Cell and Tissue Research

, Volume 365, Issue 3, pp 467–482 | Cite as

Integrin-mediated regulation of epidermal wound functions

  • C. Michael DiPersio
  • Rui Zheng
  • James Kenney
  • Livingston Van De Water
Review

Abstract

During cutaneous wound healing, keratinocyte proliferation and migration are critical for re-epithelialization. In addition the epidermis secretes growth factors, cytokines, proteases, and matricellular proteins into the wound microenvironment that modify the extracellular matrix and stimulate other wound cells that control the inflammatory response, promote angiogenesis and facilitate tissue contraction and remodeling. Wound keratinocytes express at least seven different integrins—the major cell adhesion receptors for the extracellular matrix—that collectively control essential cell-autonomous functions to ensure proper re-epithelialization, including migration, proliferation, survival and basement membrane assembly. Moreover, it has become evident in recent years that some integrins can regulate paracrine signals from wound epidermis that stimulate other wound cells involved in angiogenesis, contraction and inflammation. Importantly, it is likely that abnormal integrin expression or function in the epidermis contributes to wound pathologies such as over-exuberant healing (e.g., hypertrophic scar formation) or diminished healing (e.g., chronic wounds). In this review, we discuss current knowledge of integrin function in the epidermis, which implicates them as attractive therapeutic targets to promote wound healing or treat wound pathologies. We also discuss challenges that arise from the complex roles that multiple integrins play in wound epidermis, which may be regulated through extracellular matrix remodeling that determines ligand availability. Indeed, understanding how different integrin functions are temporally coordinated in wound epidermis and which integrin functions go awry in pathological wounds, will be important to determine how best to target them clinically to achieve maximum therapeutic benefit.

Graphical abstract

In addition to their well-characterized roles in keratinocyte adhesion, migration and wound re-epithelialization, epidermal integrins play important roles in modifying the wound microenvironment by regulating the expression and secretion of growth factors, extracellular proteases, and matricellular proteins that stimulate other wound cells, including vascular endothelial cells and fibroblasts/myofibroblasts

Keywords

Integrin Wound healing Epidermis Keratinocyte Extracellular matrix 

Notes

Acknowledgments

The authors are grateful to members of the DiPersio and Van De Water laboratories, as well as to other colleagues at Albany Medical College, for valuable discussions and insights. Research was supported by NIH grants from NIAMS to L. Van De Water and C.M. DiPersio (R01AR063778) and from NCI to C.M. DiPersio (R01CA129637). We offer our apologies to the many researchers whose valuable contributions to the field could not be cited due to space constraints.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Agren MS, Werthen M (2007) The extracellular matrix in wound healing: a closer look at therapeutics for chronic wounds. Int J Lower Extrem Wounds 6:82–97CrossRefGoogle Scholar
  2. Ahmed N, Pansino F, Clyde R, Murthi P, Quinn MA, Rice GE, Agrez MV, Mok S, Baker MS (2002) Overexpression of alpha(v)beta6 integrin in serous epithelial ovarian cancer regulates extracellular matrix degradation via the plasminogen activation cascade. Carcinogenesis 23:237–244PubMedCrossRefGoogle Scholar
  3. AlDahlawi S, Eslami A, Hakkinen L, Larjava HS (2006) The alphavbeta6 integrin plays a role in compromised epidermal wound healing. Wound Repair Regen 14:289–297PubMedCrossRefGoogle Scholar
  4. Andrews JP, Marttala J, Macarak E, Rosenbloom J, Uitto J (2016) Keloids: The paradigm of skin fibrosis - Pathomechanisms and treatment. Matrix Biol 51:37–46Google Scholar
  5. Annes JP, Chen Y, Munger JS, Rifkin DB (2004) Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1. J Cell Biol 165:723–734PubMedPubMedCentralCrossRefGoogle Scholar
  6. Ansel JC, Tiesman JP, Olerud JE, Krueger JG, Krane JF, Tara DC, Shipley GD, Gilbertson D, Usui ML, Hart CE (1993) Human keratinocytes are a major source of cutaneous platelet-derived growth factor. J Clin Invest 92:671–678PubMedPubMedCentralCrossRefGoogle Scholar
  7. Aumailley M, El Khal A, Knoss N, Tunggal L (2003) Laminin 5 processing and its integration into the ECM. Matrix Biol 22:49–54PubMedCrossRefGoogle Scholar
  8. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M (2008) Growth factors and cytokines in wound healing. Wound Repair Regen 16:585–601PubMedCrossRefGoogle Scholar
  9. Berditchevski F (2001) Complexes of tetraspanins with integrins: more than meets the eye. J Cell Sci 114:4143–4151PubMedGoogle Scholar
  10. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744PubMedPubMedCentralCrossRefGoogle Scholar
  11. Brakebusch C, Grose R, Quondamatteo F, Ramirez A, Jorcano JL, Pirro A, Svensson M, Herken R, Sasaki T, Timpl R, Werner S, Fassler R (2000) Skin and hair follicle integrity is crucially dependent on beta 1 integrin expression on keratinocytes. EMBO J 19:3990–4003PubMedPubMedCentralCrossRefGoogle Scholar
