Cellular/extracellular matrix cross-talk in scar evolution and control

Wound Repair and Regeneration

Volumn 19, Issue 2, 2011, Pages 117-133

  Widgerow, Alan D ^a,b,c  

^a UNIVERSITY OF THE WITWATERSRAND   (South Africa)

^b Adar Science Inc   (United States)

^c NONE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COLLAGEN; FIBRONECTIN; INTEGRIN; SMAD PROTEIN; TENASCIN;

CELL INTERACTION; CELL NUCLEUS; CYTOSOL; DYNAMIC RECIPROCITY; EXTRACELLULAR MATRIX; HYDRATION; INFLAMMATION; KERATINOCYTE; MECHANICAL STIMULATION; MOLECULAR INTERACTION; PRIORITY JOURNAL; REVIEW; SCAR FORMATION; SIGNAL TRANSDUCTION; WOUND HEALING;

ANIMALS; CELL COMMUNICATION; CICATRIX; CONNECTIVE TISSUE GROWTH FACTOR; EXTRACELLULAR MATRIX; GLYCOPROTEINS; HUMANS; INFLAMMATION; MECHANORECEPTORS; SIGNAL TRANSDUCTION; STRESS, MECHANICAL; WOUND HEALING;

EID: 79952269081     PISSN: 10671927     EISSN: 1524475X     Source Type: Journal    
DOI: 10.1111/j.1524-475X.2010.00662.x     Document Type: Review

References (184)

1. Elliot D, Cory-Pearce R, Rees GM., The behaviour of presternal scars in a fair-skinned population. Ann R Coll Surg Engl 1985; 67: 238-40. (Pubitemid 15072909)
2. Meyer M, McGrouther DA., A study relating wound tension to scar morphology in the presternal scar using Langers technique. Br J Plast Surg 1991; 44: 291-4.
3. Sommerlad BC, Creasey JM., The stretched scar: a clinical and histological study. Br J Plast Surg 1978; 3: 34-45. (Pubitemid 8263932)
4. Eckes B, Nischt R, Krieg T., Cell-matrix interactions in dermal repair and scarring. Fibrogenesis Tissue Repair 2010; 3: 4-15.
5. Schultz GS, Wysocki A., Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen 2009; 17: 153-62.
6. Bissell MJ, Hall HG, Parry G., How does the extracellular matrix direct gene expression? J Theor Biol 1982; 99: 31-68. (Pubitemid 13209096)
7. Reichelt J., Mechanotransduction of keratinocytes in culture and in the epidermis. Eur J Cell Biol 2007; 86: 807-16. (Pubitemid 350103020)
8. Katsumi A, Naoe T, Matsushita T, Kaibuchi K, Schwartz MA., Integrin activation and matrix binding mediate cellular responses to mechanical stretch. J Biol Chem 2005; 280: 16546-9. (Pubitemid 41389109)
9. Katsumi A, Orr AW, Tzima E, Schwartz MA., Integrins in mechanotransduction. J Biol Chem 2004; 279: 12001-4. (Pubitemid 38445760)
10. Jalali S, del Pozo MA, Chen K, Miao H, Li Y, Schwartz MA, Shyy JY, Chien S., Integrin-mediated mechanotransduction requires its dynamic interaction with specific extracellular matrix (ECM) ligands. Proc Natl Acad Sci USA 2001; 98: 1042-6. (Pubitemid 32121183)
11. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA., Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002; 3: 349-63. (Pubitemid 34619269)
12. Hinz B., Masters and servants of the force: the role of matrix adhesions in myofibroblast force perception and transmission. Eur J Cell Biol 2006; 85: 175-81.
13. Gabbiani G., The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 2003; 200: 500-3. (Pubitemid 36818250)
14. Grinnell F., Fibroblast biology in three-dimensional collagen matrices. Trends Cell Biol 2003; 13: 264-9. (Pubitemid 36556011)
15. Velling T, Risteli J, Wennerberg K, Mosher DF, Johansson S., Polymerization of type I and III collagens is dependent on fibronectin and enhanced by integrins alpha 11beta 1 and alpha 2beta 1. J Biol Chem 2002; 277: 37377-81.
16. Trebaul A, Chan EK, Midwood KS., Regulation of fibroblast migration by tenascin-C. Biochem Soc Trans 2007; 35 (Part 4): 695-7. (Pubitemid 47310345)
17. Swindle CS, Tran KT, Johnson TD, Banerjee P, Mayes AM, Griffith L, Wells A., Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor. J Cell Biol 2001; 154: 459-68. (Pubitemid 34288473)
18. Chiquet M, Gelman L, Lutz R, Maier S., From mechanotransduction to extracellular matrix gene expression in fibroblasts. Biochim Biophys Act 2009; 1793: 911-20.
19. Wipff PJ, Rifkin DB, Meister JJ, Hinz B., Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol 2007; 179: 1311-23. (Pubitemid 350277747)
20. Lindahl GE, Chambers RC, Papakrivopoulou J, Dawson SJ, Jacobsen MC, Bishop JE, Laurent GJ., Activation of fibroblast procollagen alpha 1(I) transcription by mechanical strain is transforming growth factor-beta-dependent and involves increased binding of CCAAT-binding factor (CBF/NF-Y) at the proximal promoter. J Biol Chem 2002; 277: 6153-61. (Pubitemid 34968404)
21. 2+ entry. J Cell Sci 2004; 117: 85-92. (Pubitemid 38072123)
22. Ko KS, Arora PD, McCulloch CAG., Cadherins mediate intercellular mechanical signaling in fibroblasts by activation of stretch-sensitive calcium-permeable channels. J Biol Chem 2001; 276: 35967-77.
