title: Growth factor-dependent proliferation and invasion of muscle satellite cells require the cell-associated fibrinolytic system.
abstract: The process of muscle regeneration in normal and dystrophic muscle depends on locally produced cytokines and growth factors and requires the activity of the urokinase plasminogen activator/urokinase plasminogen activator receptor/plasminogen activator inhibitor-1 system. In this study we tested the effect of basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF) and transforming growth factor-beta (TGFbeta) on the fibrinolytic pattern of normal and dystrophic satellite cells, their mitogenic and motogenic activities and the dependence of such activities on the cell-associated fibrinolytic system. We have observed that the urokinase plasminogen activator (u-PA) receptor is weakly upregulated by bFGF in normal satellite cells, while it is strongly up-regulated by TGFbeta, mainly in dystrophic myoblasts. bFGF up-regulated u-PA in both normal and dystrophic myoblasts grown in primary culture, while a striking down-regulation was observed with TGFbeta. TGFbeta was the only growth factor able to exceptionally up-regulate plasminogen activator inhibitor-1 (PAI-1), mainly in dystrophic satellite cells. HGF did not show any activity on the fibrinolytic system. Proliferation and invasion into Matrigel matrices of normal and dystrophic cells occurred regardless of the growth factor-dependent regulation of the fibrinolytic system. Nevertheless, each growth factor required the efficiency of the constitutive cell-associated fibrinolytic system to operate, as shown by impairment of growth factor activity with antagonists of u-PA and of its receptor. Noteworthy, TGFbeta induced a dose-dependent increase of Matrigel invasion only in dystrophic myoblasts. Since TGFbeta-challenged dystrophic myoblasts undergo an exceptional up-regulation of the receptor and of PAI-1, we propose the possibility that the TGFbeta-induced fibrinolytic pattern (low urokinase plasminogen activator, high receptor and high PAI-1) may be exploited to promote survival and spreading of transplanted engineered myoblasts in Duchenne muscular dystrophy.
authors.affiliation: Department of Experimental Pathology and Oncology, University of Florence, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fibbi
authors.forename: Silvia
authors.initials: S
authors.lastname: D'Alessio
authors.forename: Marco
authors.initials: M
authors.lastname: Pucci
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cerletti
authors.forename: Mario
authors.initials: M
authors.lastname: Del Rosso
mesh_terms: D016022:Case-Control Studies; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005343:Fibrinolytic Agents / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D007223:Infant; D018482:Muscle, Skeletal / Q000166:cytology*; D020388:Muscular Dystrophy, Duchenne / Q000473:pathology*; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010960:Plasminogen Activators / Q000187:drug effects / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D012038:Regeneration / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000187:drug effects / Q000378:metabolism
chemical_list: D005343:Fibrinolytic Agents; D006133:Growth Substances; C524898:PLAUR protein, human; D017395:Plasminogen Activator Inhibitor 1; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator