Cell and Tissue Research

, Volume 360, Issue 3, pp 571–582 | Cite as

Integrin-mediated adhesion and mechano-sensing in cutaneous wound healing

  • Fiona N. Kenny
  • John T. Connelly


Integrin receptors mediate the interactions between cells and the extracellular matrix. They not only provide anchorage and a physical linkage to the matrix but also participate in cell signaling and the regulation of diverse cellular functions. In the epidermis of the skin, integrins are essential for tissue structure and integrity, and, under normal homeostatic conditions, the β1 subunit specifically controls the balance between proliferation and terminal differentiation. Integrin expression can also dynamically respond to changes in the cell’s environment, and integrin-mediated adhesion is required for keratinocyte migration and re-epithelialization during wound repair. Importantly, integrins participate in keratinocyte mechanotransduction and could potentially regulate cell behavior within the altered mechanical microenvironment of a wound. While the complete functions of integrin receptors in cutaneous wound healing have yet to be determined, recent evidence suggests that cell–matrix interactions are perturbed in chronic and non-healing wounds. Integrins may therefore be a potential therapeutic target for improving wound repair and tissue regeneration.


Integrin Migration Wound healing Keratinocyte Epidermis 


  1. Adair BD, Xiong J-P, Maddock C et al (2005) Three-dimensional EM structure of the ectodomain of integrin αVβ3 in a complex with fibronectin. J Cell Biol 168:1109–1118PubMedCentralPubMedGoogle Scholar
  2. Adams JC, Watt FM (1989) Fibronectin inhibits the terminal differentiation of human keratinocytes. Nature 340:307–309PubMedGoogle Scholar
  3. Adams JC, Watt FM (1991) Expression of beta 1, beta 3, beta 4, and beta 5 integrins by human epidermal keratinocytes and non-differentiating keratinocytes. J Cell Biol 115:829–841PubMedGoogle Scholar
  4. AlDahlawi S, Eslami A, Häkkinen L, Larjava HS (2006) The alphavbeta6 integrin plays a role in compromised epidermal wound healing. Wound Repair Regen 14:289–297. doi: 10.1111/j.1743-6109.2006.00123.x PubMedGoogle Scholar
  5. Ansell DM, Holden KA, Hardman MJ (2012) Animal models of wound repair: Are they cutting it? Exp Dermatol 21:581–585. doi: 10.1111/j.1600-0625.2012.01540.x PubMedGoogle Scholar
  6. Arthur WT, Petch LA, Burridge K (2000) Integrin engagement suppresses RhoA activity via a c-Src-dependent mechanism. Curr Biol 10:719–722PubMedGoogle Scholar
  7. Bishop A (2008) Role of oxygen in wound healing. J Wound Care 17:399–402PubMedGoogle Scholar
  8. Blanpain C, Fuchs E (2009) Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol 10:207–217. doi: 10.1038/nrm2636 PubMedCentralPubMedGoogle Scholar
  9. Boekhoven J, Rubert Pérez CM, Sur S et al (2013) Dynamic display of bioactivity through host-guest chemistry. Angew Chem Int Ed Engl. doi: 10.1002/anie.201306278 PubMedCentralGoogle Scholar
  10. Borradori L, Sonnenberg A (1999) Structure and function of hemidesmosomes: more than simple adhesion complexes. J Invest Dermatol 112:411–418. doi: 10.1046/j.1523-1747.1999.00546.x PubMedGoogle Scholar
  11. Brem H, Tomic-Canic M (2007) Cellular and molecular basis of wound healing in diabetes. J Clin Invest 117:1219–1222PubMedCentralPubMedGoogle Scholar
  12. Brizzi MF, Defilippi P, Rosso A et al (1999) Integrin-mediated adhesion of endothelial cells induces JAK2 and STAT5A activation: role in the control of c-fos gene expression. Mol Biol Cell 10:3463–3471PubMedCentralPubMedGoogle Scholar
  13. Brooks PC, Clark RA, Cheresh DA (1994) Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264:569–571PubMedGoogle Scholar