23. ten Dijke P, Hill C., New insights into TGF-beta-Smad signaling. Trends Biochem Sci 2004; 29: 265-73.
24. Dai P, Nakagami T, Tanaka H, Hitomi T, Takamatsu T., Cx43 mediates TGF-β signaling through competitive smads binding to microtubules. Mol Biol Cell 2007; 18: 2264-73. (Pubitemid 46911376)
25. Sisco M, Kryger ZB, O'Shaughnessy KD, Kim PS, Schultz GS, Ding XZ, Roy NK, Dean NM, Mustoe TA., Antisense inhibition of connective tissue growth factor (CTGF/CCN2) mRNA limit hypertrophic scarring without affecting wound healing in vivo. Wound Rep Regen 2008; 16: 661-73.
26. Ehrlich HP, Allison GM, Leggett M., The myofibroblast, cadherin, α smooth muscle actin and the collagen effect. Cell Biochem Funct 2004; 24: 63-70.
27. Martinac B., Mechanosensitive ion channels: molecule of mechanotransduction. J. Cell Sci 2004; 117: 2449-60. (Pubitemid 38877841)
28. Li C, Xu Q., Mechanical stress-initiated signal transduction in vascular smooth muscle cells in vitro and in vivo. Cell Signal 2007; 19: 881-91. (Pubitemid 46436444)
29. Sawada Y, Sone K., Hydration and occlusion treatment for hypertrophic scars and keloids. Br J Plast Surg 1992; 45: 599-603.
30. Mustoe TA, Cooter RD, Gold MH, Hobbs FD, Ramelet AA, Shakespeare PG, Stella M, Téot L, Wood FM, Ziegler UE., International clinical recommendations on scar management (review). Plast Reconstr Surg 2002; 110: 560-71. (Pubitemid 34815962)
31. Sawada Y, Urushidate S, Nihei Y., Hydration and occlusive treatment of a sutured wound. Ann Plast Surg 1998; 41: 508-12. (Pubitemid 28511794)
32. Mustoe TA., Evolution of silicone therapy and mechanism of action in scar management. Aesthet Plast Surg 2008; 32: 82-92.
33. Tandara AA, Mustoe TA., The role of the epidermis in the control of scarring: evidence for mechanism of action for silicone gel. J Plast Reconstr Aesthet Surg 2008; 61: 1219-25.
34. Tandara AA, Mustoe TA., MMP- and TIMP-secretion by human cutaneous keratinocytes and fibroblasts impact of coculture and hydration. J Plast Reconstr Aesthet Surg 2011; 64: 108-16.
35. Gallant-Behm CL, Mustoe TA., Occlusion regulates epidermal cytokine production and inhibits scar formation. Wound Repair Regen 2010; 18: 235-44.
36. Greenwel P, Tanaka S, Penkov D, Zhang W, Olive M, Moll J, Vinson C, Di Liberto M, Ramirez F., Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins through repressive. Mol Cell Biol 2000; 20: 912-8. (Pubitemid 30044228)
37. Kouba DJ, Chung KY, Nishiyama T, Vindevoghel L, Kon A, Klement JF, Uitto J, Mauviel A., Nuclear factor-kappa B mediates TNF-alpha inhibitory effect on alpha 2(I) collagen (COL1A2) gene transcription in human dermal fibroblasts. J Immunol 1999; 162: 4226-34. (Pubitemid 29314811)
38. Bock O, Yu H, Zitron S, Bayat A, Ferguson M, Mrowietz U., Studies of transforming growth factors beta 1-3 and their receptors I and II in fibroblasts of keloid and hypertrophic scars. Acta Derm Venereol 2005; 85: 216-20. (Pubitemid 40695163)
39. Lee T, Chin G, Kim W, Chau D, Gittes G, Longaker M., Expression of transforming growth factor beta 1, 2 and 3 proteins in keloids. Ann Plast Surg 1999; 43: 179-84. (Pubitemid 29380019)
40. ten Dijke P, Hill C., New insights into TGF-beta-Smad signalling. Trends Biochem Sci 2004; 29: 265-73.
41. Flanders K., Smad3 as a mediator of the fibrotic response. Int J Exp Pathol 2004; 86: 47-64. (Pubitemid 38703594)
42. Kopp J, Pries E, Said H, Hafemann B, Wickert L, Gressner A, Pallua N, Dooley S., Abrogation of transforming growth factor-beta signaling by Smad 7 inhibits collagen gel contraction of human dermal fibroblasts. J Biol Chem 2005; 280: 21570-6. (Pubitemid 40805724)
43. Nakao A, Afrakhte M, Moren A, Nakayama T, Christian J, Heuchel R, Itoh S, Kawabata M, Heldin N, Heldin C, ten Dijke P., Identification of Smad 7, a TGF-beta-inducible antagonist of TGF-beta signalling. Nature 1997; 389: 549-51.
44. Singer AJ, Clark RA., Cutaneous wound healing. N Engl J Med 1999; 341: 738-46. (Pubitemid 29407375)
45. White CR., Alterations of collagen and elastin. In:, Barnhill RL, Crowson AN, editors. Textbook of dermatopathology. New York: McGraw Hill, 2004: 349-55.
