Cellular and Molecular Life Sciences

, Volume 68, Issue 11, pp 1871–1881 | Cite as

Matrix control of scarring



Repair of wounds usually results in restoration of organ function, even if suboptimal. However, in a minority of situations, the healing process leads to significant scarring that hampers homeostasis and leaves the tissue compromised. This scar is characterized by an excess of matrix deposition that remains poorly organized and weakened. While we know much of the early stages of the repair process, the transition to wound resolution that limits scar formation is poorly understood. This is particularly true of the inducers of scar formation. Here, we present a hypothesis that it is the matrix itself that is a primary driver of scar, rather than being simply the result of other cellular dysregulations.


Fibrosis ECM CXCR3 Tenascin C Fibronectin 



These studies were supported by grants from the National Institute of General Medical Science of the National Institutes of Health (USA) (GM063569). Services in kind were provided by the Pittsburgh VA Medical Center.


  1. 1.
    Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341:738–746PubMedCrossRefGoogle Scholar
  2. 2.
    Harty M, Neff AW, King MW, Mescher AL (2003) Regeneration or scarring: an immunologic perspective. Dev Dyn 226:268–279PubMedCrossRefGoogle Scholar
  3. 3.
    Hynes RO (2009) The extracellular matrix: not just pretty fibrils. Science 326:1216–1219PubMedCrossRefGoogle Scholar
  4. 4.
    Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 45:314–321CrossRefGoogle Scholar
  5. 5.
    Trent JT, Kirsner RS (2006) Wounds and malignancy. Adv Skin Wound Care 16:31–34CrossRefGoogle Scholar
  6. 6.
    Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E (2004) Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118:635–648PubMedCrossRefGoogle Scholar
  7. 7.
    Nelson CM, Bissell MJ (2006) Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu Rev Cell Dev Biol 22:287–309PubMedCrossRefGoogle Scholar
  8. 8.
    Liu Y, Min D, Bolton T et al (2009) Increased matrix metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care 32:117–119PubMedCrossRefGoogle Scholar
  9. 9.
    James GA, Swogger E, Wolcott R et al (2008) Biofilms in chronic wounds. Wound Repair Regen 16:37–44PubMedCrossRefGoogle Scholar
  10. 10.
    Wynn T (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210PubMedCrossRefGoogle Scholar
  11. 11.
    Werner S, Krieg T, Smola H (2007) Keratinocyte–fibroblast interactions in wound healing. J Invest Dermatol 127:998–1008PubMedCrossRefGoogle Scholar
  12. 12.
    Martin P (1997) Wound healing—aiming for perfect skin regeneration. Science 276:75–81PubMedCrossRefGoogle Scholar
  13. 13.
    Adzick NS, Harrison MR, Glick PL, Beckstead JH, Villa RL, Scheuenstuhl H, Goodson WH (1985) Comparison of fetal, newborn, and adult wound healing by histologic, enzyme-histochemical, and hydroxyproline determinations. J Pediatr Surg 20:315–319PubMedCrossRefGoogle Scholar
  14. 14.
    Yamaguchi Y, Yoshikawa K (2001) Cutaneous wound healing: an update. J Dermatol 28:521–534PubMedGoogle Scholar
  15. 15.
    Schultz G (2008) Dynamic reciprocity—how cells and extracellular matrix communicate to heal wounds. Third Congress of the World Union of Wound Healing Societies, CanadaGoogle Scholar
  16. 16.
    Eckes B, Nischt R, Krieg T (2010) Cell–matrix interactions in dermal repair and scarring. Fibrogenesis Tissue Repair 3:4PubMedCrossRefGoogle Scholar
  17. 17.
    Widgerow AD, Chait LAC, Stals R, Stals P, Candy G (2009) Multimodality scar management program. Aesthetic Plast Surg 33:533PubMedCrossRefGoogle Scholar
  18. 18.
    Siebert JW, Burd AR, McCarthy JG, Weinzweig J, Ehrlich HP (1990) Fetal wound healing: a biochemical study of scarless healing. Plast Reconstr Surg 85:495–504PubMedCrossRefGoogle Scholar
  19. 19.
    Woolley K, Martin P (2000) Conserved mechanisms of repair: from damaged single cells to wounds in multicellular tissues. Bioessays 22:911–919PubMedCrossRefGoogle Scholar
  20. 20.
    Coolen NA, Schouten KC, Middelkoop E et al (2010) Comparison between human fetal and adult skin. Arch Dermatol Res 302:47–55PubMedCrossRefGoogle Scholar
  21. 21.