  14. Broughton G, Janis JE, Attinger CE (2006) The basic science of wound healing. Plast Reconstr Surg 117:12s–34sPubMedGoogle Scholar
  15. Byzova TV, Goldman CK, Pampori N et al (2000) A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol Cell 6:851–860PubMedGoogle Scholar
  16. Calderwood DA, Campbell ID, Critchley DR (2013) Talins and kindlins: partners in integrin-mediated adhesion. Nat Rev Mol Cell Biol 14:503–517. doi: 10.1038/nrm3624 PubMedCentralPubMedGoogle Scholar
  17. Carter WG, Ryan MC, Gahr PJ (1991) Epiligrin, a new cell adhesion ligand for integrin alpha 3 beta 1 in epithelial basement membranes. Cell 65:599–610PubMedGoogle Scholar
  18. Caskey RC, Zgheib C, Morris M et al (2014) Dysregulation of collagen production in diabetes following recurrent skin injury: contribution to the development of a chronic wound. Wound Repair Regen 22:515–520. doi: 10.1111/wrr.12199 PubMedGoogle Scholar
  19. Caswell PT, Chan M, Lindsay AJ et al (2008) Rab-coupling protein coordinates recycling of alpha5beta1 integrin and EGFR1 to promote cell migration in 3D microenvironments. J Cell Biol 183:143–155PubMedCentralPubMedGoogle Scholar
  20. Cavani A, Zambruno G, Marconi A et al (1993) Distinctive integrin expression in the newly forming epidermis during wound healing in humans. J Invest Dermatol 101:600–604PubMedGoogle Scholar
  21. Chen CS, Mrksich M, Huang S et al (1997) Geometric control of cell life and death. Science 276:1425–1428PubMedGoogle Scholar
  22. Chen J, Diacovo TG, Grenache DG et al (2002) The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 161:337–344PubMedCentralPubMedGoogle Scholar
  23. Choma DP, Pumiglia K, DiPersio CM (2004) Integrin alpha3beta1 directs the stabilization of a polarized lamellipodium in epithelial cells through activation of Rac1. J Cell Sci 117:3947–3959PubMedGoogle 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 Invest Dermatol 127:31–40. doi: 10.1038/sj.jid.5700505 PubMedGoogle Scholar
  25. Choquet D, Felsenfeld DP, Sheetz MP (1997) Extracellular matrix rigidity causes strengthening of integrin-cytoskeleton linkages. Cell 88:39–48PubMedGoogle Scholar
  26. Chrzanowska-Wodnicka M, Burridge K (1996) Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J Cell Biol 133:1403–1415PubMedGoogle Scholar
  27. Clark RA, Lanigan JM, DellaPelle P et al (1982) Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. J Invest Dermatol 79:264–269PubMedGoogle Scholar
  28. Clark RA, Ashcroft GS, Spencer MJ et al (1996) Re-epithelialization of normal human excisional wounds is associated with a switch from alpha v beta 5 to alpha v beta 6 integrins. Br J Dermatol 135:46–51PubMedGoogle Scholar
  29. Clark EA, King WG, Brugge JS et al (1998) Integrin-mediated signals regulated by members of the rho family of GTPases. J Cell Biol 142:573–586PubMedCentralPubMedGoogle Scholar
  30. Clark RAF, An J-Q, Greiling D et al (2003) Fibroblast migration on fibronectin requires three distinct functional domains. J Invest Dermatol 121:695–705. doi: 10.1046/j.1523-1747.2003.12484.x PubMedGoogle Scholar
  31. Connelly JT, Gautrot JE, Trappmann B et al (2010) Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisions. Nat Cell Biol 12:711–718. doi: 10.1038/ncb2074 PubMedGoogle Scholar
  32. Costa P, Gautrot JE, Connelly JT (2014) Directing cell migration using micropatterned and dynamically adhesive polymer brushes. Acta Biomater. doi: 10.1016/j.actbio.2014.01.029 Google Scholar
  33. De S, Razorenova O, McCabe NP et al (2005) VEGF-integrin interplay controls tumor growth and vascularization. Proc Natl Acad Sci U S A 102:7589–7594. doi: 10.1073/pnas.0502935102 PubMedCentralPubMedGoogle Scholar