46. Chen W, Fu X, Ge S, Sun T, Zhou G, Jiang D, Sheng Z., Ontogeny of expression of transforming growth factor-beta and its receptors and their possible relationship with scarless healing in human fetal skin. Wound Repair Regen 2005; 13: 68-75. (Pubitemid 40250431)
47. Wilgus TA, Bergdall VK, Tober KL, Hill KJ, Mitra S, Flavahan NA, Oberyszyn TM., The impact of cyclooxygenase-2 mediated inflammation on scarless fetal wound healing. Am J Pathol 2004; 165: 753-61. (Pubitemid 39129283)
48. Werner S, Grose R., Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003; 83: 835-70. (Pubitemid 36828927)
49. Moyer K, Saggers G, Ehrlich H., Mast cells promote fibroblast-populated collagen lattice contraction through gap junction intercellular communication. Wound Repair Regen 2004; 12: 269-75. (Pubitemid 38880435)
50. Sheridan RL, Tompkins RG., What's new in burns and metabolism. J Am Coll Surg 2004; 198: 243-63. (Pubitemid 38175242)
51. Saika S, Ikeda K, Yamanaka O, Flanders KC, Okada Y, Miyamoto T, Kitano A, Ooshima A, Nakajima Y, Ohnishi Y, Kao WW., Loss of tumor necrosis factor alpha potentiates transforming growth factor beta-mediated pathogenic tissue response during wound healing. Am J Pathol 2006; 168: 1848-60. (Pubitemid 43825305)
52. Aarabi S, Longaker MT, Gurtner GC., Hypertrophic scar formation following burns and trauma: new approaches to treatment. PLoS Med 2007; 4: 1-5.
53. Armour A, Scott PG, Tredget EE., Cellular and molecular pathology of HTS: basis for treatment. Wound Rep Regen 2007; 15: S6-17. (Pubitemid 47301668)
54. Gailit J, Marchese MJ, Kew RR, Gruber BL., The differentiation and function of myofibroblasts is regulated by mast cell mediators. J Invest Dermatol 2001; 117: 1113-9. (Pubitemid 34205906)
55. Kendall JC, Li XH, Galli SJ, Gordon JR., Promotion of mouse fibroblast proliferation by IgE-dependent activation of mouse mast cells: role for mast cell tumor necrosis factor-alpha and transforming growth factor-beta 1. J Allergy Clin Immunol 1997; 99: 113-23.
56. Kupietzky A, Levi-Schaffer F., The role of mast cell-derived histamine in the closure of an in vitro wound. Inflamm Res 1996; 45: 176-80. (Pubitemid 26135073)
57. van der Veer W, Bloemen MCT, Ulrich MMW, Molema G, van Zuijlen PP, Middelkoop E, Niessen FB., Potential cellular and molecular causes of hypertrophic scar formation. Burns 2009; 35: 15-29.
58. Chen L, Liu S, Li SR, Cong L, Wu JL, Wang ZX., Influence of substance P on the release of histamine in the human hypertrophic scar tissue. Zhonghua Shao Shang Z Zhi 2006; 22: 192-4.
59. Werner S, Grose R., Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003; 83: 835-70. (Pubitemid 36828927)
60. Niessen FB, Spauwen PH, Schalkwijk J, Kon M., On the nature of hypertrophic scars and keloids: a review. Plast Reconstr Surg 1999; 104: 1435-58. (Pubitemid 29466295)
61. Ishida Y, Gao JL, Murphy PM., Chemokine receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function. J Immunol 2008; 180: 569-79.
62. Wynn T., Cellular and molecular mechanisms of fibrosis. J Pathol 2008; 214: 199-210. (Pubitemid 351160157)
63. Tredget EE, Yang L, Delehanty M, Shankowsky H, Scott PG., Polarized Th2 cytokine production in patients with hypertrophic scar following thermal injury. J Interferon Cytokine Res 2006; 26: 179-89.
64. Niessen FB, Schalkwijk J, Vos H, Timens W., Hypertrophic scar formation is associated with an increased number of epidermal Langerhans cells. J Pathol 2004; 202: 121-9. (Pubitemid 38072853)
65. Liechty KW, Kim HB, Adzick NS, Crombleholme TM., Fetal wound repair results in scar formation in interleukin-10-deficient mice in a syngeneic murine model of scarless fetal wound repair. J Pediatr Surg 2000; 35: 866-72, discussion 72-3.
66. Tanaka A, Hatoko M, Tada H, Iioka H, Niitsuma K, Miyagawa S., Expression of p53 family in scars. J Dermatol Sci 2004; 34: 17-24. (Pubitemid 38134469)
67. Akasaka Y, Fujita K, Ishikawa Y, Asuwa N, Inuzuka K, Ishihara M, Ito M, Masuda T, Akishima Y, Zhang L, Ito K, Ishii T., Detection of apoptosis in keloids and a comparative study on apoptosis between keloids, hypertrophic scars, normal healed flat scars, and dermatofibroma. Wound Rep Regen 2001; 9: 501-6. (Pubitemid 34266730)
68. Stramer BM, Mori R, Martin P., The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J Invest Dermatol 2007; 127: 1009-17. (Pubitemid 46625163)