    Lorenz HP, Longaker MT, Perkocha LA et al (1992) Scarless wound repair: a human fetal skin model. Development 114:253–259PubMedGoogle Scholar
  22. 22.
    Tran KT, Lamb P, Deng JS (2004) Matrikines and matricryptins: implications for cutaneous cancers and skin repair. J Dermatol Sci 40:11–20CrossRefGoogle Scholar
  23. 23.
    Tran KT, Griffith L, Wells A (2004) Extracellular matrix signaling through growth factor receptors during wound healing. Wound Repair Regen 12:262–268PubMedCrossRefGoogle Scholar
  24. 24.
    Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V (1997) Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277:225–228PubMedCrossRefGoogle Scholar
  25. 25.
    Aarabi S, Longaker MT, Gurtner GC (2007) Hypertrophic scar formation following burns and trauma: new approaches to treatment. PLoS Med 4:e234PubMedCrossRefGoogle Scholar
  26. 26.
    Niessen FB, Spauwen PH, Schalkwijk J, Kon M (2008) On the nature of hypertrophic scars and keloids: a review. Plast Reconstr Surg 104:1435–1458Google Scholar
  27. 27.
    Martin P, Parkhurst SM (2004) Parallels between tissue repair and embryo morphogenesis. Development 131:3021–3034PubMedCrossRefGoogle Scholar
  28. 28.
    Martin P, Lewis J (1992) Actin cables and epidermal movement in embryonic wound healing. Nature 360:179–183PubMedCrossRefGoogle Scholar
  29. 29.
    Colwell AS, Longaker MT, Lorenz H (2003) Fetal wound healing. Front Biosci 8:s1240–s1248PubMedCrossRefGoogle Scholar
  30. 30.
    ChenW FuX, Ge S, Sun T, Zhou G, Jiang D, Sheng Z (2005) Ontogeny of expression of transforming growth factor-beta and its receptors and their possible relationship with scarless healing in human fetal skin. Wound Repair Regen 13:68–75CrossRefGoogle Scholar
  31. 31.
    Ferguson MW, O’Kane S (2004) Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Philos Trans R Soc Lond B 359:839–850CrossRefGoogle Scholar
  32. 32.
    Armour A, Scott PG, Tredget EE (2007) Cellular and molecular pathology of HTS: basis for treatment. Wound Repair Regen 15:S6–S17PubMedCrossRefGoogle Scholar
  33. 33.
    Mehrad B, Keane MP, Gomperts BN, Strieter RM (2007) Circulating progenitor cells in chronic lung disease. Expert Rev Respir Med 1:157–165PubMedCrossRefGoogle Scholar
  34. 34.
    Zeisberg EM, Tarnavski O, Zeisberg M et al (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13:952–961PubMedCrossRefGoogle Scholar
  35. 35.
    Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R (2007) Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 282:23337–23347PubMedCrossRefGoogle Scholar
  36. 36.
    National Heart Blood Institute Lung Mortality Morbidity (2002) Chart book on cardiovascular, lung, and blood diseases. US Department of Health and Human Services, BethesdaGoogle Scholar
  37. 37.
    Babu M, Wells A (2002) Dermal–epidermal communication in wound healing. Wounds 200113:183–189Google Scholar
  38. 38.
    Neilson EG (2006) Mechanisms of disease fibroblasts—a new look at an old problem. Nat Clin Pract Nephrol 2:101–108PubMedCrossRefGoogle Scholar
  39. 39.
    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3:349–363PubMedCrossRefGoogle Scholar
  40. 40.
    Eckes B, Krieg T (2004) Regulation of connective tissue homeostasis in the skin by mechanical forces. Clin Exp Rheumatol 22:S73–S76PubMedGoogle Scholar
  41. 41.
    Rivera J, Lozano ML, Navarro-Nunez L, Vicente V (2009) Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 94:700–711PubMedCrossRefGoogle Scholar
  42. 42.
    Nieswandt B, Varga-Szabo D, Elvers M (2009) Integrins in platelet activation. J Thromb Haemost 7:206–209PubMedCrossRefGoogle Scholar
  43. 43.
    Theilgaard-Monch K, Knudsen S, Follin P, Borregaard N (2004) The transcriptional activation program of human neutrophils in skin lesions supports their important role in wound healing. J Immunol 172:7684–7693PubMedGoogle Scholar
  44. 44.
    Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83:835–870PubMedGoogle Scholar
  45. 45.
    Clark RA (1993) Biology of dermal wound repair. Dermatol Clin 11:647–666PubMedGoogle Scholar
  46. 46.
