Archives of Dermatological Research

, Volume 304, Issue 8, pp 589–597 | Cite as

Mechanosignaling pathways in cutaneous scarring

Review Article

Abstract

Mechanotransduction is the process by which physical forces are sensed and converted into biochemical signals that then result in cellular responses. The discovery and development of various molecular pathways involved in this process have revolutionized the fundamental and clinical understanding regarding the formation and progression of cutaneous scars. The aim of this review is to report the recent advances in scar mechanosignaling research. The mechanosignaling pathways that participate in the formation and growth of cutaneous scars can be divided into those whose role in mechanoresponsiveness has been proven (the TGF-β/Smad, integrin, and calcium ion pathways) and those who have a possible but as yet unproven role (such as MAPK and G protein, Wnt/β-catenin, TNF-α/NF-κB, and interleukins). During scar development, these cellular mechanosignaling pathways interact actively with the extracellular matrix. They also crosstalk extensively with the hypoxia, inflammation, and angiogenesis pathways. The elucidation of scar mechanosignaling pathways provides a new platform for understanding scar development. This better understanding will facilitate research into this promising field and may help to promote the development of pharmacological interventions that could ultimately prevent, reduce, or even reverse scar formation or progression.

Keywords

Mechanobiology Mechanotransduction Fibroblast Scar Keloid 

Notes

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Aberle H, Bauer A, Stappert J, Kispert A, Kemler R (1997) Beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 16:3797–3804PubMedCrossRefGoogle Scholar
  2. 2.
    Akaishi S, Akimoto M, Ogawa R, Hyakusoku H (2008) The relationship between keloid growth pattern and stretching tension visual analysis using the finite element method. Ann Plast Surg 60:445–451PubMedCrossRefGoogle Scholar
  3. 3.
    Akaishi S, Ogawa R, Hyakusoku H (2008) Keloid and hypertrophic scar: neurogenic inflammation hypotheses. Med Hypotheses 71:32–38PubMedCrossRefGoogle Scholar
  4. 4.
    Arora PD, Narani N, McCulloch CA (1999) The compliance of collagen gels regulates transforming growth factor-beta induction of alpha-smooth muscle actin in fibroblasts. Am J Pathol 154:871–882PubMedCrossRefGoogle Scholar
  5. 5.
    Balaban NQ, Schwarz US, Riveline D et al (2001) Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates. Nat Cell Biol 3:466–472PubMedCrossRefGoogle Scholar
  6. 6.
    Balasubramanian L, Ahmed A, Lo CM, Sham JS, Yip KP (2007) Integrin-mediated mechanotransduction in renal vascular smooth muscle cells: activation of calcium sparks. Am J Physiol Regul Integr Comp Physiol 293:1586–1594CrossRefGoogle Scholar
  7. 7.
    Behrens J, Jerchow BA, Würtele M et al (1998) Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science 280:596–599PubMedCrossRefGoogle Scholar
  8. 8.
    Berridge MJ (1993) Inositol trisphosphate and calcium signalling. Nature 361:315–325PubMedCrossRefGoogle Scholar
  9. 9.
    Bhanot P, Brink M, Samos CH et al (1996) A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382:225–230PubMedCrossRefGoogle Scholar
  10. 10.
    Bowley E, O’Gorman DB, Gan BS (2007) Beta-catenin signaling in fibroproliferative disease. J Surg Res 138:141–150PubMedCrossRefGoogle Scholar
  11. 11.
    Bronneberg D, Spiekstra SW, Cornelissen LH et al (2007) Cytokine and chemokine release upon prolonged mechanical loading of the epidermis. Exp Dermatol 16:567–573PubMedCrossRefGoogle Scholar
  12. 12.
    Brown RA, Sethi KK, Gwanmesia I, Raemdonck D, Eastwood M, Mudera V (2002) Enhanced fibroblast contraction of 3D collagen lattices and integrin expression by TGF-beta1 and -beta3: mechanoregulatory growth factors? Exp Cell Res 274:310–322PubMedCrossRefGoogle Scholar
  13. 13.