69. Gill SE, Parks WC., Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol 2008; 40: 1334-47.
70. Nakamura T, Kuwai T, Kim JS, Fan D, Kim SJ, Fidler IJ., Stromal metalloproteinase-9 is essential to angiogenesis and progressive growth of orthotopic human pancreatic cancer in parabiont nude mice. Neoplasia 2007; 9: 979-86. (Pubitemid 350086443)
71. Xie JL, Bian HN, Qi SH, Chen HD, Li HD, Xu YB, Li TZ, Liu XS, Liang HZ, Xin BR, Huan Y., Basic fibroblast growth factor (bFGF) alleviates the scar of the rabbit ear model in wound healing. Wound Rep Regen 2008; 16: 576-81. (Pubitemid 352000323)
72. Freedberg IM, Tomic-Canic M, Komine M, Blumenberg M., Keratins and the keratinocyte activation cycle. J Invest Dermatol 2001; 116: 633-40. (Pubitemid 32467639)
73. Graves DT, Nooh N, Gillen T, Davey M, Patel S, Cottrell D, Amar S., IL-1 plays a critical role in oral, but not dermal, wound healing. J Immunol 2001; 167: 5316-20. (Pubitemid 33009770)
74. Maas-Szabowski N, Szabowski A, Stark HJ, Andrecht S, Kolbus A, Schorpp-Kistner M, Angel P, Fusenig NG., Organotypic cocultures with genetically modified mouse fibroblasts as a tool to dissect molecular mechanisms regulating keratinocyte growth and differentiation. J Invest Dermatol 2001; 116: 816-20. (Pubitemid 32467667)
75. Szabowski A, Maas-Szabowski N, Andrecht S, Kolbus A, Schorpp-Kistner M, Fusenig NE, Angel P., c-Jun and JunB antagonistically control cytokine-regulated mesenchymal-epidermal interaction in skin. Cell 2000; 103: 745-55.
76. Morasso MI, Tomic-Canic M., Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. Biol Cell 2005; 97: 173-83. (Pubitemid 40360890)
77. Cesarman-Maus G, Hajjar KA., Molecular mechanisms of fibrinolysis. Br J Haematol 2005; 129: 307-21. (Pubitemid 40646889)
78. Daniel RJ, Groves RW., Increased migration of murine keratinocytes under hypoxia is mediated by induction of urokinase plasminogen activator. J Invest Dermatol 2002; 119: 1304-9. (Pubitemid 36005613)
79. Garner WL., Epidermal regulation of dermal fibroblast activity. Plast Reconstr Surg 1998; 102: 135-9. (Pubitemid 28303977)
80. Harrison CA, Gossiel F, Bullock AJ, Sun T, Blumsohn A, Mac Neil S., Investigation of keratinocyte regulation of collagen I synthesis by dermal fibroblasts in a simple in vitro model. Br J Dermatol 2006; 154: 401-10. (Pubitemid 43382644)
81. Werner S, Krieg T, Smola H., Keratinocyte-fibroblast interactions in wound healing. J Invest Dermatol 2001; 127: 998-1008.
82. Coulombe PA., Wound epithelialization: accelerating the pace of discovery. J Invest Dermatol 2003; 121: 219-30.
83. Andriessen MP, Niessen FB, Van de Kerkhof PC, Schalkwijk J., Hypertrophic scarring is associated with epidermal abnormalities: an immunohistochemical study. J Pathol 1998; 186: 192-200. (Pubitemid 28467830)
84. Machesney M, Tidman N, Waseem A, Kirby L, Leigh I., Activated keratinocytes in the epidermis of hypertrophic scars. Am J Pathol 1998; 152: 1133-41. (Pubitemid 28221864)
85. Ulrich MM, Verkerk M, Reijnen L, Vlig M, van den Bogaerdt AJ, Middelkoop E., Expression profile of proteins involved in scar formation in the healing process of full-thickness excisional wounds in the porcine model. Wound Repair Regen 2007; 15: 482-90. (Pubitemid 47087640)
86. van der Slot AJ, Zuurmond AM, van den Bogaerdt AJ, Ulrich MM, Middelkoop E, Boers W, Karel Ronday H, DeGroot J, Huizinga TW, Bank RA., Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon. Matrix Biol 2004; 23: 251-7. (Pubitemid 39013983)
87. Inoue I, Kitagawa M, Onozaki K, Hyashi H., Contribution of the constitutive and inducible degradation of Smad3 by the ubiquitin-proteasome pathway to transforming growth factor-b signaling. J Interf Cytok Res 2004; 24: 43-54. (Pubitemid 38147266)
88. Moors MA, Mizel SB., Proteasome-mediated regulation of interleukin-1{beta} turnover and export in human monocytes. J Leukoc Biol 2000; 68: 131-6.
89. Zhang F, Laiho M., On and off: proteasome and TGF-β signaling. Exp Cell Res 2003; 291: 275-81.
90. Attisano L, Wotton L., Signal transduction by the TGF-β super-family. Science 2002; 296: 1646-7.
91. ten Dijke P, Goumans MJ, Itoh F, Itoh S., Regulation of cell proliferation by Smad proteins. J Cell Physiol 2002; 191: 1-16. (Pubitemid 34195213)
92. Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA Jr, Wrana JL, Falb D., The MAD-related protein Smad7 associates with the TGF receptor and functions as an antagonist of TGF β signalling. Cell 1997; 89: 1165-73. (Pubitemid 127678749)
93. Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P., Identification of Smad7, a TGF-inducible antagonist of TGF-β signalling. Nature 1997; 389: 631-5. (Pubitemid 27446184)
94. Ju-Lin X, Shao-Hai Q, Tian-Zeng T, Bin H, Jing-Ming T, Ying-Bin X, Xu-Sheng L, Bin S, Hui-Zhen L, Yong H., Effect of asiaticoside on hypertrophic scar in the rabbit ear model. J Cutan Pathol 2009; 36: 234-9.
