Interactions between extracellular matrix and growth factors in wound healing

Dynamic interactions between growth factors and extracellular matrix (ECM) are integral to wound healing. These interactions take several forms that may be categorized as direct or indirect. The ECM can directly bind to and release certain growth factors (e.g., heparan sulfate binding to fibroblast growth factor‐2), which may serve to sequester and protect growth factors from degradation, and/or enhance their activity. Indirect interactions include binding of cells to ECM via integrins, which enables cells to respond to growth factors (e.g., integrin binding is necessary for vascular endothelial growth factor‐induced angiogenesis) and can induce growth factor expression (adherence of monocytes to ECM stimulates synthesis of platelet‐derived growth factor). Additionally, matrikines, or subcomponents of ECM molecules, can bind to cell surface receptors in the cytokine, chemokine, or growth factor families and stimulate cellular activities (e.g., tenascin‐C and laminin bind to epidermal growth factor receptors, which enhances fibroblast migration). Growth factors such as transforming growth factor‐β also regulate the ECM by increasing the production of ECM components or enhancing synthesis of matrix degrading enzymes. Thus, the interactions between growth factors and ECM are bidirectional. This review explores these interactions, discusses how they are altered in difficult to heal or chronic wounds, and briefly considers treatment implications.

[1]  J. Massagué,et al.  Regulation of cell adhesion receptors by transforming growth factor-beta. Regulation of vitronectin receptor and LFA-1. , 1989, The Journal of biological chemistry.

[2]  G. Giannelli,et al.  Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. , 1997, Science.

[3]  B. Olwin,et al.  Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation , 1991, Science.

[4]  C. Damsky,et al.  Extracellular Matrix Survival Signals Transduced by Focal Adhesion Kinase Suppress p53-mediated Apoptosis , 1998, The Journal of cell biology.

[5]  Gary R. Grotendorst,et al.  Stimulation of granulation tissue formation by platelet-derived growth factor in normal and diabetic rats. , 1985, The Journal of clinical investigation.

[6]  George Broughton,et al.  The Basic Science of Wound Healing , 2006, Plastic and reconstructive surgery.

[7]  R. Langer,et al.  Temporal study of the activity of matrix metalloproteinases and their endogenous inhibitors during wound healing , 1996, Journal of cellular biochemistry.

[8]  V. Freedman,et al.  Tumorigenicity of virus-transformed cells in nude mice is correlated specifically with anchorage independent growth in vitro. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. Keski‐Oja,et al.  Latent TGF-β Binding Proteins: Extracellular Matrix Association and Roles in TGF-β Activation , 2004 .

[10]  Jeffrey D. Esko,et al.  Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor , 1991, Cell.

[11]  F. Grinnell,et al.  Fibronectin profiles in normal and chronic wound fluid. , 1990, Laboratory investigation; a journal of technical methods and pathology.

[12]  M. Bissell,et al.  Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. , 2006, Annual review of cell and developmental biology.

[13]  J. Murphy-Ullrich,et al.  Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology. , 2000, Cytokine & growth factor reviews.

[14]  J. Folkman,et al.  Role of cell shape in growth control , 1978, Nature.

[15]  S. Amano,et al.  Increase of laminin 5 synthesis in human keratinocytes by acute wound fluid, inflammatory cytokines and growth factors, and lysophospholipids , 2004, The British journal of dermatology.

[16]  J. Thiery,et al.  Fibroblast growth factor-2. , 2000, The international journal of biochemistry & cell biology.

[17]  F. Grinnell,et al.  Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. , 1993, The Journal of investigative dermatology.

[18]  J. Wrana,et al.  Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta. , 1989, The Journal of biological chemistry.

[19]  Alan Wells,et al.  Extracellular matrix signaling through growth factor receptors during wound healing , 2004, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[20]  T. Kawai,et al.  Acceleration of wound healing in healing‐impaired db/db mice with a photocrosslinkable chitosan hydrogel containing fibroblast growth factor‐2 , 2005, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[21]  C. von Schacky,et al.  IGF-1, PDGF and CD18 are adherence-responsive genes: regulation during monocyte differentiation. , 1998, Biochimica et biophysica acta.

[22]  Masashi Suzuki,et al.  Expression of fibroblast growth factors and their receptors during full-thickness skin wound healing in young and aged mice. , 2005, The Journal of endocrinology.