    Carracedo S, Lu N, Popova SN, Jonsson R, Eckes B, Gullberg D (2010) The fibroblast integrin alpha11beta1 is induced in a mechanosensitive manner involving activin A and regulates myofibroblast differentiation. J Biol Chem 285:10434–10445PubMedCrossRefGoogle Scholar
  14. 14.
    Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410:37–40PubMedCrossRefGoogle Scholar
  15. 15.
    Chau CH, Chen KY, Deng HT et al (2002) Coordinating Etk/Bmx activation and VEGF upregulation to promote cell survival and proliferation. Oncogene 21:8817–8829PubMedCrossRefGoogle Scholar
  16. 16.
    Chau CH, Clavijo CA, Deng HT et al (2005) Etk/Bmx mediates expression of stress-induced adaptive genes VEGF, PAI-1, and iNOS via multiple signaling cascades in different cell systems. Am J Physiol Cell Physiol 289:444–454CrossRefGoogle Scholar
  17. 17.
    Cheon SS, Cheah AY, Turley S et al (2002) beta-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds. Proc Natl Acad Sci USA 99:6973–6978PubMedCrossRefGoogle Scholar
  18. 18.
    Choquet D, Felsenfeld DP, Sheetz MP (1997) Extracellular matrix rigidity causes strengthening of integrin-cytoskeleton linkages. Cell 88:39–48PubMedCrossRefGoogle Scholar
  19. 19.
    Dabiri G, Campaner A, Morgan JR, Van De Water L (2006) A TGF-beta1 dependent autocrine loop regulates the structure of focal adhesions in hypertrophic scar fibroblasts. J Invest Dermatol 126:963–970PubMedCrossRefGoogle Scholar
  20. 20.
    Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584PubMedCrossRefGoogle Scholar
  21. 21.
    Eckes B, Zweers MC, Zhang ZG et al (2006) Mechanical tension and integrin alpha 2 beta 1 regulate fibroblast functions. J Investig Dermatol Symp Proc 11:66–72PubMedCrossRefGoogle Scholar
  22. 22.
    Fitsialos G, Chassot AA, Turchi L et al (2007) Transcriptional signature of epidermal keratinocytes subjected to in vitro scratch wounding reveals selective roles for ERK1/2, p38, and phosphatidylinositol 3-kinase signaling pathways. J Biol Chem 282:15090–15102PubMedCrossRefGoogle Scholar
  23. 23.
    Foley TT, Saggers GC, Moyer KE, Ehrlich HP (2011) Rat mast cells enhance fibroblast proliferation and fibroblast-populated collagen lattice contraction through gap junctional intercellular communications. Plast Reconstr Surg 127:1478–1486PubMedCrossRefGoogle Scholar
  24. 24.
    Follonier L, Schaub S, Meister JJ, Hinz B (2008) Myofibroblast communication is controlled by intercellular mechanical coupling. J Cell Sci 121:3305–3316PubMedCrossRefGoogle Scholar
  25. 25.
    Fujimura T, Moriwaki S, Imokawa G, Takema Y (2007) Crucial role of fibroblast integrins alpha2 and beta1 in maintaining the structural and mechanical properties of the skin. J Dermatol Sci 45:45–53PubMedCrossRefGoogle Scholar
  26. 26.
    Ghazizadeh M (2007) Essential role of IL-6 signaling pathway in keloid pathogenesis. J Nihon Med Sch 74:11–22PubMedCrossRefGoogle Scholar
  27. 27.
    Glogauer M, Arora P, Yao G, Sokholov I, Ferrier J, McCulloch CA (1997) Calcium ions and tyrosine phosphorylation interact coordinately with actin to regulate cytoprotective responses to stretching. J Cell Sci 110:11–21PubMedGoogle Scholar
  28. 28.
    Gönczi M, Szentandrássy N, Fülöp L et al (2007) Hypotonic stress influence the membrane potential and alter the proliferation of keratinocytes in vitro. Exp Dermatol 16:302–310PubMedCrossRefGoogle Scholar
  29. 29.
    Goto M, Ikeyama K, Tsutsumi M, Denda S, Denda M (2010) Calcium ion propagation in cultured keratinocytes and other cells in skin in response to hydraulic pressure stimulation. J Cell Physiol 224:229–233PubMedGoogle Scholar
  30. 30.