  12. Breuss JM, Gallo J, DeLisser HM, Klimanskaya IV, Folkesson HG, Pittet JF, Nishimura SL, Aldape K, Landers DV, Carpenter W (1995) Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci 108:2241–2251PubMedGoogle Scholar
  13. Brown LF, Dubin D, Lavigne L, Logan B, Dvorak HF, Van De Water L (1993) Macrophages and fibroblasts express embryonic fibronectins during cutaneous wound healing. Am J Pathol 142:793–801PubMedPubMedCentralGoogle Scholar
  14. Burgeson RE, Christiano AM (1997) The dermal-epidermal junction. Curr Opin Cell Biol 9:651–658PubMedCrossRefGoogle Scholar
  15. Camussi G, Deregibus MC, Bruno S, Cantaluppi V, Biancone L (2010) Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int 78:838–848PubMedCrossRefGoogle Scholar
  16. Carter WG, Kaur P, Gil SG, Gahr PJ, Wayner EA (1990a) Distinct functions for integrins a3b1 in focal adhesions and a6b4/bullous antigen in a new stable anchoring contact (SAC) of keratinocytes: relation to hemidesmosomes. J Cell Biol 111:3141–3154PubMedCrossRefGoogle Scholar
  17. Carter WG, Wayner EA, Bouchard TS, Kaur P (1990b) The role of integrins a2b1 and a3b1 in cell-cell and cell-substrate adhesion of human epidermal cells. J Cell Biol 110:1387–1404PubMedCrossRefGoogle Scholar
  18. Carter WG, Ryan MC, Gahr PJ (1991) Epiligrin, a new cell adhesion ligand for integrin a3b1 in epithelial basement membranes. Cell 65:599–610PubMedCrossRefGoogle Scholar
  19. Cary LA, Guan JL (1999) Focal adhesion kinase in integrin-mediated signaling. Front Biosci 4:D102–113PubMedCrossRefGoogle Scholar
  20. Chapman HA, Wei Y, Simon DI, Waltz DA (1999) Role of urokinase receptor and caveolin in regulation of integrin signaling. Thromb Haemost 82:291–297PubMedGoogle Scholar
  21. Chavez-Munoz C, Kilani RT, Ghahary A (2009) Profile of exosomes related proteins released by differentiated and undifferentiated human keratinocytes. J Cell Physiol 221:221–231PubMedCrossRefGoogle Scholar
  22. Chen J, Diacovo TG, Grenache DG, Santoro SA, Zutter MM (2002) The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 161:337–344PubMedPubMedCentralCrossRefGoogle Scholar
  23. Choma DP, Pumiglia K, DiPersio CM (2004) Integrin a3b1 directs the stabilization of a polarized lamellipodium in epithelial cells through activation of Rac1. J Cell Sci 117:3947–3959PubMedCrossRefGoogle Scholar
  24. Choma DP, Milano V, Pumiglia KM, DiPersio CM (2007) Integrin alpha3beta1-dependent activation of FAK/Src regulates Rac1-mediated keratinocyte polarization on laminin-5. J Investig Dermatol 127:31–40PubMedCrossRefGoogle Scholar
  25. Comoglio PM, Boccaccio C, Trusolino L (2003) Interactions between growth factor receptors and adhesion molecules: breaking the rules. Curr Opin Cell Biol 15:565–571PubMedCrossRefGoogle Scholar
  26. Cowin AJ, Adams D, Geary SM, Wright MD, Jones JC, Ashman LK (2006) Wound healing is defective in mice lacking tetraspanin CD151. J Investig Dermatol 126:680–689PubMedPubMedCentralCrossRefGoogle Scholar
  27. Dayer C, Stamenkovic I (2015) Recruitment of Matrix Metalloproteinase-9 (MMP-9) to the Fibroblast Cell Surface by Lysyl Hydroxylase 3 (LH3) Triggers Transforming Growth Factor-beta (TGF-beta) Activation and Fibroblast Differentiation. J Biol Chem 290:13763–13778PubMedPubMedCentralCrossRefGoogle Scholar
  28. deHart GW, Healy KE, Jones JC (2003) The role of alpha3beta1 integrin in determining the supramolecular organization of laminin-5 in the extracellular matrix of keratinocytes. Exp Cell Res 283:67–79PubMedCrossRefGoogle Scholar
  29. Delon I, Brown NH (2007) Integrins and the actin cytoskeleton. Curr Opin Cell Biol 19:43–50PubMedCrossRefGoogle Scholar
  30. DiPersio CM, Hodivala-Dilke KM, Jaenisch R, Kreidberg JA, Hynes RO (1997) a3b1 integrin is required for normal development of the epidermal basement membrane. J Cell Biol 137:729–742PubMedCentralCrossRefPubMedGoogle Scholar
  31. DiPersio CM, Shao M, Di Costanzo L, Kreidberg JA, Hynes RO (2000a) Mouse keratinocytes immortalized with large T antigen acquire a3b1 integrin-dependent secretion of MMP-9/gelatinase B. J Cell Sci 113:2909–2921PubMedGoogle Scholar
  32. DiPersio CM, van der Neut R, Georges-Labouesse E, Kreidberg JA, Sonnenberg A, Hynes RO (2000b) alpha3beta1 and alpha6beta4 integrin receptors for laminin-5 are not essential for epidermal morphogenesis and homeostasis during skin development. J Cell Sci 113:3051–3062PubMedGoogle Scholar
  33. DiPietro LA (1995) Wound healing: the role of the macrophage and other immune cells. Shock 4:233–240PubMedCrossRefGoogle Scholar
  34. Dowling J, Yu Q-C, Fuchs E (1996) b4 integrin is required for hemidesmosomal formation, cell adhesion and cell survival. J Cell Biol 134:559–572PubMedCrossRefGoogle Scholar
  35. Ehrlich HP, Desmouliere A, Diegelmann RF, Cohen IK, Compton CC, Garner WL, Kapanci Y, Gabbiani G (1994) Morphological and immunochemical differences between keloid and hypertrophic scar. Am J Pathol 145:105–113PubMedPubMedCentralGoogle Scholar
  36. Eming SA, Krieg T, Davidson JM (2007) Inflammation in wound repair: molecular and cellular mechanisms. J Investig Dermatol 127:514–525PubMedCrossRefGoogle Scholar
  37. Eming SA, Martin P, Tomic-Canic M (2014) Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med 6:265–266CrossRefGoogle Scholar
  38. Essayem S, Kovacic-Milivojevic B, Baumbusch C, McDonagh S, Dolganov G, Howerton K, Larocque N, Mauro T, Ramirez A, Ramos DM, Fisher SJ, Jorcano JL, Beggs HE, Reichardt LF, Ilic D (2005) Hair cycle and wound healing in mice with a keratinocyte-restricted deletion of FAK. Oncogene 25:1081–108CrossRefGoogle Scholar