[23]  W. Parks,et al.  Distinct localization of collagenase and tissue inhibitor of metalloproteinases expression in wound healing associated with ulcerative pyogenic granuloma. , 1992, The Journal of clinical investigation.

[24]  D. Rifkin,et al.  Release of basic fibroblast growth factor-heparan sulfate complexes from endothelial cells by plasminogen activator-mediated proteolytic activity , 1990, The Journal of cell biology.

[25]  P. Peplow Glycosaminoglycan: a candidate to stimulate the repair of chronic wounds , 2005, Thrombosis and Haemostasis.

[26]  M. Jünger,et al.  Microcirculatory Dysfunction in Chronic Venous Insufficiency (CVI) , 2000, Microcirculation.

[27]  M J Bissell,et al.  How does the extracellular matrix direct gene expression? , 1982, Journal of theoretical biology.

[28]  J. Tarlton,et al.  Mechanisms of chronic skin ulceration linking lactate, transforming growth factor-beta, vascular endothelial growth factor, collagen remodeling, collagen stability, and defective angiogenesis. , 2007, The Journal of investigative dermatology.

[29]  J. Turnbull,et al.  Specific heparan sulfate saccharides mediate the activity of basic fibroblast growth factor. , 1994, The Journal of biological chemistry.

[30]  E. Ruoslahti,et al.  Negative regulation of transforming growth factor-β by the proteoglycan decorin , 1990, Nature.

[31]  A. C. van der Wal,et al.  Causes, investigation and treatment of leg ulceration , 2003, The British journal of dermatology.

[32]  P. Preux,et al.  Epidemiological and clinical aspects. , 2005 .

[33]  I. K. Cohen,et al.  Hyaluronic acid modulates proliferation, collagen and protein synthesis of cultured fetal fibroblasts. , 1993, Matrix.

[34]  E. Sage,et al.  Regulation of interactions between cells and extracellular matrix: a command performance on several stages. , 2001, The Journal of clinical investigation.

[35]  C. Little,et al.  Antibodies to β1‐integrins cause alterations of aortic vasculogenesis, in vivo , 1992 .

[36]  A. Ergul,et al.  Type-2 diabetes-induced changes in vascular extracellular matrix gene expression: Relation to vessel size , 2006, Cardiovascular diabetology.

[37]  M. Sporn,et al.  Transforming growth factor-beta. Major role in regulation of extracellular matrix. , 1990, Annals of the New York Academy of Sciences.

[38]  M. Detmar,et al.  Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Halimi,et al.  Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing , 2008, Diabetic medicine : a journal of the British Diabetic Association.

[40]  N. Boudreau,et al.  Extracellular matrix and integrin signalling: the shape of things to come. , 1999, The Biochemical journal.

[41]  J. McPherson,et al.  Collagen in Dermal Wound Repair , 1988 .

[42]  E. Brown,et al.  Fibronectin receptors of phagocytes. Characterization of the Arg-Gly- Asp binding proteins of human monocytes and polymorphonuclear leukocytes , 1988, The Journal of experimental medicine.

[43]  Christopher J. Robinson,et al.  The splice variants of vascular endothelial growth factor (VEGF) and their receptors. , 2001, Journal of cell science.

[44]  R. Clark Fibronectin matrix deposition and fibronectin receptor expression in healing and normal skin. , 1990, The Journal of investigative dermatology.

[45]  C. Kumar Integrin alpha v beta 3 as a therapeutic target for blocking tumor-induced angiogenesis. , 2003, Current drug targets.

[46]  J. Murphy-Ullrich,et al.  Activation of latent TGF-β by thrombospondin-1: mechanisms and physiology , 2000 .

[47]  E. Ruoslahti,et al.  Elevated expression of transforming growth factor-beta and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix. , 1990, The Journal of clinical investigation.

[48]  F. Arnold,et al.  Angiogenesis in wound healing. , 1991, Pharmacology & therapeutics.

[49]  J. E. Lee,et al.  Induced expression of insulin-like growth factor-1 by amniotic membrane-conditioned medium in cultured human corneal epithelial cells. , 2006, Investigative ophthalmology & visual science.

[50]  J. Plouët,et al.  Control of vascular endothelial growth factor angiogenic activity by the extracellular matrix. , 1998, Biology of the cell.