    Goumans MJ, Mummery C (2000) Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. Int J Dev Biol 44:253–265PubMedGoogle Scholar
  31. 31.
    Gurtner GC, Dauskardt RH, Wong VW et al (2011) Improving cutaneous scar formation by controlling the mechanical environment: large animal and phase I studies. Ann Surg 254:217–225PubMedCrossRefGoogle Scholar
  32. 32.
    Harris AK, Stopak D, Wild P (1981) Fibroblast traction as a mechanism for collagen morphogenesis. Nature 290:249–251PubMedCrossRefGoogle Scholar
  33. 33.
    Huang H, Kamm RD, Lee RT (2004) Cell mechanics and mechanotransduction: pathways, probes, and physiology. Am J Physiol Cell Physiol 287:C1–C11PubMedCrossRefGoogle Scholar
  34. 34.
    Ingber DE (2003) Mechanobiology and diseases of mechanotransduction. Ann Med 35:564–577PubMedCrossRefGoogle Scholar
  35. 35.
    Ingber DE (2006) Cellular mechanotransduction: putting all the pieces together again. FASEB J 20:811–827PubMedCrossRefGoogle Scholar
  36. 36.
    Ingber DE (2008) Tensegrity-based mechanosensing from macro to micro. Prog Biophys Mol Biol 97:163–179PubMedCrossRefGoogle Scholar
  37. 37.
    Ito S, Suki B, Kume H et al (2010) Actin cytoskeleton regulates stretch-activated Ca2+ influx in human pulmonary microvascular endothelial cells. Am J Respir Cell Mol Biol 43:26–34PubMedCrossRefGoogle Scholar
  38. 38.
    Javad F, Day PJ (2012) Protein profiling of keloidal scar tissue. Arch Dermatol Res. (Epub ahead of print 11 Mar 2012)Google Scholar
  39. 39.
    Katsumi A, Naoe T, Matsushita T, Kaibuchi K, Schwartz MA (2005) Integrin activation and matrix binding mediate cellular responses to mechanical stretch. J Biol Chem 280:16546–16549PubMedCrossRefGoogle Scholar
  40. 40.
    Kessler D, Dethlefsen S, Haase I et al (2001) Fibroblasts in mechanically stressed collagen lattices assume a “synthetic” phenotype. J Biol Chem 276:36575–36585PubMedCrossRefGoogle Scholar
  41. 41.
    Khalsa PS, Ge W, Uddin MZ, Hadjiargyrou M (2004) Integrin alpha2beta1 affects mechano-transduction in slowly and rapidly adapting cutaneous mechanoreceptors in rat hairy skin. Neuroscience 129:447–459PubMedCrossRefGoogle Scholar
  42. 42.
    Kippenberger S, Bernd A, Loitsch S et al (2000) Signaling of mechanical stretch in human keratinocytes via MAP kinases. J Invest Dermatol 114:408–412PubMedCrossRefGoogle Scholar
  43. 43.
    Kischer CW, Bunce H 3rd, Shetlah MR (1978) Mast cell analyses in hypertrophic scars, hypertrophic scars treated with pressure and mature scars. J Invest Dermatol 70:355–357PubMedCrossRefGoogle Scholar
  44. 44.
    Klein CE, Dressel D, Steinmayer T et al (1991) Integrin alpha 2 beta 1 is upregulated in fibroblasts and highly aggressive melanoma cells in three-dimensional collagen lattices and mediates the reorganization of collagen I fibrils. J Cell Biol 115:1427–1436PubMedCrossRefGoogle Scholar
  45. 45.
    Ko KS, Arora PD, McCulloch CA (2001) Cadherins mediate intercellular mechanical signaling in fibroblasts by activation of stretch-sensitive calcium-permeable channels. J Biol Chem 276:35967–35977PubMedCrossRefGoogle Scholar
  46. 46.
    Laboureau J, Dubertret L, Lebreton-De Coster C, Coulomb B (2004) ERK activation by mechanical strain is regulated by the small G proteins rac-1 and rhoA. Exp Dermatol 13:70–77PubMedCrossRefGoogle Scholar
  47. 47.