    Greiling D, Clark RA (1997) Fibronectin provides a conduit for fibroblast transmigration from collagenous stroma into fibrin clot provisional matrix. J Cell Sci 110:861–870PubMedGoogle Scholar
  47. 47.
    McDonald JA, Kelley DG, Broekelmann TJ (1982) Role of fibronectin in collagen deposition: fab’ to the gelatin-binding domain of fibronectin inhibits both fibronectin and collagen organization in fibroblast extracellular matrix. J Cell Biol 92:485–495PubMedCrossRefGoogle Scholar
  48. 48.
    Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Müller W, Roers A, Eming SA (2010) Differential roles of macrophages in diverse phases of skin repair. J Immunol 184:3964–3977PubMedCrossRefGoogle Scholar
  49. 49.
    Roberts AB, Heine UI, Flanders KC, Sporn MB (1990) Transforming growth factor-beta. Major role in regulation of extracellular matrix. Ann NY Acad Sci 580:225–232PubMedCrossRefGoogle Scholar
  50. 50.
    Raab G, Klagsbrun M (1997) Heparin-binding EGF-like growth factor. Biochim Biophys Acta 1333:F179–F199PubMedGoogle Scholar
  51. 51.
    Marikovsky M, Breuing K, Liu PY et al (1993) Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury. Proc Natl Acad Sci USA 90:3889–3893PubMedCrossRefGoogle Scholar
  52. 52.
    Tonnesen MG, Feng X, Clark RA (2000) Angiogenesis in wound healing. J Investig Dermatol Symp Proc 5:40–46PubMedCrossRefGoogle Scholar
  53. 53.
    Herrick SE, Sloan P, McGurk M, Freak L, McCollum CN, Ferguson MW (1992) Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am J Pathol 141:1085–1095PubMedGoogle Scholar
  54. 54.
    Flaumenhaft R, Rifkin DB (1991) Extracellular matrix regulation of growth factor and protease activity. Curr Opin Cell Biol 3:817–823PubMedCrossRefGoogle Scholar
  55. 55.
    Baneyx G, Baugh L, Vogel V (2002) Fibronectin extension and unfolding within cell matrix fibrils controlled by cytoskeletal tension. Proc Natl Acad Sci USA 99:5139–5143PubMedCrossRefGoogle Scholar
  56. 56.
    Yan C, Grimm WA, Garner WL et al (2010) Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol 176:2247–2258PubMedCrossRefGoogle Scholar
  57. 57.
    Spaeth EL, Dembinski JL, Sasser AK et al (2009) Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One 4:e4992PubMedCrossRefGoogle Scholar
  58. 58.
    Papetti M, Herman IM (2002) Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol 282:C947–C970PubMedGoogle Scholar
  59. 59.
    Iozzo RV, Schaefer L (2010) Proteoglycans in health and disease: novel regulatory signaling mechanisms evoked by the small leucine-rich proteoglycans. FEBS J 277:3864–3875PubMedCrossRefGoogle Scholar
  60. 60.
    Hynes RO (1999) The dynamic dialogue between cells and matrices: implications of fibronectin’s elasticity. Proc Natl Acad Sci USA 96:2588–2590PubMedCrossRefGoogle Scholar
  61. 61.
    Clark RA (1990) Fibronectin matrix deposition and fibronectin receptor expression in healing and normal skin. J Invest Dermatol 94:128S–134SPubMedCrossRefGoogle Scholar
  62. 62.
    Schultz GS, Wysocki A (2009) Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen 17:153–162PubMedCrossRefGoogle Scholar
  63. 63.
    Heino J (2007) The collagen family members as cell adhesion proteins. Bioessays 29:1001–1010PubMedCrossRefGoogle Scholar
  64. 64.
    Romagnani P, Lasagni L, Annunziato F, Serio M, Romagnani S (2004) CXC chemokines: the regulatory link between inflammation and angiogenesis. Trends Immunol 25:201–209PubMedCrossRefGoogle Scholar
  65. 65.
    Liu L, Callahan MK, Huang D, Ransohoff RM (2005) Chemokine receptor CXCR3: an unexpected enigma. Curr Top Dev Biol 68:149–181PubMedCrossRefGoogle Scholar
  66. 66.
    Clark RA (1993) Regulation of fibroplasia in cutaneous wound repair. Am J Med Sci 306:42–48PubMedCrossRefGoogle Scholar
  67. 67.
    Juhasz I, Murphy GF, Yan HC, Herlyn M, Albelda S (1993) Regulation of extracellular matrix proteins and integrin cell substratum adhesion receptors on epithelium during cutaneous human wound healing in vivo. Am J Pathol 143:1458–1469PubMedGoogle Scholar
  68. 68.