  34. deHart GW, Healy KE, Jones JCR (2003) The role of alpha3beta1 integrin in determining the supramolecular organization of laminin-5 in the extracellular matrix of keratinocytes. Exp Cell Res 283:67–79PubMedGoogle Scholar
  35. Desmoulière A, Chaponnier C, Gabbiani G (2005) Tissue repair, contraction, and the myofibroblast. Wound Repair Regen 13:7–12. doi: 10.1111/j.1067-1927.2005.130102.x PubMedGoogle Scholar
  36. DiPersio CM, Hodivala-Dilke KM, Jaenisch R et al (1997) alpha3beta1 Integrin is required for normal development of the epidermal basement membrane. J Cell Biol 137:729–742PubMedCentralPubMedGoogle Scholar
  37. DiPersio CM, Van der Neut R, Georges-Labouesse E et al (2000) alpha3beta1 and alpha6beta4 integrin receptors for laminin-5 are not essential for epidermal morphogenesis and homeostasis during skin development. J Cell Sci 113(Pt 17):3051–3062PubMedGoogle Scholar
  38. Dowling J, Yu QC, Fuchs E (1996) Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J Cell Biol 134:559–572PubMedGoogle Scholar
  39. Edwards R, Harding KG (2004) Bacteria and wound healing. Curr Opin Infect Dis 17:91–96PubMedGoogle Scholar
  40. Elosegui-Artola A, Bazellières E, Allen MD et al (2014) Rigidity sensing and adaptation through regulation of integrin types. Nat Mater 13:631–637. doi: 10.1038/nmat3960 PubMedCentralPubMedGoogle Scholar
  41. Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126:677–689. doi: 10.1016/j.cell.2006.06.044 PubMedGoogle Scholar
  42. Evans ND, Oreffo ROC, Healy E et al (2013) Epithelial mechanobiology, skin wound healing, and the stem cell niche. J Mech Behav Biomed Mater 28:397–409. doi: 10.1016/j.jmbbm.2013.04.023 PubMedGoogle Scholar
  43. Frye M, Gardner C, Li ER et al (2003) Evidence that Myc activation depletes the epidermal stem cell compartment by modulating adhesive interactions with the local microenvironment. Development 130:2793–2808PubMedGoogle Scholar
  44. Gaggioli C, Hooper S, Hidalgo-Carcedo C et al (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol 9:1392–1400. doi: 10.1038/ncb1658 PubMedGoogle Scholar
  45. Gailit J, Clark RA (1996) Studies in vitro on the role of alpha v and beta 1 integrins in the adhesion of human dermal fibroblasts to provisional matrix proteins fibronectin, vitronectin, and fibrinogen. J Invest Dermatol 106:102–108PubMedGoogle Scholar
  46. Gailit J, Clarke C, Newman D et al (1997) Human fibroblasts bind directly to fibrinogen at RGD sites through integrin alpha(v)beta3. Exp Cell Res 232:118–126. doi: 10.1006/excr.1997.3512 PubMedGoogle Scholar
  47. Gandarillas A, Watt FM (1995) Changes in expression of members of the fos and jun families and myc network during terminal differentiation of human keratinocytes. Oncogene 11:1403–1407PubMedGoogle Scholar
  48. Gardner H, Broberg A, Pozzi A et al (1999) Absence of integrin alpha1beta1 in the mouse causes loss of feedback regulation of collagen synthesis in normal and wounded dermis. J Cell Sci 112(Pt 3):263–272PubMedGoogle Scholar
  49. Georges-Labouesse E, Messaddeq N, Yehia G et al (1996) Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice. Nat Genet 13:370–373PubMedGoogle Scholar
  50. Geuijen CAW, Sonnenberg A (2002) Dynamics of the alpha6beta4 integrin in keratinocytes. Mol Biol Cell 13:3845–3858. doi: 10.1091/mbc.02-01-0601 PubMedCentralPubMedGoogle Scholar
  51. Giangreco A, Goldie SJ, Failla V, et al. (2010) Human skin aging is associated with reduced expression of the stem cell markers beta1 integrin and MCSP. J Invest Dermatol 30:604–608Google Scholar
  52. Gregor M, Osmanagic-Myers S, Burgstaller G et al (2014) Mechanosensing through focal adhesion-anchored intermediate filaments. FASEB J 28:715–729. doi: 10.1096/fj.13-231829 PubMedGoogle Scholar