[51]  J. Keski‐Oja,et al.  Latent TGF-beta binding proteins: extracellular matrix association and roles in TGF-beta activation. , 2004, Critical reviews in clinical laboratory sciences.

[52]  Nima P. Patel,et al.  Current Management of Venous Ulceration , 2006, Plastic and reconstructive surgery.

[53]  A. D'Angelo,et al.  Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in diabetic and healthy subjects. , 2007, Diabetes & metabolism.

[54]  D. Rifkin,et al.  Extracellular matrix regulation of growth factor and protease activity. , 1991, Current opinion in cell biology.

[55]  D. Carey,et al.  Control of growth and differentiation of vascular cells by extracellular matrix proteins. , 1991, Annual review of physiology.

[56]  D. Rifkin,et al.  Role of extracellular matrix in the action of basic fibroblast growth factor: Matrix as a source of growth factor for long‐term stimulation of plasminogen activator production and DNA synthesis , 1989, Journal of cellular physiology.

[57]  P. Bornstein,et al.  Diversity of Function Is Inherent in Matricellular Proteins: an Appraisal of Thrombospondin I , 1995 .

[58]  T. Phillips,et al.  Chronic wound fluid suppresses proliferation of dermal fibroblasts through a Ras-mediated signaling pathway. , 2005, The Journal of investigative dermatology.

[59]  D. Grobelny,et al.  Treatment of alkali-injured rabbit corneas with a synthetic inhibitor of matrix metalloproteinases. , 1992, Investigative ophthalmology & visual science.

[60]  A. Chauhan,et al.  Regulated splicing of the fibronectin EDA exon is essential for proper skin wound healing and normal lifespan , 2003, The Journal of cell biology.

[61]  V. Falanga,et al.  Extravasation of macromolecules and possible trapping of transforming growth factor‐β in venous ulceration , 1995, The British journal of dermatology.

[62]  R. Timpl,et al.  Domains of laminin with growth-factor activity , 1989, Cell.

[63]  M. Ågren,et al.  The Extracellular Matrix in Wound Healing: A Closer Look at Therapeutics for Chronic Wounds , 2007, The international journal of lower extremity wounds.

[64]  S. Tseng,et al.  Keratocan Expression of Murine Keratocytes Is Maintained on Amniotic Membrane by Down-regulating Transforming Growth Factor-β Signaling* , 2005, Journal of Biological Chemistry.

[65]  S. Friedman,et al.  Discoidin Domain Receptor 2 Regulates Fibroblast Proliferation and Migration through the Extracellular Matrix in Association with Transcriptional Activation of Matrix Metalloproteinase-2* , 2002, The Journal of Biological Chemistry.

[66]  Wei Li,et al.  How does amniotic membrane work? , 2004, The ocular surface.

[67]  Koichi Hattori,et al.  Angiogenesis: vascular remodeling of the extracellular matrix involves metalloproteinases , 2003, Current opinion in hematology.

[68]  W. Olszewski,et al.  Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers , 2006, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[69]  S. Haskill,et al.  Signal transduction from the extracellular matrix , 1993, The Journal of cell biology.

[70]  A. Boulton,et al.  Evidence-Based Protocol for Diabetic Foot Ulcers , 2006, Plastic and reconstructive surgery.

[71]  D. Cheresh,et al.  Requirement of vascular integrin alpha v beta 3 for angiogenesis. , 1994, Science.

[72]  W. Halfter,et al.  Induction of tenascin in healing wounds , 1988, The Journal of cell biology.

[73]  J. Rosenbloom,et al.  Transforming growth factor beta (TGF beta) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human dermal fibroblasts. , 1987, The Biochemical journal.

[74]  K. Tran,et al.  Matrikines and matricryptins: Implications for cutaneous cancers and skin repair. , 2005, Journal of dermatological science.

[75]  D. Gospodarowicz,et al.  Heparin protects basic and acidic FGF from inactivation , 1986, Journal of cellular physiology.

[76]  Jon R. Cohen The Molecular and Cellular Biology of Wound Repair , 1997, Springer US.

[77]  J. Heath,et al.  Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. , 1987, The EMBO journal.

[78]  R. Clark Basics of cutaneous wound repair. , 1993, The Journal of dermatologic surgery and oncology.