    Werner S, Krieg T, Smola H (2001) Keratinocyte–fibroblast interactions in wound healing. J Invest Dermatol 127:998–1008CrossRefGoogle Scholar
  69. 69.
    Vuorio E, de Crombrugghe B (1990) The family of collagen genes. Annu Rev Biochem 59:837–872PubMedCrossRefGoogle Scholar
  70. 70.
    Jaffe AT, Heymann WR, Lawrence N (1995) Epidermal maturation arrest. Dermatol Surg 25:900–903CrossRefGoogle Scholar
  71. 71.
    Gipson IK, Spurr-Michaud SJ, Tisdale AS (1988) Hemidesmosomes and anchoring fibril collagen appear synchronously during development and wound healing. Dev Biol 126:253–262PubMedCrossRefGoogle Scholar
  72. 72.
    Shiraha H, Gupta K, Drabik KA, Wells A (2000) Aging fibroblasts present reduced epidermal growth factor (EGF) responsiveness due to preferential loss of EGF receptors. J Biol Chem 275:19343–19351PubMedCrossRefGoogle Scholar
  73. 73.
    Chen P, Gupta K, Wells A (1994) Cell movement elicited by epidermal growth factor receptor requires kinase and autophosphorylation but is separable from mitogenesis. J Cell Biol 124:547–555PubMedCrossRefGoogle Scholar
  74. 74.
    Shiraha H, Glading A, Wells A (2002) Activation of M-calpain (calpain II) by epidermal growth factor is limited by PKA phosphorylation of M-calpain. Mol Cell Biol 22:2716–2727PubMedCrossRefGoogle Scholar
  75. 75.
    Muro AF, Chauhan AK, Gajovic S, Iaconcig A, Porro F, Stanta G, Baralle FE (2003) Regulated splicing of the fibronectin EDA exon is essential for proper skin wound healing and normal lifespan. J Cell Biol 162:149–160PubMedCrossRefGoogle Scholar
  76. 76.
    Wierzbicka-Patynowski I, Schwarzbauer JE (2003) The ins and outs of fibronectin matrix assembly. J Cell Sci 116:3269–3276PubMedCrossRefGoogle Scholar
  77. 77.
    Velling T, Risteli J, Wennerberg K, Mosher DF, Johansson S (2002) Polymerization of type I and III collagens is dependent on fibronectin and enhanced by integrins alpha 11beta 1 and alpha 2beta 1. J Biol Chem 277:37377–37381PubMedCrossRefGoogle Scholar
  78. 78.
    Iyer AK, Tran KT, Borysenko CW, Cascio M, Camacho CJ, Blair HC, Bahar I, Wells A (2007) Tenascin cytotactin epidermal growth factor-like repeat binds epidermal growth factor receptor with low affinity. J Cell Physiol 211:748–758PubMedCrossRefGoogle Scholar
  79. 79.
    Iyer AK, Tran KT, Griffith L, Wells A (2008) Cell surface restriction of EGFR by a tenascin cytotactin-encoded EGF-like repeat is preferential for motility-related signaling. J Cell Physiol 214:504–512PubMedCrossRefGoogle Scholar
  80. 80.
    Swindle CS, Tran KT, Johnson TD, Banerjee P, Mayes AM, Griffith L, Wells A (2001) Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor. J Cell Biol 154:459–468PubMedCrossRefGoogle Scholar
  81. 81.
    Chiquet-Ehrismann R, Chiquet M (2003) Tenascins: regulation and putative functions during pathological stress. J Pathol 200:488–499PubMedCrossRefGoogle Scholar
  82. 82.
    Trebaul A, Chan EK, Midwood KS (2007) Regulation of fibroblast migration by tenascin-C. Biochem Soc Trans 35:695–697PubMedCrossRefGoogle Scholar
  83. 83.
    Mann K, Deutzmann R, Aumailley M, Timpl R, Raimondi L, Yamada Y, Pan TC, Conway D, Chu ML (1989) Amino acid sequence of mouse nidogen, a multidomain basement membrane protein with binding activity for laminin, collagen IV and cells. EMBO 8:65–72Google Scholar
  84. 84.
    Chakravarti S, Tam MF, Cheung AE (1990) The basement membrane glycoprotein entactin promotes cell attachment and binds calcium. J Biol Chem 265:10597–10603PubMedGoogle Scholar
  85. 85.