95. Huang L, Chen CH., Proteasome regulators: activators and inhibitors. Curr Med Chem 2009; 16: 931-9.
96. Katsiki M, Chondrogianni N, Chinou I, Rivett AJ, Gonos ES., The olive constituent oleuropein exhibits proteasome stimulatory properties in vitro and confers life span extension of human embryonic fibroblasts. Rejuvenation Res 2007; 10: 157-72. (Pubitemid 46944984)
97. Wilgus TA, Vodovotz Y, Vittadini E, Clubbs EA, Oberyszyn TM., Reduction of scar formation in full-thickness wounds with topical celecoxib treatment. Wound Repair Regen 2003; 11: 25-34. (Pubitemid 36268606)
98. Muscara MN, McKnight W, Asfaha S, Wallace JL., Wound collagen deposition in rats: effects of an NO-NSAID and a selective COX-2 inhibitor. Br J Pharmacol 2000; 129: 681-6. (Pubitemid 30153851)
99. Wilgus TA, Bergdall VK, Tober KL, Hill KJ, Mitra S, Flavahan NA, Oberyszyn TM., The impact of cyclooxygenase-2 mediated inflammation on scarless fetal wound healing. Am J Pathol 2004; 165: 753-61. (Pubitemid 39129283)
100. Parekh A, Sandulache VC, Singh T, Cetin S, Sacks MS, Dohar JE, Hebda PA., Prostaglandin E2 differentially regulates contraction and structural reorganization of anchored collagen gels by human adult and fetal dermal fibroblasts. Wound Rep Regen 2009; 17: 88-98.
101. Wynn T., Fibrotic disease and the TH1/TH2 paradigm. Nat Rev Immunol 2004; 4: 583-94.
102. Medina A, Kilani RT, Carr N, Brown E, Ghahary A., Transdifferentiation of peripheral blood mononuclear cells into epithelial-like cells. Am J Pathol 2007; 171: 1140-52. (Pubitemid 47582889)
103. Medina A, Kilani RT, Carr N, Brown E, Ghahary A., Circulating monocytes have the capacity to be transdifferentiated into keratinocyte-like cells. Wound Rep Regen 2007; 17: 268-77.
104. Medina A, Ghahary A., Transdifferentiated circulating monocytes release exosomes containing 14-3-3 proteins with matrix metalloproteinase-1 stimulating effect for dermal fibroblasts. Wound Rep Regen 2010; 18: 245-53.
105. Zhang Z, Li XJ, Liu Y, Zhang X, Li YY, Xu WS., Recombinant human decorin inhibits cell proliferation and downregulates TGF-beta1 production in hypertrophic scar fibroblasts. Burns 2007; 33: 634-41. (Pubitemid 46880036)
106. Puig A, Antõn JM, Mangues M., A new decorin-like tetrapeptide for optimal organization of collagen fibres. Int J Cosmet Sci 2008; 30: 97-104. (Pubitemid 351392883)
107. Wess TJ., Collagen fibril form and function. Adv Protein Chem 2005; 70: 341-74. (Pubitemid 40544787)
108. Liu X, Wu H, Byrne M, Krane S, Jaenisch R., Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proc Natl Acad Sci USA 1997; 94: 1852-6. (Pubitemid 27113925)
109. Hayakawa T, Hashimoto Y, Myokei Y, Aoyama H, Izawa Y., Changes in type of collagen during the development of human post-burn hypertrophic scars. Clin Chim Acta 1979; 93: 119-25.
110. Zhang K, Garner W, Cohen L, Rodriguez J, Phan S., Increased types I and III collagen and transforming growth factor-beta 1mRNA and protein in hypertrophic burn scar. J Invest Dermatol 1995; 104: 750-4.
111. Eyre DR, Koob TJ, Van Ness KP., Quantitation of hydroxypyridinium crosslinks in collagen by high-performance liquid chromatography. Anal Biochem 1984; 137: 380-8. (Pubitemid 14127584)
112. Romanic AM, Adachi E, Hojima Y, Engel J, Prockop DJ., Polymerization of pNcollagen I and copolymerization of pNcollagen I with collagen. I. A kinetic, thermodynamic, and morphologic study. J Biol Chem 1992; 267: 22265-71.
113. van der Slot-Verhoeven AJ, van Dura EA, Attema J, Blauw B, DeGroot J, Huizinga TW, Zuurmond AM, Bank RA., The type of collagen cross-link determines the reversibility of experimental skin fibrosis. Biochim Biophys Acta 2005; 1740: 60-7. (Pubitemid 40692699)
114. Wan KC, Chan HP, Hung LK, Wu HT., Effects of antioxidants on pyridinoline cross-link formation in culture supernatants of fibroblasts from normal skin and hypertrophic scars. Clin Exp Dermatol 2002; 27: 507-12. (Pubitemid 35278946)
115. Moriguchi T, Fujimoto D., Crosslink of collagen in hypertrophic scar. J Invest Dermatol 1979; 72: 143-9.
116. Eyre DR, Paz MA, Gallop PM., Cross-linking in collagen and elastin. Ann Rev Biochem 1984; 53: 717-48. (Pubitemid 14059149)
117. Castagnoli C, Trombotto C, Ondei S, Stella M, Calcagni M, Magliacani G, Alasia ST., Characterization of T-cell subsets infiltrating post-burn hypertrophic scar tissues. Burns 1997; 23: 565-72. (Pubitemid 28142378)
118. Rosen GM, Pou S, Ramos CL, Cohen MS, Britigan BE., Free radicals and phagocytic cells. FASEB J 1995; 9: 200-9.
119. Widgerow AD, Chait LA, Stals R, Stals P., New innovations in scar management. Aesthet Plast Surg 2000; 24: 227.
120. Widgerow AD, Chait LAC, Stals R, Stals P, Candy G., Multimodality scar management program. Aesthet Plast Surg 2009; 33: 4-533-43.