  39. Evans ND, Oreffo RO, Healy E, Thurner PJ, Man YH (2013) Epithelial mechanobiology, skin wound healing, and the stem cell niche. J Mech Behav Biomed Mater 28:397–409PubMedCrossRefGoogle Scholar
  40. Fedele C, Singh A, Zerlanko BJ, Iozzo RV, Languino LR (2015) The alphavbeta6 integrin is transferred intercellularly via exosomes. J Biol Chem 290:4545–4551PubMedPubMedCentralCrossRefGoogle Scholar
  41. Feldmeyer L, Werner S, French LE, Beer HD (2010) Interleukin-1, inflammasomes and the skin. Eur J Cell Biol 89:638–644PubMedCrossRefGoogle Scholar
  42. Ffrench-Constant C, Van De Water L, Dvorak HF, Hynes RO (1989) Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat. J Cell Biol 109:903–914PubMedCrossRefGoogle Scholar
  43. Foster TJ, Geoghegan JA, Ganesh VK, Hook M (2014) Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat Rev Microbiol 12:49–62PubMedCrossRefGoogle Scholar
  44. Frank DE, Carter WG (2004) Laminin 5 deposition regulates keratinocyte polarization and persistent migration. J Cell Sci 117:1351–1363CrossRefPubMedGoogle Scholar
  45. Gagnoux-Palacios L, Allegra M, Spirito F, Pommeret O, Romero C, Ortonne JP, Meneguzzi G (2001) The short arm of the laminin gamma2 chain plays a pivotal role in the incorporation of laminin 5 into the extracellular matrix and in cell adhesion. J Cell Biol 153:835–850PubMedPubMedCentralCrossRefGoogle Scholar
  46. Georges-Labouesse E, Messaddeq N, Yehia G, Cadalbert L, Dierich A, Le Meur M (1996) Absence of integrin a6 leads to epidermolysis bullosa and neonatal death in mice. Nat Genet 13:370–373PubMedCrossRefGoogle Scholar
  47. Ghaffari A, Kilani RT, Ghahary A (2009) Keratinocyte-conditioned media regulate collagen expression in dermal fibroblasts. J Investig Dermatol 129:340–347PubMedCrossRefGoogle Scholar
  48. Ghahary A, Ghaffari A (2007) Role of keratinocyte-fibroblast cross-talk in development of hypertrophic scar. Wound Repair Regen 15(Suppl 1):S46–53CrossRefPubMedGoogle Scholar
  49. Ghosh S, Brown R, Jones JC, Ellerbroek SM, Stack MS (2000) Urinary-type plasminogen activator (uPA) expression and uPA receptor localization are regulated by alpha 3beta 1 integrin in oral keratinocytes. J Biol Chem 275:23869–23876PubMedCrossRefGoogle Scholar
  50. Gill SE, Parks WC (2008) Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol 40:1334–1347PubMedCrossRefGoogle Scholar
  51. Goldfinger LE, Stack MS, Jones JCR (1998) Processing of laminin-5 and its functional consequences: role of plasmin and tissue-type plasminogen activator. J Cell Biol 141:255–265PubMedPubMedCentralCrossRefGoogle Scholar
  52. Gonzales M, Haan K, Baker SE, Fitchmun M, Todorov I, Weitzman S, Jones JCR (1999) A cell signal pathway involving laminin-5, a3b1 integrin, and mitogen-activated protein kinase can regulate epithelial cell proliferation. Mol Biol Cell 10:259–270PubMedPubMedCentralCrossRefGoogle Scholar
  53. Grenache DG, Zhang Z, Wells LE, Santoro SA, Davidson JM, Zutter MM (2007) Wound healing in the alpha2beta1 integrin-deficient mouse: altered keratinocyte biology and dysregulated matrix metalloproteinase expression. J Investig Dermatol 127:455–466PubMedCrossRefGoogle Scholar
  54. Grose R, Hutter C, Bloch W, Thorey I, Watt FM, Fassler R, Brakebusch C, Werner S (2002) A crucial role of beta 1 integrins for keratinocyte migration in vitro and during cutaneous wound repair. Development 129:2303–2315PubMedGoogle Scholar
  55. Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453:314–321PubMedCrossRefGoogle Scholar
  56. Hakkinen L, Koivisto L, Gardner H, Saarialho-Kere U, Carroll JM, Lakso M, Rauvala H, Laato M, Heino J, Larjava H (2004) Increased expression of beta6-integrin in skin leads to spontaneous development of chronic wounds. Am J Pathol 164:229–242PubMedPubMedCentralCrossRefGoogle Scholar
  57. Hamelers IH, Olivo C, Mertens AE, Pegtel DM, van der Kammen RA, Sonnenberg A, Collard JG (2005) The Rac activator Tiam1 is required for a3b1-mediated laminin-5 deposition, cell spreading, and cell migration. J Cell Biol 171:871–881PubMedPubMedCentralCrossRefGoogle Scholar
  58. Hamidi S, Salo T, Kainulainen T, Epstein J, Lerner K, Larjava H (2000) Expression of alpha(v)beta6 integrin in oral leukoplakia. Br J Cancer 82:1433–1440PubMedPubMedCentralCrossRefGoogle Scholar
  59. Hamill KJ, Hopkinson SB, Hoover P, Todorovic V, Green KJ, Jones JC (2012) Fibronectin expression determines skin cell motile behavior. J Investig Dermatol 132:448–457PubMedCrossRefGoogle Scholar
  60. Has C, Sparta G, Kiritsi D, Weibel L, Moeller A, Vega-Warner V, Waters A, He Y, Anikster Y, Esser P, Straub BK, Hausser I, Bockenhauer D, Dekel B, Hildebrandt F, Bruckner-Tuderman L, Laube GF (2012) Integrin alpha3 mutations with kidney, lung, and skin disease. N Engl J Med 366:1508–1514PubMedPubMedCentralCrossRefGoogle Scholar
  61. Hata S, Okamura K, Hatta M, Ishikawa H, Yamazaki J (2014) Proteolytic and non-proteolytic activation of keratinocyte-derived latent TGF-beta1 induces fibroblast differentiation in a wound-healing model using rat skin. J Pharmacol Sci 124:230–243PubMedCrossRefGoogle Scholar
  62. Hattori N, Mochizuki S, Kishi K, Nakajima T, Takaishi H, D’Armiento J, Okada Y (2009) MMP-13 plays a role in keratinocyte migration, angiogenesis, and contraction in mouse skin wound healing. Am J Pathol 175:533–546PubMedPubMedCentralCrossRefGoogle Scholar