    Langholz O, Röckel D, Mauch C et al (1995) Collagen and collagenase gene expression in three-dimensional collagen lattices are differentially regulated by alpha 1 beta 1 and alpha 2 beta 1 integrins. J Cell Biol 131:1903–1915PubMedCrossRefGoogle Scholar
  48. 48.
    Lee DJ, Rosenfeldt H, Grinnell F (2000) Activation of ERK and p38 MAP kinases in human fibroblasts during collagen matrix contraction. Exp Cell Res 257:190–197PubMedCrossRefGoogle Scholar
  49. 49.
    Lo CM, Wang HB, Dembo M, Wang YL (2000) Cell movement is guided by the rigidity of the substrate. Biophys J 79:144–152PubMedCrossRefGoogle Scholar
  50. 50.
    Lu F, Ogawa R, Nguyen DT et al (2011) Microdeformation of three-dimensional cultured fibroblasts induces gene expression and morphological changes. Ann Plast Surg 66:296–300PubMedCrossRefGoogle Scholar
  51. 51.
    Malmström J, Lindberg H, Lindberg C et al (2004) Transforming growth factor-beta 1 specifically induce proteins involved in the myofibroblast contractile apparatus. Mol Cell Proteomics 3:466–477PubMedCrossRefGoogle Scholar
  52. 52.
    Massagué J, Attisano L, Wrana JL (1994) The TGF-beta family and its composite receptors. Trends Cell Biol 4:172–178PubMedCrossRefGoogle Scholar
  53. 53.
    Massagué J, Wotton D (2000) Transcriptional control by the TGF-beta/Smad signaling system. EMBO J 19:1745–1754PubMedCrossRefGoogle Scholar
  54. 54.
    McNulty AK, Schmidt M, Feeley T, Villanueva P, Kieswetter K (2009) Effects of negative pressure wound therapy on cellular energetics in fibroblasts grown in a provisional wound (fibrin) matrix. Wound Repair Regen 17:192–199PubMedCrossRefGoogle Scholar
  55. 55.
    Messadi DV, Doung HS, Zhang Q et al (2004) Activation of NFkappaB signal pathways in keloid fibroblasts. Arch Dermatol Res 296:125–133PubMedCrossRefGoogle Scholar
  56. 56.
    Nebe B, Bohn W, Sanftleben H, Rychly J (1996) Induction of a physical linkage between integrins and the cytoskeleton depends on intracellular calcium in an epithelial cell line. Exp Cell Res 229:100–110PubMedCrossRefGoogle Scholar
  57. 57.
    Nishimura K, Blume P, Ohqi S, Sumpio BE (2007) Effect of different frequencies of tensile strain on human dermal fibroblast proliferation and survival. Wound Repair Regen 15:646–656PubMedCrossRefGoogle Scholar
  58. 58.
    Noszczyk BH, Klein E, Holtkoetter O, Krieg T, Majewski S (2002) Integrin expression in the dermis during scar formation in humans. Exp Dermatol 11:311–318PubMedCrossRefGoogle Scholar
  59. 59.
    Occleston NL, Laverty HG, O’Kane S, Ferguson MW (2008) Prevention and reduction of scarring in the skin by transforming growth factor beta 3 (TGFbeta3): from laboratory discovery to clinical pharmaceutical. J Biomater Sci Polym Ed 19:1047–1063PubMedCrossRefGoogle Scholar
  60. 60.
    Ogawa H (1996) The Merkel cell as a possible mechanoreceptor cell. Prog Neurobiol 49:317–334PubMedGoogle Scholar
  61. 61.
    Ogawa R (2008) Keloid and hypertrophic scarring may result from a mechanoreceptor or mechanosensitive nociceptor disorder. Med Hypotheses 71:493–500PubMedCrossRefGoogle Scholar
  62. 62.
    Omori Y, Akaishi S, Ogawa R, Hyakusoku H (2010) Analysis of the regions where keloids tend to occur. Scar Management 4:112–115Google Scholar
  63. 63.
    Orgill DP, Bayer LR (2011) Update on negative-pressure wound therapy. Plast Reconstr Surg 127:105S–115SPubMedCrossRefGoogle Scholar
  64. 64.
