title: Fibrinogen and fibrin are anti-adhesive for keratinocytes: a mechanism for fibrin eschar slough during wound repair.
abstract: During cutaneous wound repair the epidermis avoids the fibrin-rich clot; rather it migrates down the collagen-rich dermal wound margin and over fibronectin-rich granulation tissue. The mechanism(s) underlying keratinocyte movement in this precise pathway has not been previously addressed. Here we demonstrate that cultured human keratinocytes do not express functional fibrinogen/fibrin receptors, specifically alpha v beta 3. Biologic modifiers known to induce integrin expression or activation did not induce adhesion to fibrin, fibrinogen, or its fragments. Epidermal explant outgrowth and single epidermal cell migration failed to occur on either fibrin or fibrinogen. Surprisingly, fibrin and fibrinogen mixed at physiologic molar ratios with fibronectin abrogated keratinocyte attachment to fibronectin. Keratinocytes transduced with the beta 3 integrin subunit cDNA, expressed alpha v beta 3 on their surface and attached to and spread on fibrinogen and fibrin. beta-gal cDNA-transduced keratinocytes did not demonstrate this activity. Furthermore, beta 3 cDNA-transduced keratinocyte adhesion to fibrin was inhibited by LM609 monoclonal antibody to alpha v beta 3 in a concentration-dependent fashion. From these data, we conclude that normal human keratinocytes cannot interact with fibrinogen and its derivatives due to the lack of alpha v beta 3. Thus, fibrinogen and fibrin are authentic anti-adhesive for keratinocytes. This may be a fundamental reason why the migrating epidermis dissects the fibrin eschar from wounds.
authors.affiliation: Department of Dermatology, School of Medicine, SUNY at Stony Brook, Stony Brook, New York, New York 11794-8165, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kubo
authors.forename: L
authors.initials: L
authors.lastname: Van de Water
authors.forename: L C
authors.initials: LC
authors.lastname: Plantefaber
authors.forename: M W
authors.initials: MW
authors.lastname: Mosesson
authors.forename: M
authors.initials: M
authors.lastname: Simon
authors.forename: M G
authors.initials: MG
authors.lastname: Tonnesen
authors.forename: L
authors.initials: L
authors.lastname: Taichman
authors.forename: R A
authors.initials: RA
authors.lastname: Clark
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002413:Cations, Divalent / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002498:Centrifugation; D018076:DNA, Complementary; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004817:Epidermis / Q000293:injuries; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism / Q000494:pharmacology*; D005338:Fibrin Fibrinogen Degradation Products / Q000494:pharmacology; D005340:Fibrinogen / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D039661:Integrin beta3; D015603:Keratinocytes / Q000166:cytology* / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D002273:Carcinogens; D002413:Cations, Divalent; D018076:DNA, Complementary; D016326:Extracellular Matrix Proteins; D005338:Fibrin Fibrinogen Degradation Products; D039661:Integrin beta3; D010980:Platelet Membrane Glycoproteins; D019030:Receptors, Vitronectin; D016212:Transforming Growth Factor beta; C015214:fibrinogen D fragment; C018543:fibrinogen fragment E; D004815:Epidermal Growth Factor; D003994:Bucladesine; D005337:Fibrin; D005340:Fibrinogen; D013755:Tetradecanoylphorbol Acetate