  63. Hemler ME (2005) Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 6:801–811PubMedCrossRefGoogle Scholar
  64. Hermes O, Schlage P, auf dem Keller U (2011) Wound degradomics - current status and future perspectives. Biol Chem 392:949–954PubMedCrossRefGoogle Scholar
  65. Hinz B (2010) The myofibroblast: paradigm for a mechanically active cell. J Biomech 43:146–155PubMedCrossRefGoogle Scholar
  66. Hobbs RM, Watt FM (2003) Regulation of interleukin-1alpha expression by integrins and epidermal growth factor receptor in keratinocytes from a mouse model of inflammatory skin disease. J Biol Chem 278:19798–19807PubMedCrossRefGoogle Scholar
  67. Hoye AM, Couchman JR, Wewer UM, Fukami K, Yoneda A (2012) The newcomer in the integrin family: integrin alpha9 in biology and cancer. Adv Biol Regul 52:326–339PubMedCrossRefGoogle Scholar
  68. Huang X, Griffiths M, Wu J, Farese RV Jr, Sheppard D (2000) Normal development, wound healing, and adenovirus susceptibility in beta5-deficient mice. Mol Cell Biol 20:755–759PubMedPubMedCentralCrossRefGoogle Scholar
  69. Humphrey JD, Dufresne ER, Schwartz MA (2014) Mechanotransduction and extracellular matrix homeostasis. Nat Rev Mol Cell Biol 15:802–812PubMedPubMedCentralCrossRefGoogle Scholar
  70. Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687PubMedCrossRefGoogle Scholar
  71. Iwamoto DV, Calderwood DA (2015) Regulation of integrin-mediated adhesions. Curr Opin Cell Biol 36:41–47PubMedCrossRefGoogle Scholar
  72. Iyer V, Pumiglia K, DiPersio CM (2005) a3b1 integrin regulates MMP-9 mRNA stability in immortalized keratinocytes: a novel mechanism of integrin-mediated MMP gene expression. J Cell Sci 118:1185–1195PubMedCrossRefGoogle Scholar
  73. Janes SM, Watt FM (2004) Switch from alphavbeta5 to alphavbeta6 integrin expression protects squamous cell carcinomas from anoikis. J Cell Biol 166:419–431PubMedPubMedCentralCrossRefGoogle Scholar
  74. Johnson A, DiPietro LA (2013) Apoptosis and angiogenesis: an evolving mechanism for fibrosis. FASEB J 27:3893–3901PubMedCentralCrossRefPubMedGoogle Scholar
  75. Johnson KE, Wilgus TA (2014) Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care 3:647–661CrossRefGoogle Scholar
  76. Jones J, Watt FM, Speight PM (1997) Changes in the expression of alpha v integrins in oral squamous cell carcinomas. J Oral Pathol Med 26:63–68PubMedCrossRefGoogle Scholar
  77. Kazarov AR, Yang X, Stipp CS, Sehgal B, Hemler ME (2002) An extracellular site on tetraspanin CD151 determines alpha 3 and alpha 6 integrin-dependent cellular morphology. J Cell Biol 158:1299–1309PubMedPubMedCentralCrossRefGoogle Scholar
  78. Kenny FN, Connelly JT (2015) Integrin-mediated adhesion and mechano-sensing in cutaneous wound healing. Cell Tissue Res 360:571–582PubMedCrossRefGoogle Scholar
  79. Kim LT, Wu J, Bier-Laning C, Dollar BT, Turnage RH (2000) Focal adhesion kinase up-regulation and signaling in activated keratinocytes. J Surg Res 91:65–69PubMedCrossRefGoogle Scholar
  80. Kim Y, Kugler MC, Wei Y, Kim KK, Li X, Brumwell AN, Chapman HA (2009) Integrin alpha3beta1-dependent beta-catenin phosphorylation links epithelial Smad signaling to cell contacts. J Cell Biol 184:309–322PubMedPubMedCentralCrossRefGoogle Scholar
  81. Kiritsi D, Has C, Bruckner-Tuderman L (2013) Laminin 332 in junctional epidermolysis bullosa. Cell Adhes Migr 7:135–141CrossRefGoogle Scholar
  82. Kligys KR, Wu Y, Hopkinson SB, Kaur S, Platanias LC, Jones JC (2012) alpha6beta4 integrin, a master regulator of expression of integrins in human keratinocytes. J Biol Chem 287:17975–17984PubMedPubMedCentralCrossRefGoogle Scholar
  83. Kobayashi T, Kim H, Liu X, Sugiura H, Kohyama T, Fang Q, Wen FQ, Abe S, Wang X, Atkinson JJ, Shipley JM, Senior RM, Rennard SI (2014) Matrix metalloproteinase-9 activates TGF-beta and stimulates fibroblast contraction of collagen gels. Am J Physiol Lung Cell Mol Physiol 306:L1006–1015PubMedPubMedCentralCrossRefGoogle Scholar
  84. Koh TJ, DiPietro LA (2011) Inflammation and wound healing: the role of the macrophage. Exp Rev Mol Med 13:e23CrossRefGoogle Scholar
  85. Koivisto L, Heino J, Hakkinen L, Larjava H (2014) Integrins in Wound Healing. Adv Wound Care 3:762–783CrossRefGoogle Scholar
  86. Lam E, Kilani RT, Li Y, Tredget EE, Ghahary A (2005) Stratifin-induced matrix metalloproteinase-1 in fibroblast is mediated by c-fos and p38 mitogen-activated protein kinase activation. J Investig Dermatol 125:230–238PubMedGoogle Scholar
  87. Lamar JM, Iyer V, DiPersio CM (2008) Integrin alpha3beta1 potentiates TGFbeta-mediated induction of MMP-9 in immortalized keratinocytes. J Investig Dermatol 128:575–586PubMedCrossRefGoogle Scholar
  88. Lancerotto L, Bayer LR, Orgill DP (2012) Mechanisms of action of microdeformational wound therapy. Semin Cell Dev Biol 23:987–992PubMedCrossRefGoogle Scholar
  89. Legate KR, Fassler R (2009) Mechanisms that regulate adaptor binding to beta-integrin cytoplasmic tails. J Cell Sci 122:187–198PubMedCrossRefGoogle Scholar
  90. Liao YF, Gotwals PJ, Koteliansky VE, Sheppard D, Van De Water L (2002) The EIIIA segment of fibronectin is a ligand for integrins alpha 9beta 1 and alpha 4beta 1 providing a novel mechanism for regulating cell adhesion by alternative splicing. J Biol Chem 277:14467–14474PubMedCrossRefGoogle Scholar