    Merline R, Schaefer RM, Schaefer L (2009) The matricellular functions of small leucine-rich proteoglycans (SLRPs). J Cell Commun Signal 3:323–335PubMedCrossRefGoogle Scholar
  86. 86.
    Reed CC, Iozzo RV (2002) The role of decorin in collagen fibrillogenesis and skin homeostasis. Glycoconj J 19:249–255PubMedCrossRefGoogle Scholar
  87. 87.
    Zhang Z, Li XJ, Liu Y, Zhang X, Li YY, Xu WS (2007) Recombinant human decorin inhibits cell proliferation and downregulates TGF-beta1 production in hypertrophic scar fibroblasts. Burns 33:634–641PubMedCrossRefGoogle Scholar
  88. 88.
    Krishna P, Regner M, Palko J, Liu F, Abramowitch S, Jiang J, Wells A (2010) The effects of decorin and HGF-primed vocal fold fibroblasts in vitro and ex vivo in a porcine model of vocal fold scarring. Laryngoscope 120:2247–2257PubMedCrossRefGoogle Scholar
  89. 89.
    Flier J, Boorsma DM, van Beek PJ, Nieboer C, Stoof TJ, Willemze R, Tensen CP (2001) Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation. J Pathol 194:398–405PubMedCrossRefGoogle Scholar
  90. 90.
    Tensen CP, Flier J, van der Raaij-Helmer EM et al (1999) Human IP-9. A keratinocyte-derived high affinity CXC-chemokine ligand for the IP-10/Mig receptor (CXCR3). J Invest Dermatol 112:716–722PubMedCrossRefGoogle Scholar
  91. 91.
    Satish L, Yager D, Wells A (2003) ELR-negative CXC chemokine IP-9 as a mediator of epidermal–dermal communication during wound repair. J Invest Dermatol 120:1110–1117PubMedCrossRefGoogle Scholar
  92. 92.
    Yates CC, Whaley D, Kulasekeran P, Hancock WW, Lu B, Bodnar R, Newsome J, Hebda PA, Wells A (2007) Delayed and deficient dermal mat-uration in mice lacking the CXCR3 ELR-negative CXC chemokine receptor. Am J Pathol 171:484–495PubMedCrossRefGoogle Scholar
  93. 93.
    Yates CC, Whaley D, Yen A, Kulesekaran P, Hebda PA, Wells A (2008) ELR-negative CXC chemokine CXCL11(IP-9/I-TAC) facilitates dermal and epidermal maturation during wound repair. Am J Pathol 173:643–652PubMedCrossRefGoogle Scholar
  94. 94.
    Bodnar R, Yates C, Wells A (2006) IP-10 blocks VEGF-induced endothelial cell motility and tube formation via inhibition of calpain. Circ Res 98:617–625PubMedCrossRefGoogle Scholar
  95. 95.
    Bodnar RJ, Yates CC, Du X, Wells A (2009) ELR-negative chemokine IP-10/CXCL10 induces dissociation of newly-formed vessels secondary to calpain cleavage of beta3 integrin. J Cell Sci 122:2064–2077PubMedCrossRefGoogle Scholar
  96. 96.
    Shiraha H, Glading A, Chou J, Jia Z, Wells A (2002) Activation of m-calpain (calpain II) by epidermal growth factor is limited by PKA phosphorylation of m-calpain. Mol Cell Biol 22:2716–2720Google Scholar
  97. 97.
    Yates CC, Whaley D, Hooda S, Hebda PA, Bodnar RJ, Wells A (2009) Delayed re-epithelialization and basement membrane regeneration after wounding in mice lacking CXCR3. Wound Repair Regen 17:34–41PubMedCrossRefGoogle Scholar
  98. 98.
    Yates CC, Krishna P, Whaley D, Bodnar R, Turner T, Wells A (2010) Lack of CXC chemokine receptor 3 signaling leads to hypertrophic and hypercellular scarring. Am J Pathol 176:1743–1755PubMedCrossRefGoogle Scholar
  99. 99.
    Stramer BM, Mori R, Martin P (2007) The inflammation–fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J Invest Dermatol 127:1009–1017PubMedCrossRefGoogle Scholar
  100. 100.
    Raghow R (1994) The role of extracellular matrix in postinflammatory wound healing and fibrosis. FASEB J 8:823–831PubMedGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Cecelia C. Yates
    • 1
  • Richard Bodnar
    • 1
    • 2
  • Alan Wells
    • 1
    • 2
  1. 1.Department of PathologyUniversity of PittsburghPittsburghUSA
  2. 2.Pittsburgh VAMCPittsburghUSA

Personalised recommendations