultured normal human dermal skin fibroblasts in relaxed collagen gels, fibronectin-rich cultures or stressed fibrin gels, and stressed collagen gels to model normal dermis, early wound provisional matrix, and late granulation tissue, respectively. Integri n subunits, alpha(2), alpha(3), and alpha(5), that define receptor spe cificity for collagen and provisional matrix, respectively, were measu red at mRNA steady-state level before and after stimulation with plate let-derived growth factor-BE (PDGF-BB), a potent mitogen and chemoattr actant for fibroblasts. Fibronectin-rich cultures and fibrin gels supp orted PDGF-BB induction of alpha(3) and alpha(5) mRNA. In contrast, bo th stressed and relaxed collagen attenuated these responses while prom oting maximal alpha(2) mRNA expression. Posttranscriptional regulation was an important mechanism in this differential response. Together PD GF-BB and collagen gels promoted alpha(2), but not alpha(3) and alpha( 5), mRNA stability. Conversely, when fibroblasts were in fibronectin-r ich cultures, PDGF-BB promoted alpha(3) and alpha(5), but not alpha(2) , mRNA stability. We suggest that ECM alterations during wound healing or any new tissue formation cause cells to respond differently to rep eated growth factor stimuli. An ordered progression of cell phenotypes results, ultimately consummating tissue repair or morphogenesis.