Authors
- Stavrou, Demetris MD
- Haik, Joseph MD
- Weissman, Oren MD
- Millet, Eran MD
- Winkler, Eyal MD
Article Content
Wound contraction plays a major role in the closure of a wound. Many theories have been proposed to interpret this process,1 but only 2 main themes are supported nowadays: the cell contraction theory2 and the cell traction theory.3 In the cell contraction theory, the protagonist is the myofibroblast, a cell with the characteristics of smooth muscle cells, that provides the contractile force from a muscle-like cellular contraction4 and derives from at least 3 kinds of mesenchymal cells: fibroblasts,5 smooth muscle cells, and pericytes.6,7 The myofibroblast contracts and holds fibrils until their position is stabilized.4 The differentiation to myofibroblasts begins with changes in the composition and mechanical property of the extracellular matrix.8 Differentiation occurs under the regulation of cytokines from inflammatory cells9 that activate quiescent fibroblasts to transform to protomyofibroblast, characterized by mature focal adhesions (FAs) and contractile stress fibers ([beta]- and [gamma]-cytoplasmic actins).10 In time, the contractile force is augmented by stress fibers and the 2- to 6-[mu]m long mature FAs11 enlarge to 8-[mu]m long supermature FAs.12 Differentiation to myofibroblast continues with the appearance of the alpha-smooth muscle actin ([alpha]-SMA) within the stress fibers, although expression of [alpha]-SMA has also been detected in low contractile areas before contraction begins.13 [alpha]-SMA is expressed in a mechanically stressed environment and with the action of transforming growth factor [beta]1 (TGF-[beta]1)14 and the ED-A splice variant of fibronectin.15 Several other factors, such as the connective tissue growth factor16 or the cell-surface protein galectin-3,17 have been found to cooperate with TGF-[beta]1 in myofibroblast differentiation, and others, such as interferon (IL)-118 or INF-[gamma], exhibit inhibitory effects on TGF-[beta]1.19 In time, a network of cell-matrix contacts is created, called the fibronexus,20 that holds the wound bed in position during contraction.21
In the cell traction theory, the protagonist is the fibroblast, which is postulated to exert uncoordinated traction forces, tangential to its surface, along with deposition and remodeling of collagen fibrils around it, which result in wound approximation.22 The contraction capacity of fibroblasts has been demonstrated in vitro,23 and it was suggested that F-actin bundles generate the force of contraction through connection with fibronectin and other extracellular matrix proteins24 under the stimuli of platelet-derived growth factor or TGF-[beta].25 In contrast to myofibroblasts, fibroblasts elongate in the direction of the contractile force.2 The traction theory supports the finding that 25% to 40% of total contraction began before myofibroblast activity was even detected.26,27
Wound contraction is a physiological process yet to be thoroughly understood. It appears that fibroblasts migrate to the wound area and generate sufficient force to initiate wound contraction, but for it to be completed, they differentiate to myofibroblasts that use muscle cell-like forces. The hypothesis that only 1 cell type is responsible for wound contraction is not reflected in recent literature; therefore, further research is needed to understand the interactions between different cell types and regulating molecules.
References
1. Van Winkle W Jr. Wound contraction. Surg Gynecol Obstet. 1967;125(1):131-142. [Context Link]
2. Gabbiani G, Ryan GB, Majne G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia. 1971;27(5):549-550. [Context Link]
3. Ehrlich HP, Rajaratnam JB. Cell locomotion forces versus cell contraction forces for collagen lattice contraction: an in vitro model of wound contraction. Tissue Cell. 1990;22(4):407-417. [Context Link]
4. Rudolph R. Contraction and the control of contraction. World J Surg. 1980;4(3):279-287. [Context Link]
5. Desmouliere A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen. 2005;13(1):7-12. [Context Link]
6. Desmouliere A, Darby IA, Gabbiani G. Normal and pathologic soft tissue remodeling: role of the myofibroblast, with special emphasis on liver and kidney fibrosis. Lab Invest. 2003;83(12):1689-1707. [Context Link]
7. Rajkumar VS, Howell K, Csiszar K, Denton CP, Black CM, Abraham DJ. Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis. Arthritis Res Ther. 2005;7(5):R1113-R1123. [Context Link]
8. Hinz B, Gabbiani G. Mechanisms of force generation and transmission by myofibroblasts. Curr Opin Biotechnol. 2003;14(5):538-546. [Context Link]
9. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003;83(3):835-870. [Context Link]
10. 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(5):349-363. [Context Link]
11. Geiger B, Bershadsky A, Pankov R, Yamada KM. Transmembrane crosstalk between the extracellular matrix-cytoskeleton crosstalk. Nat Rev Mol Cell Biol. 2001;2(11):793-805. [Context Link]
12. Dugina V, Fontao L, Chaponnier C, Vasiliev J, Gabbiani G. Focal adhesion features during myofibroblastic differentiation are controlled by intracellular and extracellular factors. J Cell Sci. 2001;114(pt 18):3285-3296. [Context Link]
13. Majno G, Gabbiani G, Hirschel BJ, Ryan GB, Statkov PR. Contraction of granulation tissue in vitro: similarity to smooth muscle. Science. 1971;173(996):548-550. [Context Link]
14. Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993;122(1):103-111. [Context Link]
15. Serini G, Bochaton-Piallat ML, Ropraz P, et al. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J Cell Biol. 1998;142(3):873-881. [Context Link]
16. Leask A, Holmes A, Abraham DJ. Connective tissue growth factor: a new and important player in the pathogenesis of fibrosis. Curr Rheumatol Rep. 2002;4(2):136-142. [Context Link]
17. Henderson NC, Mackinnon AC, Farnworth SL, et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc Natl Acad Sci U S A. 2006;103(13):5060-5065. [Context Link]
18. Shephard P, Martin G, Smola-Hess S, Brunner G, Krieg T, Smola H. 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. 2004;164(6):2055-2066. [Context Link]
19. Higashi K, Inagaki Y, Fujimori K, Nakao A, Kaneko H, Nakatsuka I. Interferon-gamma interferes with transforming growth factor-beta signaling through direct interaction of YB-1 with Smad3. J Biol Chem. 2003;278(44):43470-43479. [Context Link]
20. Singer II, Kawka DW, Kazazis DM, Clark RA. In vivo co-distribution of fibronectin and actin fibers in granulation tissue: immunofluorescence and electron microscope studies of the fibronexus at the myofibroblast surface. J Cell Biol. 1984;98(6):2091-2106. [Context Link]
21. Rudolph R, Guber S, Suzuki M, Woodward M. The life cycle of the myofibroblast. Surg Gynecol Obstet. 1977;145(3):389-394. [Context Link]
22. Stopak D, Harris AK. Connective tissue morphogenesis by fibroblast traction, I: tissue culture observations. Dev Biol. 1982;90(2):383-398. [Context Link]
23. Ehrlich HP. Wound closure: evidence of cooperation between fibroblasts and collagen matrix. Eye. 1988;2(pt 2):149-157. [Context Link]
24. Postlethwaite AE, Keski-Oja J, Moses HL, Kang AH. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J Exp Med. 1987;165(1):251-256. [Context Link]
25. Sporn MB, Roberts AB, Wakefield LM, de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol. 1987;105(3):1039-1045. [Context Link]
26. McGrath MH, Hundahl SA. The spatial and temporal quantification of myofibroblasts. Plast Reconstr Surg. 1982;69(6):975-985. [Context Link]
27. Darby I, Skalli O, Gabbiani G. Alpha-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Invest. 1990;63(1):21-29. [Context Link]