  91. Litjens SH, de Pereda JM, Sonnenberg A (2006) Current insights into the formation and breakdown of hemidesmosomes. Trends Cell Biol 16:376–383PubMedCrossRefGoogle Scholar
  92. Liu S, Calderwood DA, Ginsberg MH (2000) Integrin cytoplasmic domain-binding proteins. J Cell Sci 113:3563–3571PubMedGoogle Scholar
  93. Lobmann R, Ambrosch A, Schultz G, Waldmann K, Schiweck S, Lehnert H (2002) Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia 45:1011–1016PubMedCrossRefGoogle Scholar
  94. Longmate LM, DiPersio CM (2014) Integrin regulation of epidermal functions in wounds. Adv Wound Care 3:229–246CrossRefGoogle Scholar
  95. Longmate WM, Monichan R, Chu ML, Tsuda T, Mahoney MG, DiPersio CM (2014) Reduced fibulin-2 contributes to loss of basement membrane integrity and skin blistering in mice lacking integrin alpha3beta1 in the epidermis. J Investig Dermatol 134:1609–1617PubMedPubMedCentralCrossRefGoogle Scholar
  96. Low QE, Drugea IA, Duffner LA, Quinn DG, Cook DN, Rollins BJ, Kovacs EJ, DiPietro LA (2001) Wound healing in MIP-1alpha(-/-) and MCP-1(-/-) mice. Am J Pathol 159:457–463PubMedPubMedCentralCrossRefGoogle Scholar
  97. Lubin FD, Segal M, McGee DW (2003) Regulation of epithelial cell cytokine responses by the alpha3beta1 integrin. Immunology 108:204–210PubMedPubMedCentralCrossRefGoogle Scholar
  98. Manohar A, Shome SG, Lamar J, Stirling L, Iyer V, Pumiglia K, DiPersio CM (2004) Alpha 3 beta 1 integrin promotes keratinocyte cell survival through activation of a MEK/ERK signaling pathway. J Cell Sci 117:4043–4054PubMedCrossRefGoogle Scholar
  99. Margadant C, Raymond K, Kreft M, Sachs N, Janssen H, Sonnenberg A (2009) Integrin alpha3beta1 inhibits directional migration and wound re-epithelialization in the skin. J Cell Sci 122:278–288PubMedCrossRefGoogle Scholar
  100. Margadant C, Charafeddine RA, Sonnenberg A (2010) Unique and redundant functions of integrins in the epidermis. FASEB J 24:4133–4152PubMedCrossRefGoogle Scholar
  101. Mariotti A, Kedeshian PA, Dans M, Curatola AM, Gagnoux-Palacios L, Giancotti FG (2001) EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion. J Cell Biol 155:447–458PubMedPubMedCentralCrossRefGoogle Scholar
  102. Martin P (1997) Wound healing-aiming for perfect skin regeneration. Science 276:75–81PubMedCrossRefGoogle Scholar
  103. Martinez CE, Smith PC, Palma Alvarado VA (2015) The influence of platelet-derived products on angiogenesis and tissue repair: a concise update. Front Physiol 6:290PubMedPubMedCentralCrossRefGoogle Scholar
  104. McCawley LJ, Matrisian LM (2001) Matrix metalloproteinases: they’re not just for matrix anymore! Curr Opin Cell Biol 13:534–540PubMedCrossRefGoogle Scholar
  105. McLean GW, Komiyama NH, Serrels B, Asano H, Reynolds L, Conti F, Hodivala-Dilke K, Metzger D, Chambon P, Grant SG, Frame MC (2004) Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression. Genes Dev 18:2998–3003PubMedPubMedCentralCrossRefGoogle Scholar
  106. Mirastschijski U, Haaksma CJ, Tomasek JJ, Agren MS (2004) Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds. Exp Cell Res 299:465–475PubMedCrossRefGoogle Scholar
  107. Missan DD, Chittur SV, DiPersio CM (2014) Regulation of fibulin-2 gene expression by integrin α3β1 contributes to the invasive phenotype of transformed keratinocytes. J Investig Dermatol 134:2418–27PubMedCrossRefPubMedCentralGoogle Scholar
  108. Missan D, Mitchell K, Subbaram S, DiPersio CM (2015) Integrin α3β1 signaling through MEK/ERK determines alternative polyadenylation of the MMP-9 mRNA transcript in immortalized mouse keratinocytes. PLoS ONE 10:e0119539PubMedPubMedCentralCrossRefGoogle Scholar
  109. Mitchell K, Szekeres C, Milano V, Svenson KB, Nilsen-Hamilton M, Kreidberg JA, DiPersio CM (2009) Alpha3beta1 integrin in epidermis promotes wound angiogenesis and keratinocyte-to-endothelial-cell crosstalk through the induction of MRP3. J Cell Sci 122:1778–1787PubMedPubMedCentralCrossRefGoogle Scholar
  110. Mitra SK, Schlaepfer DD (2006) Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18:516–523PubMedCrossRefGoogle Scholar
  111. Morgan MR, Thomas GJ, Russell A, Hart IR, Marshall JF (2004) The integrin cytoplasmic-tail motif EKQKVDLSTDC is sufficient to promote tumor cell invasion mediated by matrix metalloproteinase (MMP)-2 or MMP-9. J Biol Chem 279:26533–26539PubMedCrossRefGoogle Scholar
  112. Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D (1999) The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96:319–328PubMedCrossRefGoogle Scholar
  113. Mustoe TA, Gurjala A (2011) The role of the epidermis and the mechanism of action of occlusive dressings in scarring. Wound Repair Regen 19(Suppl 1):s16–21PubMedPubMedCentralCrossRefGoogle Scholar
  114. Nguyen BP, Ryan MC, Gil SG, Carter WG (2000) Deposition of laminin 5 in epidermal wounds regulates integrin signaling and adhesion. Curr Opin Cell Biol 12:554–562PubMedCrossRefGoogle Scholar
  115. Nguyen BP, Ren XD, Schwartz MA, Carter WG (2001) Ligation of integrin alpha 3beta 1 by laminin 5 at the wound edge activates Rho-dependent adhesion of leading keratinocytes on collagen. J Biol Chem 276:43860–43870PubMedCrossRefGoogle Scholar
  116. Nissen NN, Polverini PJ, Koch AE, Volin MV, Gamelli RL, DiPietro LA (1998) Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am J Pathol 152:1445–1452PubMedPubMedCentralGoogle Scholar