    Oriente A, Fedarko NS, Pacocha SE, Huang SK, Lichtenstein LM, Essayan DM (2000) Interleukin-13 modulates collagen homeostasis in human skin and keloid fibroblasts. J Pharmacol Exp Ther 292:988–994PubMedGoogle Scholar
  65. 65.
    Pan S, An P, Zhang R, He X, Yin G, Min W (2002) Etk/Bmx as a tumor necrosis factor receptor type 2-specific kinase: role in endothelial cell migration and angiogenesis. Mol Cell Biol 22:7512–7523PubMedCrossRefGoogle Scholar
  66. 66.
    Pawson T (1995) Protein modules and signalling networks. Nature 373:573–580PubMedCrossRefGoogle Scholar
  67. 67.
    Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC (2000) An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407:535–538PubMedCrossRefGoogle Scholar
  68. 68.
    Piskorowski R, Haeberle H, Panditrao MV, Lumpkin EA (2008) Voltage-activated ion channels and Ca(2+)-induced Ca(2+) release shape Ca(2+) signaling in Merkel cells. Pflugers Arch 457:197–209PubMedCrossRefGoogle Scholar
  69. 69.
    Pozzi A, Wary KK, Giancotti FG, Gardner HA (1998) Integrin alpha1beta1 mediates a unique collagen-dependent proliferation pathway in vivo. J Cell Biol 142:587–594PubMedCrossRefGoogle Scholar
  70. 70.
    Quaglino D Jr, Nanney LB, Ditesheim JA, Davidson JM (1991) Transforming growth factor-beta stimulates wound healing and modulates extracellular matrix gene expression in pig skin: incisional wound model. J Invest Dermatol 97:34–42PubMedGoogle Scholar
  71. 71.
    Renò F, Sabbatini M, Lombardi F et al (2003) In vitro mechanical compression induces apoptosis and regulates cytokines release in hypertrophic scars. Wound Repair Regen 11:331–336PubMedCrossRefGoogle Scholar
  72. 72.
    Sakamoto Y, Ishijima M, Kaneko H et al (2010) Distinct mechanosensitive Ca2+ influx mechanisms in human primary synovial fibroblasts. J Orthop Res 28:859–864PubMedGoogle Scholar
  73. 73.
    Sato M (2006) Upregulation of the Wnt/beta-catenin pathway induced by transforming growth factor-beta in hypertrophic scars and keloids. Acta Derm Venereol 86:300–307PubMedCrossRefGoogle Scholar
  74. 74.
    Schiro JA, Chan BM, Roswit WT et al (1991) Integrin alpha 2 beta 1 (VLA-2) mediates reorganization and contraction of collagen matrices by human cells. Cell 67:403–410PubMedCrossRefGoogle Scholar
  75. 75.
    Seifert O, Mrowietz U (2009) Keloid scarring: bench and bedside. Arch Dermatol Res 301:259–272PubMedCrossRefGoogle Scholar
  76. 76.
    Shih B, Bayat A (2010) Genetics of keloid scarring. Arch Dermatol Res 302:319–339PubMedCrossRefGoogle Scholar
  77. 77.
    Simon MI, Strathmann MP, Gautam N (1991) Diversity of G proteins in signal transduction. Science 252:802–808PubMedCrossRefGoogle Scholar
  78. 78.
    Takei T, Kito H, Du W, Mills I, Sumpio BE (1998) Induction of interleukin (IL)-1 alpha and beta gene expression in human keratinocytes exposed to repetitive strain: their role in strain-induced keratinocyte proliferation and morphological change. J Cell Biochem 69:95–103PubMedCrossRefGoogle Scholar
  79. 79.
    Tazaki M, Suzuki T (1998) Calcium inflow of hamster Merkel cells in response to hyposmotic stimulation indicate a stretch activated ion channel. Neurosci Lett 243:69–72PubMedCrossRefGoogle Scholar
  80. 80.
    Thannickal VJ, Lee DY, White ES et al (2003) Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem 278:12384–12389PubMedCrossRefGoogle Scholar
  81. 81.