121. Reiffel RS., Prevention of hypertrophic scars by long term paper tape application. Plast Reconstr Surg 1995; 96: 1715-8.
122. Atkinson JA, McKenna KT, Barnett AG, McGrath DJ, Rudd M., A randomized controlled trial to determine the efficacy of paper tape in preventing hypertrophic scar formation in surgical excisions that travers langers skin tension lines. Plast Reconstr Surg 2005; 116: 1648-56. (Pubitemid 41608332)
123. Xiao Z, Zhang F, Lin W, Zhang M, Liu Y., Effect of botulinum toxin type A on transforming growth factor β 1 in fibroblasts derived from hypertrophic scar: a preliminary report. Aesthet Plast Surg 2010; 34: 428-9.
124. Chan KY, Lau CL, Adeeb SM, Somasundaram S, Nasir-Zahari M., A randomized, placebo-controlled, double-blind, pro-spective clinical trial of silicone gel in prevention of hypertrophic scar development in median sternotomy wound. Plast Reconstr Surg 2005; 116: 1013-20. (Pubitemid 41324918)
125. Gold MH, Foster TD, Adair MA, Burlison K, Lewis T., Prophylactic use of topical silicone gel sheets following a surgical procedure in an office setting. Dermatol Surg 2001; 27: 641-4.
126. Niessen FB, Spauwen PH, Robinson PH, Fidler V, Kon M., The use of silicone occlusive sheeting (Sil-K) and silicone occlusive gel (Epiderm) in the prevention of hypertrophic scar formation. Plast Reconstr Surg 1998; 102: 1962-72. (Pubitemid 28518520)
127. Momeni M, Hafezi F, Rahbar H, Karimi H., Effects of silicone gel on burn scars. Burns 2009; 35: 70-4.
128. Draelos ZD., The ability of onion extract gel to improve the cosmetic appearance of postsurgical scars. J Cosmet Dermatol 2008; 7: 101-4. (Pubitemid 351676528)
129. Jackson BA, Shelton AJ., Pilot study evaluating topical onion extract as treatment for postsurgical scars. Dermatol Surg 1999; 25: 267-9. (Pubitemid 29191310)
130. Saulis AS, Mogford JH, Mustoe TA., Effect of Mederma on hypertrophic scarring in the rabbit ear model. Plast Reconstr Surg 2002; 110: 177-83. (Pubitemid 34686266)
131. Lee T, Chin G, Kim W, Chau D, Gittes G, Longaker M., Expression of transforming growth factor beta 1, 2 and 3 proteins in keloids. Ann Plast Surg 1999; 43: 179-84. (Pubitemid 29380019)
132. Bush J,. A double-blind, placebo-controlled, randomised dose ranging trial to investigate the efficacy of two different dosing regimens of avotermin (juvista) in the improvement of scar appearance when applied to approximated wound margins in healthy volunteers. ClinicalTrials.govIdentifierNCT00629811. ClinicalTrials.gov. Available at (accessed August 1, 2010).
133. Capon A, Iarmarcovai G, Gonnelli D, Degardin N, Magalon G, Mordon S., Scar prevention using laser-assisted skin healing (LASH) in plastic surgery. Aesthet Plast Surg 2010; 34: 438-46.
134. Zhang Z, Qin DL, Wan JY, Zhou QX, Xiao SH, Wu K., Effects of asiaticoside on the balance of inflammatory factors of mouse's acute lung injury induced by LPS (article in Chinese). Zhong Yao Cai 2008; 31: 547-9.
135. Shukla A, Rasik AM, Dhawan BN., Asiaticoside-induced elevation of antioxidant levels in healing wounds. Phytother Res 1999; 13: 50-4. (Pubitemid 29092498)
136. Hong SS, Kim JH, Li H, Shim CK., Advanced formulation and pharmacological activity of hydrogel of the titrated extract of C. asiatica. Arch Pharm Res 2005; 28: 502-8. (Pubitemid 43073661)
137. Brinkhaus B, Lindner M, Schuppan D, Hahn EG., Chemical, pharmacological and clinical profile of the East Asian medical plant Centella asiatica. Phytomedicine 2000; 7: 427-48.
138. Shetty BS, Udupa SL, Udupa AL, Somayaji SN., Effect of Centella asiatica (Umbelliferae) on normal and dexamethasone-suppressed wound healing in Wistar Albino rats. Int J Low Extrem Wounds 2006; 5: 137-43. (Pubitemid 44215094)
139. Zhang T, Rong XZ, Yang RH, Li TZ, Xu YB., Effect of asiaticoside on the expression of transforming growth factor-beta mRNA and matrix metalloproteinases in hypertrophic scars (article in Chinese). Nan Fang Yi Ke Da Xue Xue Bao 2006; 26: 67-70.
140. Maquart FX, Bellon G, Gillery P, Wegrowski Y, Borel JP., Stimulation of collagen synthesis in fibroblast cultures by a triterpene extracted from Centella asiatica. Connect Tissue Res 1990; 24: 107-20.