  117. Nowinski D, Lysheden AS, Gardner H, Rubin K, Gerdin B, Ivarsson M (2004) Analysis of gene expression in fibroblasts in response to keratinocyte-derived factors in vitro: potential implications for the wound healing process. J Investig Dermatol 122:216–221PubMedCrossRefGoogle Scholar
  118. Nunan R, Harding KG, Martin P (2014) Clinical challenges of chronic wounds: searching for an optimal animal model to recapitulate their complexity. Dis Model Mech 7:1205–1213PubMedPubMedCentralCrossRefGoogle Scholar
  119. Oliver-Kozup H, Martin KH, Schwegler-Berry D, Green BJ, Betts C, Shinde AV, Van De Water L, Lukomski S (2013) The group A streptococcal collagen-like protein-1, Scl1, mediates biofilm formation by targeting the extra domain A-containing variant of cellular fibronectin expressed in wounded tissue. Mol Microbiol 87:672–689PubMedCrossRefGoogle Scholar
  120. Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8:221–233PubMedCentralCrossRefPubMedGoogle Scholar
  121. Pastar I, Stojadinovic O, Tomic-Canic M (2008) Role of keratinocytes in healing of chronic wounds. Surg Technol Int 17:105–112PubMedGoogle Scholar
  122. Penke LR, Huang SK, White ES, Peters-Golden M (2014) Prostaglandin E2 inhibits alpha-smooth muscle actin transcription during myofibroblast differentiation via distinct mechanisms of modulation of serum response factor and myocardin-related transcription factor-A. J Biol Chem 289:17151–17162PubMedPubMedCentralCrossRefGoogle Scholar
  123. Pierce GF, Mustoe TA, Altrock BW, Deuel TF, Thomason A (1991) Role of platelet-derived growth factor in wound healing. J Cell Biochem 45:319–326PubMedCrossRefGoogle Scholar
  124. Pilcher BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG, Parks WC (1997) The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol 137:1445–1457PubMedPubMedCentralCrossRefGoogle Scholar
  125. Piwko-Czuchra A, Koegel H, Meyer H, Bauer M, Werner S, Brakebusch C, Fassler R (2009) b1 integrin-mediated adhesion signalling is essential for epidermal progenitor cell expansion. PLoS ONE 4:e5488PubMedPubMedCentralCrossRefGoogle Scholar
  126. Porter JC, Hogg N (1998) Integrins take partners: cross-talk between integrins and other membrane receptors. Trends Cell Biol 8:390–396PubMedCrossRefGoogle Scholar
  127. Raghavan S, Bauer C, Mundschau G, Li Q, Fuchs E (2000) Conditional ablation of beta1 integrin in skin. Severe defects in epidermal proliferation, basement membrane formation, and hair follicle invagination. J Cell Biol 150:1149–1160PubMedPubMedCentralCrossRefGoogle Scholar
  128. Rahmani-Neishaboor E, Hartwell R, Jalili R, Jackson J, Brown E, Ghahary A (2012) Localized controlled release of stratifin reduces implantation-induced dermal fibrosis. Acta Biomater 8:3660–3668PubMedCrossRefGoogle Scholar
  129. Ramos DM, But M, Regezi J, Schmidt BL, Atakilit A, Dang D, Ellis D, Jordan R, Li X (2002) Expression of integrin beta 6 enhances invasive behavior in oral squamous cell carcinoma. Matrix Biol 21:297–307PubMedCrossRefGoogle Scholar
  130. Reish RG, Eriksson E (2008) Scars: a review of emerging and currently available therapies. Plast Reconstr Surg 122:1068–1078PubMedCrossRefGoogle Scholar
  131. Reynolds LE, Conti FJ, Silva R, Robinson SD, Iyer V, Rudling R, Cross B, Nye E, Hart IR, DiPersio CM, Hodivala-Dilke KM (2008) alpha3beta1 integrin-controlled Smad7 regulates reepithelialization during wound healing in mice. J Clin Invest 118:965–974PubMedPubMedCentralGoogle Scholar
  132. Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, Horwitz AR (2003) Cell migration: integrating signals from front to back. Science 302:1704–1709PubMedCrossRefGoogle Scholar
  133. Russell AJ, Fincher EF, Millman L, Smith R, Vela V, Waterman EA, Dey CN, Guide S, Weaver VM, Marinkovich MP (2003) Alpha 6 beta 4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of alpha 3 beta 1 integrin. J Cell Sci 116:3543–3556PubMedCrossRefGoogle Scholar
  134. Ruzzi L, Gagnoux-Palacios L, Pinola M, Belli S, Meneguzzi G, D’Alessio M, Zambruno G (1997) A homozygous mutation in the integrin a6 gene in junctional epidermolysis bullosa with pyloric atresia. J Clin Invest 99:2826–2831PubMedPubMedCentralCrossRefGoogle Scholar
  135. Salanueva IJ, Cerezo A, Guadamillas MC, del Pozo MA (2007) Integrin regulation of caveolin function. J Cell Mol Med 11:969–980PubMedPubMedCentralCrossRefGoogle Scholar
  136. Santoro MM, Gaudino G (2005) Cellular and molecular facets of keratinocyte reepithelization during wound healing. Exp Cell Res 304:274–286PubMedCrossRefGoogle Scholar
  137. Sasaki T, Gohring W, Mann K, Brakebusch C, Yamada Y, Fassler R, Timpl R (2001) Short arm region of laminin-5 gamma2 chain: structure, mechanism of processing and binding to heparin and proteins. J Mol Biol 314:751–763PubMedCrossRefGoogle Scholar
  138. Sato T, Kirimura Y, Mori Y (1997) The co-culture of dermal fibroblasts with human epidermal keratinocytes induces increased prostaglandin E2 production and cyclooxygenase 2 activity in fibroblasts. J Investig Dermatol 109:334–339PubMedCrossRefGoogle Scholar
  139. Sauder DN, Kilian PL, McLane JA, Quick TW, Jakubovic H, Davis SC, Eaglstein WH, Mertz PM (1990) Interleukin-1 enhances epidermal wound healing. Lymphokine Res 9:465–473PubMedGoogle Scholar
  140. Schenk S, Quaranta V (2003) Tales from the crypt[ic] sites of the extracellular matrix. Trends Cell Biol 13:366–375PubMedCrossRefGoogle Scholar
