Matrix-fibrinogen enhances wound closure by increasing both cell proliferation and migration.
Fibrinogen (FBG) assembles into matrix fibrils of fibroblasts, lung and mammary epithelial cells, but not endothelial cells. Furthermore, cryptic beta15-21 residues are exposed in FBG fibrils with no evidence of thrombin or plasmin proteolysis. Herein, the effects of FBG on migration and proliferation of wounded dermal fibroblasts were investigated. FBG preassembled into matrix prior to scrape-wounding induced 3H-thymidine incorporation 8-fold and shortened the time to wound closure 1.6-fold +/- 0.1-fold. FBG added immediately after wounding did not enhance either response. Fibroblast growth factor-2/platelet-derived growth factor (FGF-2/PDGF) stimulated cell proliferation 2.2-fold for FGF-2 and 3.2-fold for PDGF and wound closure 1.5-fold +/- 0.1-fold in the absence of matrix-FBG. Surprisingly, exogenous growth factors had negligible effect on wound closure and cell proliferation already enhanced by matrix-FBG. Matrix-FBG-enhanced wound closure required active assembly of an FBG-fibronectin matrix, engagement of alphavbeta3, and FBG Aalpha-RGDS572-575 integrin recognition sites; Aalpha-RGDF95-98 sites were not sufficient for matrix-FBG assembly, enhanced wound closure, or cell proliferation. Although Bbeta1-42 was not necessary for matrix assembly, it was required for matrix-FBG-enhanced cell migration. These data indicate that FBG serves as an important matrix constituent in the absence of fibrin formation to enhance wound repair and implicate Bbeta1-42 as a physiologic inducer of signal transduction to promote an intermediate state of cell adhesion and a migratory cell phenotype.
Rybarczyk
Brian J
BJ
Department of Medicine-Hem/Onc, PO Box 610, University of Rochester, 601 Elmwood Ave, Rochester, NY 14642, USA.
Lawrence
Sarah O
SO
Simpson-Haidaris
Patricia J
PJ
D000595:Amino Acid Sequence; D001665:Binding Sites; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D005338:Fibrin Fibrinogen Degradation Products / Q000502:physiology; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D010446:Peptide Fragments / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D013997:Time Factors; D014945:Wound Healing
D005338:Fibrin Fibrinogen Degradation Products; D039302:Integrin alphaVbeta3; D010446:Peptide Fragments; D010982:Platelet-Derived Growth Factor; C035285:fibrinogen Bbeta (1-42); D016222:Fibroblast Growth Factor 2; D005340:Fibrinogen