  53. Grenache DG, Zhang Z, Wells LE et al (2007) Wound healing in the alpha2beta1 integrin-deficient mouse: altered keratinocyte biology and dysregulated matrix metalloproteinase expression. J Invest Dermatol 127:455–466. doi: 10.1038/sj.jid.5700611 PubMedGoogle Scholar
  54. Grinnell F, Billingham RE, Burgess L (1981) Distribution of fibronectin during wound healing in vivo. J Invest Dermatol 76:181–189PubMedGoogle Scholar
  55. Grinnell F, Ho CH, Wysocki A (1992) Degradation of fibronectin and vitronectin in chronic wound fluid: analysis by cell blotting, immunoblotting, and cell adhesion assays. J Invest Dermatol 98:410–416PubMedGoogle Scholar
  56. Grose R, Hutter C, Bloch W et al (2002) A crucial role of beta 1 integrins for keratinocyte migration in vitro and during cutaneous wound repair. Development 129:2303–2315PubMedGoogle Scholar
  57. Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453:314–321. doi: 10.1038/nature07039 PubMedGoogle Scholar
  58. Häkkinen L, Koivisto L, Gardner H et al (2004) Increased expression of beta6-integrin in skin leads to spontaneous development of chronic wounds. Am J Pathol 164:229–242PubMedCentralPubMedGoogle Scholar
  59. Hamelers IH, Olivo C, Mertens AE et al (2005) The Rac activator Tiam1 is required for (alpha)3(beta)1-mediated laminin-5 deposition, cell spreading, and cell migration. J Cell Biol 171:871–881. doi: 10.1083/jcb.200509172 PubMedCentralPubMedGoogle Scholar
  60. Harding KG, Morris HL, Patel GK (2002) Healing chronic wounds. BMJ 324:160PubMedCentralPubMedGoogle Scholar
  61. Has C, Spartà G, Kiritsi D et al (2012) Integrin α3 mutations with kidney, lung, and skin disease. N Engl J Med 366:1508–1514. doi: 10.1056/NEJMoa1110813 PubMedCentralPubMedGoogle Scholar
  62. Herouy Y, Mellios P, Bandemir E et al (2000) Autologous platelet-derived wound healing factor promotes angiogenesis via alphavbeta3-integrin expression in chronic wounds. Int J Mol Med 6:515–519PubMedGoogle Scholar
  63. Herrick SE, Sloan P, McGurk M et al (1992) Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am J Pathol 141:1085–1095PubMedCentralPubMedGoogle Scholar
  64. Hertle MD, Adams JC, Watt FM (1991) Integrin expression during human epidermal development in vivo and in vitro. Development 112:193–206PubMedGoogle Scholar
  65. Hertle MD, Kubler MD, Leigh IM, Watt FM (1992) Aberrant integrin expression during epidermal wound healing and in psoriatic epidermis. J Clin Invest 89:1892–1901. doi: 10.1172/JCI115794 PubMedCentralPubMedGoogle Scholar
  66. Huang XZ, Wu JF, Cass D et al (1996) Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J Cell Biol 133:921–928PubMedGoogle Scholar
  67. Huang X, Griffiths M, Wu J et al (2000) Normal development, wound healing, and adenovirus susceptibility in beta5-deficient mice. Mol Cell Biol 20:755–759PubMedCentralPubMedGoogle Scholar
  68. Humphries JD, Wang P, Streuli C et al (2007) Vinculin controls focal adhesion formation by direct interactions with talin and actin. J Cell Biol 179:1043–1057. doi: 10.1083/jcb.200703036 PubMedCentralPubMedGoogle Scholar
  69. Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687PubMedGoogle Scholar
  70. Jackson B, Peyrollier K, Pedersen E et al (2011) RhoA is dispensable for skin development, but crucial for contraction and directed migration of keratinocytes. Mol Biol Cell 22:593–605. doi: 10.1091/mbc.E09-10-0859 PubMedCentralPubMedGoogle Scholar
  71. Jones PH, Watt FM (1993) Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell 73:713–724PubMedGoogle Scholar