  141. Schwartz MA, Ginsberg MH (2002) Networks and crosstalk: integrin signalling spreads. Nat Cell Biol 4:E65–68PubMedCrossRefGoogle Scholar
  142. Sehgal BU, DeBiase PJ, Matzno S, Chew TL, Claiborne JN, Hopkinson SB, Russell A, Marinkovich MP, Jones JC (2006) Integrin beta4 regulates migratory behavior of keratinocytes by determining laminin-332 organization. J Biol Chem 281:35487–35498PubMedPubMedCentralCrossRefGoogle Scholar
  143. Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, Gottrup F, Gurtner GC, Longaker MT (2009) Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen 17:763–771PubMedPubMedCentralCrossRefGoogle Scholar
  144. Shephard P, Martin G, Smola-Hess S, Brunner G, Krieg T, Smola H (2004) Myofibroblast differentiation is induced in keratinocyte-fibroblast co-cultures and is antagonistically regulated by endogenous transforming growth factor-beta and interleukin-1. Am J Pathol 164:2055–2066PubMedPubMedCentralCrossRefGoogle Scholar
  145. Sheppard D (2005) Integrin-mediated activation of latent transforming growth factor beta. Cancer Metastasis Rev 24:395–402PubMedCrossRefGoogle Scholar
  146. Shinde AV, Bystroff C, Wang C, Vogelezang MG, Vincent PA, Hynes RO, Van De Water L (2008) Identification of the peptide sequences within the EIIIA (EDA) segment of fibronectin that mediate integrin alpha9beta1-dependent cellular activities. J Biol Chem 283:2858–2870PubMedCrossRefGoogle Scholar
  147. Shirakawa M, Isseroff RR (2005) Topical negative pressure devices: use for enhancement of healing chronic wounds. Arch Dermatol 141:1449–1453PubMedCrossRefGoogle Scholar
  148. Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341:738–746PubMedCrossRefGoogle Scholar
  149. Singh P, Reimer CL, Peters JH, Stepp MA, Hynes RO, Van De Water L (2004) The spatial and temporal expression patterns of integrin alpha9beta1 and one of its ligands, the EIIIA segment of fibronectin, in cutaneous wound healing. J Investig Dermatol 123:1176–1181PubMedCrossRefGoogle Scholar
  150. Singh P, Chen C, Pal-Ghosh S, Stepp MA, Sheppard D, Van De Water L (2009) Loss of integrin alpha9beta1 results in defects in proliferation, causing poor re-epithelialization during cutaneous wound healing. J Investig Dermatol 129:217–228PubMedCrossRefGoogle Scholar
  151. Singh V, Barbosa FL, Torricelli AA, Santhiago MR, Wilson SE (2014) Transforming growth factor b and platelet-derived growth factor modulation of myofibroblast development from corneal fibroblasts in vitro. Exp Eye Res 120:152–160PubMedCentralCrossRefPubMedGoogle Scholar
  152. Steffensen B, Hakkinen L, Larjava H (2001) Proteolytic events of wound-healing--coordinated interactions among matrix metalloproteinases (MMPs), integrins, and extracellular matrix molecules. Crit Rev Oral Biol Med 12:373–398PubMedCrossRefGoogle Scholar
  153. Sterk LM, Geuijen CA, Oomen LC, Calafat J, Janssen H, Sonnenberg A (2000) The tetraspan molecule CD151, a novel constituent of hemidesmosomes, associates with the integrin alpha6beta4 and may regulate the spatial organization of hemidesmosomes. J Cell Biol 149:969–982PubMedPubMedCentralCrossRefGoogle Scholar
  154. Sugiura T, Berditchevski F (1999) Function of a3b1-tetraspan protein complexes in tumor cell invasion. Evidence for the role of the complexes in production of matrix metalloproteinase 2 (MMP-2). J Cell Biol 146:1375–1389PubMedPubMedCentralCrossRefGoogle Scholar
  155. Sung BH, Ketova T, Hoshino D, Zijlstra A, Weaver AM (2015) Directional cell movement through tissues is controlled by exosome secretion. Nat Commun 6:7164PubMedPubMedCentralCrossRefGoogle Scholar
  156. Taipale J, Miyazono K, Heldin CH, Keski-Oja J (1994) Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein. J Cell Biol 124:171–181PubMedCrossRefGoogle Scholar
  157. Thomas GJ, Lewis MP, Hart IR, Marshall JF, Speight PM (2001a) AlphaVbeta6 integrin promotes invasion of squamous carcinoma cells through up-regulation of matrix metalloproteinase-9. Int J Cancer 92:641–650PubMedCrossRefGoogle Scholar
  158. Thomas GJ, Poomsawat S, Lewis MP, Hart IR, Speight PM, Marshall JF (2001b) alpha v beta 6 Integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytes. J Investig Dermatol 116:898–904PubMedCrossRefGoogle Scholar
  159. Thomas GJ, Nystrom ML, Marshall JF (2006) Alphavbeta6 integrin in wound healing and cancer of the oral cavity. J Oral Pathol Med 35:1–10PubMedCrossRefGoogle Scholar
  160. Trengove NJ, Stacey MC, MacAuley S, Bennett N, Gibson J, Burslem F, Murphy G, Schultz G (1999) Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. Wound Repair Regen 7:442–452PubMedCrossRefGoogle Scholar
  161. Utani A, Nomizu M, Yamada Y (1997) Fibulin-2 binds to the short arms of laminin-5 and laminin-1 via conserved amino acid sequences. J Biol Chem 272:2814–2820PubMedCrossRefGoogle Scholar
  162. Van De Water L, Varney S, Tomasek JJ (2013) Mechanoregulation of the Myofibroblast in Wound Contraction, Scarring, and Fibrosis: Opportunities for New Therapeutic Intervention. Adv Wound Care 2:122–141CrossRefGoogle Scholar
  163. van der Neut R, Krimpenfort P, Calafat J, Niessen CM, Sonnenberg A (1996) Epithelial detachment due to absence of hemidesmosomes in integrin b4 null mice. Nat Genet 13:366–369PubMedCrossRefGoogle Scholar
  164. Van Linthout S, Miteva K, Tschope C (2014) Crosstalk between fibroblasts and inflammatory cells. Cardiovasc Res 102:258–269PubMedCrossRefGoogle Scholar