[79]  A. Ben-Ze'ev,et al.  The control of mRNA production, translation and turnover in suspended and reattached anchorage-dependent fibroblasts , 1978, Cell.

[80]  C. Murphy,et al.  Non-enzymatic glycation in corneas from normal and diabetic donors and its effects on epithelial cell attachment in vitro. , 2003, Optometry.

[81]  C. McCollum,et al.  Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. , 1992, The American journal of pathology.

[82]  R. Clark,et al.  Adherence-dependent increase in human monocyte PDGF(B) mRNA is associated with increases in c-fos, c-jun, and EGR2 mRNA , 1990, The Journal of cell biology.

[83]  T. Pawson,et al.  The discoidin domain receptor tyrosine kinases are activated by collagen. , 1997, Molecular cell.

[84]  J. Schlessinger,et al.  Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. , 2000, Molecular cell.

[85]  S. Atkins,et al.  The effect of antibodies to TGF‐β1 and TGF‐β2 at a site of sciatic nerve repair , 2006 .

[86]  Richard A.F. Clark,et al.  The Molecular and Cellular Biology of Wound Repair , 2012, Springer US.

[87]  W. Parks,et al.  Collagen-stimulated induction of keratinocyte collagenase is mediated via tyrosine kinase and protein kinase C activities. , 1994, The Journal of biological chemistry.

[88]  J. Brugge,et al.  Integrins and signal transduction pathways: the road taken. , 1995, Science.

[89]  R. Khokha,et al.  Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution , 2003, The Journal of cell biology.

[90]  R. Clark Biology of dermal wound repair. , 1993, Dermatologic clinics.

[91]  J. Winer,et al.  Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. , 1992, The Journal of biological chemistry.

[92]  E. Ruoslahti,et al.  Negative regulation of transforming growth factor-beta by the proteoglycan decorin. , 1990, Nature.

[93]  David Silverstein,et al.  Growth factor binding to the pericellular matrix and its importance in tissue engineering. , 2007, Advanced drug delivery reviews.

[94]  Alan Wells,et al.  Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor , 2001, The Journal of cell biology.

[95]  R. Clark,et al.  Three-dimensional migration of human adult dermal fibroblasts from collagen lattices into fibrin/fibronectin gels requires syndecan-4 proteoglycan. , 2005, The Journal of investigative dermatology.

[96]  J. Massagué,et al.  Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. , 1986, The Journal of biological chemistry.

[97]  C. Little,et al.  Antibodies to beta 1-integrins cause alterations of aortic vasculogenesis, in vivo. , 1992, Developmental dynamics : an official publication of the American Association of Anatomists.

[98]  I. Konigsberg,et al.  The influence of collagen on the development of muscle clones. , 1966, Proceedings of the National Academy of Sciences of the United States of America.

[99]  R. H. Harries,et al.  Effect of healing on the expression of transforming growth factor beta(s) and their receptors in chronic venous leg ulcers. , 2001, The Journal of investigative dermatology.

[100]  Z. Werb,et al.  Regulation of matrix biology by matrix metalloproteinases. , 2004, Current opinion in cell biology.

[101]  J. Massagué,et al.  Cell adhesion protein receptors as targets for transforming growth factor-β action , 1987, Cell.

[102]  Donald E Ingber,et al.  Micromechanical control of cell and tissue development: implications for tissue engineering. , 2007, Advanced drug delivery reviews.

[103]  R. Clark,et al.  Cryptic chemotactic activity of fibronectin for human monocytes resides in the 120-kDa fibroblastic cell-binding fragment. , 1988, The Journal of biological chemistry.

[104]  J. Tarlton,et al.  Abnormal extracellular matrix metabolism in chronically ischemic skin: a mechanism for dermal failure in leg ulcers. , 2005, The Journal of investigative dermatology.

[105]  F. Watt,et al.  Role of integrins in regulating epidermal adhesion, growth and differentiation , 2002, The EMBO journal.

[106]  H. Laverty,et al.  Prevention and reduction of scarring in the skin by Transforming Growth Factor beta 3 (TGFβ3): from laboratory discovery to clinical pharmaceutical , 2008, Journal of biomaterials science. Polymer edition.

[107]  Alberto Smith,et al.  Increased but ineffectual angiogenic drive in nonhealing venous leg ulcers. , 2003, Journal of vascular surgery.