  72. Juhasz I, Murphy GF, Yan HC et al (1993) Regulation of extracellular matrix proteins and integrin cell substratum adhesion receptors on epithelium during cutaneous human wound healing in vivo. Am J Pathol 143:1458–1469PubMedCentralPubMedGoogle Scholar
  73. Kim JP, Zhang K, Chen JD et al (1992) Mechanism of human keratinocyte migration on fibronectin: unique roles of RGD site and integrins. J Cell Physiol 151:443–450. doi: 10.1002/jcp.1041510303 PubMedGoogle Scholar
  74. Kim JP, Zhang K, Chen JD et al (1994) Vitronectin-driven human keratinocyte locomotion is mediated by the alpha v beta 5 integrin receptor. J Biol Chem 269:26926–26932PubMedGoogle Scholar
  75. Kiritsi D, Has C, Bruckner-Tuderman L (2013) Laminin 332 in junctional epidermolysis bullosa. Cell Adh Migr 7:135–141PubMedCentralPubMedGoogle Scholar
  76. Labat-Robert J, Leutenegger M, Llopis G et al (1984) Plasma and tissue fibronectin in diabetes. Clin Physiol Biochem 2:39–48PubMedGoogle Scholar
  77. Larjava H, Salo T, Haapasalmi K et al (1993) Expression of integrins and basement membrane components by wound keratinocytes. J Clin Invest 92:1425–1435. doi: 10.1172/JCI116719 PubMedCentralPubMedGoogle Scholar
  78. Lawson C, Lim S-T, Uryu S et al (2012) FAK promotes recruitment of talin to nascent adhesions to control cell motility. J Cell Biol 196:223–232. doi: 10.1083/jcb.201108078 PubMedCentralPubMedGoogle Scholar
  79. Levental KR, Yu H, Kass L et al (2009) Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling. Cell 139:891–906PubMedCentralPubMedGoogle Scholar
  80. Li A, Simmons PJ, Kaur P (1998) Identification and isolation of candidate human keratinocyte stem cells based on cell surface phenotype. Proc Natl Acad Sci U S A 95:3902–3907PubMedCentralPubMedGoogle Scholar
  81. Liu S, Leask A (2013) Integrin β1 is required for dermal homeostasis. J Invest Dermatol 133:899–906. doi: 10.1038/jid.2012.438 PubMedGoogle Scholar
  82. Liu S, Xu S, Blumbach K et al (2010) Expression of integrin beta1 by fibroblasts is required for tissue repair in vivo. J Cell Sci 123:3674–3682. doi: 10.1242/jcs.070672 PubMedGoogle Scholar
  83. Longmate WM, Monichan R, Chu M-L et al (2014) Reduced fibulin-2 contributes to loss of basement membrane integrity and skin blistering in mice lacking integrin α3β1 in the epidermis. J Invest Dermatol 134:1609–1617. doi: 10.1038/jid.2014.10 PubMedCentralPubMedGoogle Scholar
  84. Lopez-Rovira T, Silva-Vargas V, Watt FM (2005) Different consequences of beta1 integrin deletion in neonatal and adult mouse epidermis reveal a context-dependent role of integrins in regulating proliferation, differentiation, and intercellular communication. J Invest Dermatol 125:1215–1227PubMedGoogle Scholar
  85. Lorenz K, Grashoff C, Torka R et al (2007) Integrin-linked kinase is required for epidermal and hair follicle morphogenesis. J Cell Biol 177:501–513. doi: 10.1083/jcb.200608125 PubMedCentralPubMedGoogle Scholar
  86. Margadant C, Raymond K, Kreft M et al (2009) Integrin alpha3beta1 inhibits directional migration and wound re-epithelialization in the skin. J Cell Sci 122:278–288. doi: 10.1242/jcs.029108 PubMedGoogle Scholar
  87. Martin P (1997) Wound healing–aiming for perfect skin regeneration. Science 276:75–81PubMedGoogle Scholar
  88. McBeath R, Pirone DM, Nelson CM et al (2004) Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 6:483–495PubMedGoogle Scholar
  89. McLean GW, Komiyama NH, Serrels B et al (2004) Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression. Genes Dev 18:2998–3003. doi: 10.1101/gad.316304 PubMedCentralPubMedGoogle Scholar
  90. Mitchell K, Szekeres C, Milano V et al (2009) Alpha3beta1 integrin in epidermis promotes wound angiogenesis and keratinocyte-to-endothelial-cell crosstalk through the induction of MRP3. J Cell Sci 122:1778–1787. doi: 10.1242/jcs.040956 PubMedCentralPubMedGoogle Scholar