  165. Vedula SR, Hirata H, Nai MH, Brugues A, Toyama Y, Trepat X, Lim CT, Ladoux B (2014) Epithelial bridges maintain tissue integrity during collective cell migration. Nat Mater 13:87–96PubMedCrossRefGoogle Scholar
  166. Vidal F, Aberdam D, Miquel C, Christiano AM, Pulkkinen L, Uitto J, Ortonne JP, Meneguzzi G (1995) Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia. Nat Genet 10:229–234PubMedCrossRefGoogle Scholar
  167. Wang Y, Wang G, Luo X, Qiu J, Tang C (2012) Substrate stiffness regulates the proliferation, migration, and differentiation of epidermal cells. Burns 38:414–420PubMedCrossRefGoogle Scholar
  168. Watt FM (2002) Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J 21:3919–3926PubMedPubMedCentralCrossRefGoogle Scholar
  169. Webber J, Steadman R, Mason MD, Tabi Z, Clayton A (2010) Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res 70:9621–9630PubMedCrossRefGoogle Scholar
  170. Wei Y, Eble JA, Wang Z, Kreidberg JA, Chapman HA (2001) Urokinase receptors promote beta1 integrin function through interactions with integrin alpha3beta1. Mol Biol Cell 12:2975–2986PubMedPubMedCentralCrossRefGoogle Scholar
  171. Wells RG (2008) The role of matrix stiffness in regulating cell behavior. Hepatology 47:1394–1400PubMedCrossRefGoogle Scholar
  172. Werner S, Krieg T, Smola H (2007) Keratinocyte-fibroblast interactions in wound healing. J Investig Dermatol 127:998–1008CrossRefPubMedGoogle Scholar
  173. Wetzler C, Kampfer H, Stallmeyer B, Pfeilschifter J, Frank S (2000) Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair. J Investig Dermatol 115:245–253PubMedCrossRefGoogle Scholar
  174. Widgerow AD (2013) Chronic wounds - is cellular ‘reception’ at fault? Examining integrins and intracellular signalling. Int Wound J 10:185–192CrossRefPubMedGoogle Scholar
  175. Winograd-Katz SE, Fassler R, Geiger B, Legate KR (2014) The integrin adhesome: from genes and proteins to human disease. Nat Rev Mol Cell Biol 15:273–288PubMedCrossRefGoogle Scholar
  176. Winterwood NE, Varzavand A, Meland MN, Ashman LK, Stipp CS (2006) A critical role for tetraspanin CD151 in alpha3beta1 and alpha6beta4 integrin-dependent tumor cell functions on laminin-5. Mol Biol Cell 17:2707–2721PubMedPubMedCentralCrossRefGoogle Scholar
  177. Wong VW, Akaishi S, Longaker MT, Gurtner GC (2011) Pushing back: wound mechanotransduction in repair and regeneration. J Investig Dermatol 131:2186–2196PubMedCrossRefGoogle Scholar
  178. Wong VW, Gurtner GC, Longaker MT (2013) Wound healing: a paradigm for regeneration. Mayo Clin Proc 88:1022–1031PubMedCrossRefGoogle Scholar
  179. Yang JT, Rayburn H, Hynes RO (1993) Embryonic mesodermal defects in alpha 5 integrin-deficient mice. Development 119:1093–1105PubMedGoogle Scholar
  180. Yang XH, Richardson AL, Torres-Arzayus MI, Zhou P, Sharma C, Kazarov AR, Andzelm MM, Strominger JL, Brown M, Hemler ME (2008) CD151 accelerates breast cancer by regulating alpha 6 integrin function, signaling, and molecular organization. Cancer Res 68:3204–3213PubMedCrossRefPubMedCentralGoogle Scholar
  181. Yauch RL, Berditchevsky F, Harler MB, Reichner J, Hemler ME (1998) Highly stoichiometric, stable, and specific association of integrin a3b1 with CD151 provides a major link to phosphatidylinositol 4-kinase, and may regulate cell migration. Mol Biol Cell 9:2751–2765PubMedPubMedCentralCrossRefGoogle Scholar
  182. Yauch RL, Kazarov AR, Desai B, Lee RT, Hemler ME (2000) Direct extracellular contact between integrin a3b1 and TM4SF protein CD151. J Biol Chem 275:9230–9238PubMedCrossRefGoogle Scholar
  183. Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14:163–176PubMedPubMedCentralGoogle Scholar
  184. Yurko MA, O’Toole EA, Woodley DT (2001) Phosphorylation of focal adhesion kinase (pp 125(FAK)) is increased in human keratinocytes induced to migrate by extracellular matrices. J Cell Physiol 188:24–32CrossRefPubMedGoogle Scholar
  185. Zaidel-Bar R, Geiger B (2010) The switchable integrin adhesome. J Cell Sci 123:1385–1388PubMedPubMedCentralCrossRefGoogle Scholar
  186. Zambruno G, Marchisio PC, Marconi A, Vaschieri C, Melchiori A, Giannetti A, De Luca M (1995) Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing. J Cell Biol 129:853–865PubMedCrossRefGoogle Scholar
  187. Zarkoob H, Bodduluri S, Ponnaluri SV, Selby JC, Sander EA (2015) Substrate stiffness affects human keratinocyte colony formation. Cell Mol Bioeng 8:32–50PubMedPubMedCentralCrossRefGoogle Scholar
  188. Zigrino P, Ayachi O, Schild A, Kaltenberg J, Zamek J, Nischt R, Koch M, Mauch C (2012) Loss of epidermal MMP-14 expression interferes with angiogenesis but not with re-epithelialization. Eur J Cell Biol 91:748–756PubMedCrossRefGoogle Scholar
  189. Zweers MC, Davidson JM, Pozzi A, Hallinger R, Janz K, Quondamatteo F, Leutgeb B, Krieg T, Eckes B (2007) Integrin alpha2beta1 is required for regulation of murine wound angiogenesis but is dispensable for reepithelialization. J Investig Dermatol 127:467–478PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • C. Michael DiPersio
    • 1
    • 2
  • Rui Zheng
    • 2
  • James Kenney
    • 2
  • Livingston Van De Water
    • 2
  1. 1.Department of SurgeryAlbany Medical CollegeAlbanyUSA
  2. 2.Department of Regenerative & Cancer Cell BiologyAlbany Medical CollegeAlbanyUSA

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