141. Bonte F, Dumas M, Chaudagne C, Meybeck A., Influence of asiatic acid, madecassic acid, and asiaticoside on human collagen I synthesis. Planta Med 1994; 60: 133-5. (Pubitemid 24120896)
142. Lu L, Ying K, Wei S, Fang Y, Liu Y, Lin H, Ma L, Mao Y., Asiaticoside induction for cell-cycle progression, proliferation and collagen synthesis in human dermal fibroblasts. Int J Dermatol 2004; 43: 801-7. (Pubitemid 39529937)
143. Atiyeh BS., Nonsurgical management of hypertrophic scars: evidence-based therapies, standard practices, and emerging methods. Aesth Plast Surg 2007; 31: 468-92. (Pubitemid 47437506)
144. Kimura Y, Sumiyoshi M, Samukawa K, Satake N, Sakanaka M., Facilitating action of asiaticoside at low doses on burn wound repair and its mechanism. Eur J Pharmacol 2008; 584: 415-23.
145. Ullah MO, Sultana S, Haque A, Tasmin S., Antimicrobial, cytotoxic and antioxidant activity of Centella asiatica. Eur J Sci Res 2009; 30: 260-4.
146. Qi SH, Xie J-L, Pan S, Xu Y-B, Li T-Z, Tang J-M, Liu X-S, Shu B, Liu P., Effects of asiaticoside on the expression of Smad protein by normal skin fibroblasts and hypertrophic scar fibroblasts. Clin Exp Dermatol 2007; 33: 171-5.
147. Lee J, Jung E, Kim Y, Park J, Park J, Hong S, Kim J, Hyun C, Kim YS, Park D., Asiaticoside induces human collagen I synthesis through TG Fbeta receptor I kinase (TbetaRI kinase)-independent Smad signaling. Planta Med 2006; 72: 324-8.
148. Bush J, So K, Mason T, Occleston NO, O'Kane S, Ferguson MWJ,. Therapies with emerging evidence of efficacy: avotermin for the improvement of scarring. Dermatology Research and Practice 2010; 11: 1-6.
149. Bush J., Investigation into the scar reduction potential of prevascar (interleukin-10). ClinicalTrials.gov Identifier NCT00984646. ClinicalTrials.gov. Available at (accessed August 1, 2010).
150. Choi BM, Kwak HJ, Jun CD, Park SD, Kim KY, Kim HR, Chung HT., Control of scarring in adult wounds using antisense transforming growth factor-beta 1 oligodeoxynucleotides. Immunol Cell Biol 1996; 74: 144-50.
151. Huang JS, Wang YH, Ling TY, Chuang SS, Johnson FE, Huang SS., Synthetic TGF-beta antagonist accelerates wound healing and reduces scarring. FASEB J 2002; 16: 1269-70.
152. Bush JA., Double blind, placebo controlled trial to investigate the efficacy and safety of two concentrations of juvidex (mannose-6-phosphate) in accelerating the healing of split thickness skin graft donor sites using different dosing regimes. ClinicalTrials.gov Identifier: NCT00664352. Clinical trials.gov. Available at (accessed August 1, 2010).
153. Bates SJ, Morrow E, Zhang AW, Pham H, Longaker MT, Chang J., Mannose-6-phosphate, an inhibitor of transforming growth factor-β, improves range of motion after flexor tendon repair. J Bone Joint Surg Am 2006; 88: 2465-72. (Pubitemid 44713835)
154. Tiede S, Ernst N, Bayat A, Paus R, Tronnier V, Zechel C., Basic fibroblast growth factor: a potential new therapeutic tool for the treatment of hypertrophic and keloid scars. Ann Anat 2009; 191: 33-44.
155. Xie JL, Bian HN, Qi SH, De Chen H, Dong Li H, Bin Y, Li TZ, Liu ZS, Liang HZ, Xin BR, Huan Y., Basic fibroblast growth factor (bFGF) alleviates the scar of the rabbit ear model in wound healing. Wound Repair Regen 2008; 16: 576-81. (Pubitemid 352000323)
156. Ono I, Akasaka Y, Kikuchi R, Sakemoto A, Kamiya T, Yamashita T, Jimbow K., Basic fibroblast growth factor reduces scar formation in acute incisional wounds. Wound Repair Regen 2007; 15: 617-23. (Pubitemid 47493894)
157. Ono I, Yamashita T, Hida JTH, Ito Y, Hamada H, Akasaka Y, Ishii T, Jimbow K., Local administration of hepatocyte growth factor gene enhances the regeneration of dermis in acute incisional wounds. J Surg Res 2004; 120: 47-55. (Pubitemid 38686529)
158. Matsumoto K, Nakamura T., Emerging multipotent aspects of hepatocyte growth factor. J Biochem 1996; 119: 591-600. (Pubitemid 26131762)
159. Aoki M, Morishita R, Taniyama Y, Kidfa I, Moriguchi A, Matsumoto K, Nakamura T, Kaneda Y, Higashi J, Ogihara T., Angiogenesis induced by hepatocyte growth factor in non-regulation of essential transcription factor for angiogenesis, ets. Gene Ther 2000; 7: 417-27. (Pubitemid 30156554)
160. Qiu C, Coutinho P, Frank S, Franke S, Law LY, Martin P, Green CR., Becker DL targeting connexin43 expression accelerates the rate of wound repair. Curr Biol 2003; 13: 1697-703. (Pubitemid 37216247)
161. Coutinho P., Qiu C., Frank S., Wang CM., Brown T., Green CR., Becker DL.,
162. Abdollahi A, Li M, Ping G, Plathow C, Domhan S, Kiessling F, Lee L, McMahon G, Grone H, Lipson K, Huber P., Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J Exp Med 2005; 201: 925-35. (Pubitemid 40524462)
163. Mori R, Power KT, Wang CM, Martin P, Becker DL., Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response, enhanced keratinocyte proliferation and wound fibroblast migration. J Cell Sci 2006; 119: 5193-203. (Pubitemid 46085197)
164. Yun K-J, Kima J-Y, Kima J-B, Lee K-W, Jeong S-Y, Park H-J, Jung H-J, Cho Y-W, Yun K, Lee K., Inhibition of LPS-induced NO and PGE2 production by asiatic acid via NF-ÎB inactivation in RAW 264.7 macrophages: possible involvement of the IKK and MAPK pathways. Int Immunopharmacol 2008; 8: 431-41. (Pubitemid 351227435)
165. Procopio A, Alcaro S, Nardi M, Oliverio M, Ortuso F, Sacchetta P, Pieragostino D, Sindona G., Synthesis, biological evaluation, and molecular modeling of oleuropein and its semisynthetic derivatives as cyclooxygenase inhibitors. J Agric Food Chem 2009; 57: 11161-7.