  91. Mitra SK, Hanson DA, Schlaepfer DD (2005) Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6:56–68. doi: 10.1038/nrm1549 PubMedGoogle Scholar
  92. Moll R, Franke WW, Schiller DL et al (1982) The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31:11–24PubMedGoogle Scholar
  93. Nemes Z, Steinert PM (1999) Bricks and mortar of the epidermal barrier. Exp Mol Med 31:5–19. doi: 10.1038/emm.1999.2 PubMedGoogle Scholar
  94. Ng MR, Besser A, Danuser G, Brugge JS (2012) Substrate stiffness regulates cadherin-dependent collective migration through myosin-II contractility. J Cell Biol 199:545–563. doi: 10.1083/jcb.201207148 PubMedCentralPubMedGoogle Scholar
  95. Nobes CD, Hall A (1995) Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81:53–62PubMedGoogle Scholar
  96. O’Toole EA, Marinkovich MP, Hoeffler WK et al (1997) Laminin-5 inhibits human keratinocyte migration. Exp Cell Res 233:330–339. doi: 10.1006/excr.1997.3586 PubMedGoogle Scholar
  97. Osmanagic-Myers S, Gregor M, Walko G et al (2006) Plectin-controlled keratin cytoarchitecture affects MAP kinases involved in cellular stress response and migration. J Cell Biol 174:557–568. doi: 10.1083/jcb.200605172 PubMedCentralPubMedGoogle Scholar
  98. Paszek MJ, Zahir N, Johnson KR et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254. doi: 10.1016/j.ccr.2005.08.010 PubMedGoogle Scholar
  99. Pelham RJ, Wang Y (1997) Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc Natl Acad Sci U S A 94:13661–13665PubMedCentralPubMedGoogle Scholar
  100. Peltonen J, Larjava H, Jaakkola S et al (1989) Localization of integrin receptors for fibronectin, collagen, and laminin in human skin. Variable expression in basal and squamous cell carcinomas. J Clin Invest 84:1916–1923. doi: 10.1172/JCI114379 PubMedCentralPubMedGoogle Scholar
  101. Pierschbacher MD, Ruoslahti E (1984) Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature 309:30–33PubMedGoogle Scholar
  102. Pulkkinen L, Rouan F, Bruckner-Tuderman L et al (1998) Novel ITGB4 Mutations in Lethal and Nonlethal Variants of Epidermolysis Bullosa with Pyloric Atresia: Missense versus Nonsense. Am J Hum Genet 63:1376–1387PubMedCentralPubMedGoogle Scholar
  103. Raghavan S, Desai RA, Kwon Y et al (2010) Micropatterned dynamically adhesive substrates for cell migration. Langmuir 26:17733–17738. doi: 10.1021/la102955m PubMedGoogle Scholar
  104. Ramjaun AR, Hodivala-Dilke K (2009) The role of cell adhesion pathways in angiogenesis. Int J Biochem Cell Biol 41:521–530. doi: 10.1016/j.biocel.2008.05.030 PubMedGoogle Scholar
  105. Ramms L, Fabris G, Windoffer R et al (2013) Keratins as the main component for the mechanical integrity of keratinocytes. Proc Natl Acad Sci U S A 110:18513–18518. doi: 10.1073/pnas.1313491110 PubMedCentralPubMedGoogle Scholar
  106. Reffay M, Parrini MC, Cochet-Escartin O et al (2014) Interplay of RhoA and mechanical forces in collective cell migration driven by leader cells. Nat Cell Biol 16:217–223. doi: 10.1038/ncb2917 PubMedGoogle Scholar
  107. Reichelt J (2007) Mechanotransduction of keratinocytes in culture and in the epidermis. Eur J Cell Biol 86:807–816. doi: 10.1016/j.ejcb.2007.06.004 PubMedGoogle Scholar
  108. Reynolds LE, Conti FJ, Silva R et al (2008) alpha3beta1 integrin-controlled Smad7 regulates reepithelialization during wound healing in mice. J Clin Invest 118:965–974. doi: 10.1172/JCI33538 PubMedCentralPubMedGoogle Scholar
  109. Rice RH, Green H (1977) The cornified envelope of terminally differentiated human epidermal keratinocytes consists of cross-linked protein. Cell 11:417–422PubMedGoogle Scholar