    Thomas DW, Hopkinson I, Harding KG, Shepherd JP (1994) The pathogenesis of hypertrophic/keloid scarring. Int J Oral Maxillofac Surg 23:232–236PubMedCrossRefGoogle Scholar
  82. 82.
    Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL (1998) SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 95:779–791PubMedCrossRefGoogle Scholar
  83. 83.
    Turner CH, Pavalko FM (1998) Mechanotransduction and functional response of the skeleton to physical stress: the mechanisms and mechanics of bone adaptation. J Orthop Sci 3:346–355PubMedCrossRefGoogle Scholar
  84. 84.
    Vaughan MB, Howard EW, Tomasek JJ (2000) Transforming growth factor-beta1 promotes the morphological and functional differentiation of the myofibroblast. Exp Cell Res 257:180–189PubMedCrossRefGoogle Scholar
  85. 85.
    Vi L, de Lasa C, DiGuglielmo GM, Dagnino L (2011) Integrin-linked kinase is required for TGF-β1 induction of dermal myofibroblast differentiation. J Invest Dermatol 131:586–593PubMedCrossRefGoogle Scholar
  86. 86.
    Wang JH, Lin JS (2007) Cell traction force and measurement methods. Biomech Model Mechanobiol 6:361–371PubMedCrossRefGoogle Scholar
  87. 87.
    Wang Z, Fong KD, Phan TT, Lim IJ, Longaker MT, Yang GP (2006) Increased transcriptional response to mechanical strain in keloid fibroblasts due to increased focal adhesion complex formation. J Cell Physiol 206:510–517PubMedCrossRefGoogle Scholar
  88. 88.
    Wen H, Blume PA, Sumpio BE (2009) Role of integrins and focal adhesion kinase in the orientation of dermal fibroblasts exposed to cyclic strain. Int Wound J 6:149–158PubMedCrossRefGoogle Scholar
  89. 89.
    Wipff PJ, Rifkin DB, Meister JJ, Hinz B (2007) Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol 179:1311–1323PubMedCrossRefGoogle Scholar
  90. 90.
    Wong VW, Rustad KC, Akaishi S et al (2011) Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat Med 18:148–152PubMedCrossRefGoogle Scholar
  91. 91.
    Yamamoto Y, Gaynor RB (2001) Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest 107:135–142PubMedCrossRefGoogle Scholar
  92. 92.
    Yan X, Gao JH, Chen Y, Song M, Liu XJ (2007) Preliminary linkage analysis and mapping of keloid susceptibility locus in a Chinese pedigree. Zhonghua Zheng Xing Wai Ke Za Zhi 23:32–35PubMedGoogle Scholar
  93. 93.
    Yang S, Huang XY (2005) Ca2+ influx through L-type Ca2+ channels controls the trailing tail contraction in growth factor-induced fibroblast cell migration. J Biol Chem 280:27130–27137PubMedCrossRefGoogle Scholar
  94. 94.
    Zhao XH, Laschinger C, Arora P, Szászi K, Kapus A, McCulloch CA (2007) Force activates smooth muscle alpha-actin promoter activity through the Rho signaling pathway. J Cell Sci 120:1801–1809PubMedCrossRefGoogle Scholar
  95. 95.
    Shih B, Bayat A (2012) Comparative genomic hybridisation analysis of keloid tissue in Caucasians suggests possible involvement of HLA-DRB5 in disease pathogenesis. Arch Dermatol Res 304:241–249. Related articles recently published in the Archives of Dermatological Research (selected by the journal's editorial staff)PubMedCrossRefGoogle Scholar
  96. 96.
    Ward SV et al (2012) Association of TGFbeta1 and clinical factors with scar outcome following melanoma excision. Arch Dermatol Res 304:343–351. Related articles recently published in the Archives of Dermatological Research (selected by the journal's editorial staff)Google Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of Plastic, Reconstructive and Aesthetic SurgeryNippon Medical SchoolTokyoJapan
  2. 2.Department of Plastic SurgeryMeitan General HospitalBeijingChina
  3. 3.Division of Plastic and Reconstructive Surgery, Department of SurgeryStanford UniversityStanfordUSA

Personalised recommendations