166. Beauchamp GK, Keast RS, Morel D, Lin J, Pika J, Han Q, Lee CH, Smith AB, Breslin PA., Phytochemistry: ibuprofen-like activity in extra-virgin olive oil. Nature 2005; 437: 45-6. (Pubitemid 41613421)
167. de la Puerta R, Martinez-Dominguez E, Ruiz-Gutierrez V., Effect of minor components of virgin olive oil on topical anti-inflammatory assays. Z Naturforsch 2000; 55: 814-9.
168. Puel C., Olive oil and its main phenolic micronutrient (oleuropein) prevent inflammation-induced bone loss in the ovariectomised rat. Br J Nutr 2004; 92: 119-27. (Pubitemid 38961280)
169. Visioli F, Bogani P, Grande S, Galli C., Olive oil and oxidative stress. Grasas Aceites 2004; 55: 66-75. (Pubitemid 40025898)
170. Yamaguchi Y, Mann DM, Ruoslahti E., Negative regulation of transforming growth factor-beta by the proteoglycans decorin. Nature 1990; 346: 281-4.
171. Scott PG, Dodd CM, Ghahary A, Shen YJ, Tredget EE., Fibroblasts from post-burn hypertrophic scar tissue synthesize less decorin than normal dermal fibroblasts. Clin Sci 1998; 94: 541-7. (Pubitemid 28205921)
172. Chung VQ, Kelley L, Marra D, Jiang SB., Onion extract gel versus petrolatum emollient on new surgical scars: prospective double-blinded study. Dermatol Surg 2006; 32: 193-7.
173. Topol BM, Lewis VL Jr, Benveniste K., The use of antihistamine to retard the growth of fibroblasts derived from human skin, scar, and keloid. Plast Reconstr Surg 1981; 68: 227-32. (Pubitemid 11044150)
174. Venugopal J, Ramakrishnan M, Habibullah CM, Babu M., The effect of the anti-allergic agent avil on abnormal scar fibroblasts. Burns 1999; 25: 223-8. (Pubitemid 29182512)
175. Bock O, Yu H, Zitron S, Bayat A, FergusonM, Mrowietz U., Studies of transforming growth factors beta 1-3 and their receptors I and II in fibroblasts of keloid and hypertrophic scars. Acta Derm Venereol 2005; 85: 216-20. (Pubitemid 40695163)
176. Rahmani-Neishaboor E, Yau FM, Jalili R, Kilani RT, Ghahary A., Improvement of hypertrophic scarring by using topical anti-fibrogenic/anti- inflammatory factors in a rabbit ear model. Wound Repair Regen 2010; 18: 401-8.
177. Pehr K, Forsey R., Why don't we use vitamin E in dermatology? Can Med Assoc J 1993; 149: 1247-53. (Pubitemid 24007713)
178. Baumann LS, Spencer J., The effects of topical vitamin E on the cosmetic appearance of scars. Dermatol Surg 1999; 25: 311-5. (Pubitemid 29191320)
179. Jenkins M, Alexander JW, MacMillan BG, Waymack JP, Kopcha R., Failure of topical steroids and vitamin E to reduce postoperative scar formation following reconstructive surgery. J Burn Care Rehabil 1986; 7: 309-12. (Pubitemid 16010121)
180. Riaz Y, Cook HT, Wangoo A, Glenville B, Shaw RJ., Type 1 procollagen as a marker of severity of scarring after sternotomy: effects of topical corticosteroids. J Clin Pathol 1994; 47: 892-9.
181. Yamaguchi Y, Mann DM, Ruoslahti E., Negative regulation of transforming growth factor-beta by the proteoglycans decorin. Nature 1990; 346: 281-4.
182. Zhang Z, Li XJ, Liu Y, Zhang X, Li YY, Xu WS., Recombinant human decorin inhibits cell proliferation and downregulates TGF-beta1 production in hypertrophic scar fibroblasts. Burns 2007; 33: 634-41. (Pubitemid 46880036)
183. Nelson CM, Bissell MJ., Of extracellular matrix, scaffolds and signaling: tissue architecture regulates development, homeostasis and cancer. Annu Rev Cell Dev Biol 2006; 22: 287-309.
184. Schultz G., Dynamic reciprocity how cells and extracellular matrix communicate to heal wounds. Third Congress of the World Union of Wound Healing Societies, Toronto, Canada, 2008.