  110. Rice RH, Green H (1978) Relation of protein synthesis and transglutaminase activity to formation of the cross-linked envelope during terminal differentiation of the cultured human epidermal keratinocyte. J Cell Biol 76:705–711PubMedCentralPubMedGoogle Scholar
  111. Ridley AJ, Hall A (1992) The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70:389–399PubMedGoogle Scholar
  112. Riveline D, Zamir E, Balaban NQ et al (2001) Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism. J Cell Biol 153:1175–1186PubMedCentralPubMedGoogle Scholar
  113. Ruoslahti E, Pierschbacher MD (1986) Arg-Gly-Asp: a versatile cell recognition signal. Cell 44:517–518PubMedGoogle Scholar
  114. Schlaepfer DD, Hunter T (1997) Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src. J Biol Chem 272:13189–13195PubMedGoogle Scholar
  115. Schlaepfer DD, Hanks SK, Hunter T, Van der Geer P (1994) Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 372:786–791PubMedGoogle Scholar
  116. Seltmann K, Fritsch AW, Käs JA, Magin TM (2013) Keratins significantly contribute to cell stiffness and impact invasive behavior. Proc Natl Acad Sci U S A 110:18507–18512. doi: 10.1073/pnas.1310493110 PubMedCentralPubMedGoogle Scholar
  117. Sen CK, Gordillo GM, Roy S et al (2009) Human Skin Wounds: A Major and Snowballing Threat to Public Health and the Economy. Wound Repair Regen 17:763–771. doi: 10.1111/j.1524-475X.2009.00543.x PubMedCentralPubMedGoogle Scholar
  118. Serrano I, Díez-Marqués ML, Rodríguez-Puyol M et al (2012) Integrin-linked kinase (ILK) modulates wound healing through regulation of hepatocyte growth factor (HGF). Exp Cell Res 318:2470–2481. doi: 10.1016/j.yexcr.2012.08.001 PubMedGoogle Scholar
  119. Siegel DH, Ashton GH, Penagos HG et al (2003) Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome. Am J Hum Genet 73:174–187PubMedCentralPubMedGoogle Scholar
  120. Singh P, Chen C, Pal-Ghosh S et al (2009) Loss of integrin alpha9beta1 results in defects in proliferation, causing poor re-epithelialization during cutaneous wound healing. J Invest Dermatol 129:217–228. doi: 10.1038/jid.2008.201 PubMedCentralPubMedGoogle Scholar
  121. Stupack DG, Cheresh DA (2004) Integrins and angiogenesis. Curr Top Dev Biol 64:207–238. doi: 10.1016/S0070-2153(04)64009-9 PubMedGoogle Scholar
  122. Swift ME, Burns AL, Gray KL, DiPietro LA (2001) Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol 117:1027–1035PubMedGoogle Scholar
  123. Tadokoro S, Shattil SJ, Eto K et al (2003) Talin Binding to Integrin ß Tails: A Final Common Step in Integrin Activation. Science 302:103–106PubMedGoogle Scholar
  124. Takashima A, Grinnell F (1985) Fibronectin-mediated keratinocyte migration and initiation of fibronectin receptor function in vitro. J Invest Dermatol 85:304–308PubMedGoogle Scholar
  125. Thery M, Racine V, Pepin A et al (2005) The extracellular matrix guides the orientation of the cell division axis. Nat Cell Biol 7:947–953PubMedGoogle Scholar
  126. Theveneau E, Mayor R (2013) Collective cell migration of epithelial and mesenchymal cells. Cell Mol Life Sci. doi: 10.1007/s00018-012-1251-7 PubMedGoogle Scholar
  127. Thomas GJ, Lewis MP, Whawell SA et al (2001) Expression of the alphavbeta6 integrin promotes migration and invasion in squamous carcinoma cells. J Invest Dermatol 117:67–73. doi: 10.1046/j.0022-202x.2001.01379.x PubMedGoogle Scholar
  128. Timpl R (1989) Structure and biological activity of basement membrane proteins. Eur J Biochem 180:487–502PubMedGoogle Scholar
  129. Trappmann B, Gautrot JE, Connelly JT et al (2011) Extracellular-matrix tethering regulates stem-cell fate. Nat Mater 11:642–649. doi: 10.1038/nmat3339 Google Scholar
  130. Tscharntke M, Pofahl R, Chrostek-Grashoff A et al (2007) Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1. J Cell Sci 120:1480–1490. doi: 10.1242/jcs.03426 PubMedGoogle Scholar
  131. Tsutsumi M, Inoue K, Denda S et al (2009) Mechanical-stimulation-evoked calcium waves in proliferating and differentiated human keratinocytes. Cell Tissue Res 338:99–106. doi: 10.1007/s00441-009-0848-0 PubMedGoogle Scholar
  132. Uriu K, Morelli LG, Oates AC (2014) Interplay between intercellular signaling and cell movement in development. Semin Cell Dev Biol. doi: 10.1016/j.semcdb.2014.05.011 PubMedGoogle Scholar
  133. Van Dongen SFM, Maiuri P, Marie E et al (2013) Triggering cell adhesion, migration or shape change with a dynamic surface coating. Adv Mater Weinheim 25:1687–1691. doi: 10.1002/adma.201204474 PubMedGoogle Scholar
  134. Vedula SRK, Hirata H, Nai MH et al (2014) Epithelial bridges maintain tissue integrity during collective cell migration. Nat Mater 13:87–96. doi: 10.1038/nmat3814 PubMedGoogle Scholar
  135. Vignaud T, Galland R, Tseng Q et al (2012) Reprogramming cell shape with laser nano-patterning. J Cell Sci 125:2134–2140. doi: 10.1242/jcs.104901 PubMedGoogle Scholar
  136. Watt FM (1983) Involucrin and Other Markers of Keratinocyte Terminal Differentiation. J Investig Dermatol 81:100s–103sPubMedGoogle Scholar
  137. Watt FM (1989) Terminal differentiation of epidermal keratinocytes. Curr Opin Cell Biol 1:1107–1115PubMedGoogle Scholar
  138. Watt FM, Green H (1982) Stratification and terminal differentiation of cultured epidermal cells. Nature 295:434–436PubMedGoogle Scholar
  139. Watt FM, Jordan PW, O’Neill CH (1988) Cell shape controls terminal differentiation of human epidermal keratinocytes. Proc Natl Acad Sci U S A 85:5576–5580PubMedCentralPubMedGoogle Scholar
  140. Watt FM, Kubler MD, Hotchin NA et al (1993) Regulation of keratinocyte terminal differentiation by integrin-extracellular matrix interactions. J Cell Sci 106(Pt 1):175–182PubMedGoogle Scholar
  141. Weis S, Lee TT, Del Campo A, García AJ (2013) Dynamic cell-adhesive microenvironments and their effect on myogenic differentiation. Acta Biomater 9:8059–8066. doi: 10.1016/j.actbio.2013.06.019 PubMedGoogle Scholar
  142. White SJ, McLean WH (2005) Kindler surprise: mutations in a novel actin-associated protein cause Kindler syndrome. J Dermatol Sci 38:169–175PubMedGoogle Scholar
  143. Wysocki AB, Grinnell F (1990) Fibronectin profiles in normal and chronic wound fluid. Lab Invest 63:825–831PubMedGoogle Scholar
  144. Wysocki AB, Staiano-Coico L, Grinnell F (1993) Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol 101:64–68PubMedGoogle Scholar
  145. Xiong J-P, Stehle T, Diefenbach B et al (2001) Crystal structure of the extracellular segment of integrin αVβ3. Science 294:339–345PubMedCentralPubMedGoogle Scholar
  146. Yang JT, Rayburn H, Hynes RO (1993) Embryonic mesodermal defects in alpha 5 integrin-deficient mice. Development 119:1093–1105PubMedGoogle Scholar
  147. Yang C, Tibbitt MW, Basta L, Anseth KS (2014) Mechanical memory and dosing influence stem cell fate. Nat Mater 13:645–652. doi: 10.1038/nmat3889 PubMedCentralPubMedGoogle Scholar
  148. Zhao JH, Reiske H, Guan JL (1998) Regulation of the cell cycle by focal adhesion kinase. J Cell Biol 143:1997–2008PubMedCentralPubMedGoogle Scholar
  149. Zhu AJ, Haase I, Watt FM (1999) Signaling via beta1 integrins and mitogen-activated protein kinase determines human epidermal stem cell fate in vitro. Proc Natl Acad Sci U S A 96:6728–6733PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen MaryUniversity of LondonLondonUK

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