[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Myofibroblasts and mechano-regulation of connective tissue remodelling

Nature Reviews Molecular Cell Biology volume 3, pages 349–363 (2002)Cite this article

Key Points

  • Myofibroblasts are the predominant cell type that are present in granulation tissue of contracting wounds and fibrocontractive diseases, and are also present in some developing or normal adult tissues.

  • The putative function of myofibroblasts is generating force and altering tissue tension.

  • Myofibroblasts were initially characterized by the presence of microfilament bundles (stress fibres) that are not present in tissue fibroblasts.

  • Two types of myofibroblasts can be characterized: proto-myofibroblasts, which contain stress fibres but lack α-smooth muscle (SM) actin, and differentiated myofibroblasts, which contain both stress fibres and α-SM actin.

  • The formation and maintenance of the proto-myofibroblast is dependent on isometric tension applied onto a non-compliant substratum.

    The expression of α-SM actin that is characteristic of the differentiated myofibroblast is dependent on interaction of ED-A fibronectin with the cell surface and transforming growth factor β1 (TGF-β1).

  • Myofibroblasts in granulation tissue and in in vitro contraction assays generate contractile force in response to certain SM agonists (such as endothelin).

  • Increased expression of α-SM actin is directly correlated with increased force generation by myofibroblasts.

  • We postulate a positive feedback loop in which tension facilitates TGF-β1 production and/or activation and α-SM actin expression. This, in turn, increases force production and tension development.

  • Myofibroblast contraction is regulated by the level of myosin light chain phosphorylation and the key regulatory step seems to be activation of the Rho–Rho-kinase pathway, which results in the inhibition of myosin light chain phosphatase and increased myosin light chain phosphorylation and contraction.

  • Tissue contraction (contracture) depends on collagen remodelling, a process that is dominated by extracellular-matrix reorganization under the mechanical control of myofibroblast contraction.

Abstract

During the past 20 years, it has become generally accepted that the modulation of fibroblastic cells towards the myofibroblastic phenotype, with acquisition of specialized contractile features, is essential for connective-tissue remodelling during normal and pathological wound healing. Yet the myofibroblast still remains one of the most enigmatic of cells, not least owing to its transient appearance in association with connective-tissue injury and to the difficulties in establishing its role in the production of tissue contracture. It is clear that our understanding of the myofibroblast — its origins, functions and molecular regulation — will have a profound influence on the future effectiveness not only of tissue engineering but also of regenerative medicine generally.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Myofibroblasts in epiretinal membrane.
Figure 2: The two-stage model of myofibroblast differentiation.
Figure 3: Three-dimensional collagen-lattice model.
Figure 4: Mechanical tension induces myofibroblast differentiation in wound granulation tissue.
Figure 5: α-smooth muscle (SM) actin expression correlates with wrinkling on silicone substrates.
Figure 6: Scar contracture across the wrist following a burn injury.
Figure 7: Model of extracellular-matrix-remodelling phase of matrix contracture.
Figure 8: Contracture in three-dimensional collagen lattices.
Figure 9: Model of the role of myofibroblasts during the healing of an open wound.

Similar content being viewed by others

References

  1. Brown, R. A., Prajapati, R., McGrouther, D. A., Yannas, I. V. & Eastwood, M. Tensional homeostasis in dermal fibroblasts: mechanical responses to mechanical loading in three-dimensional substrates. J. Cell Physiol. 175, 323–332 (1998).Describes the first evidence that fibroblasts respond cytomechanically to externally applied mechanical loads that maintain a set level of pre-stress in their matrix, which is termed tensional homeostasis.

    Article  CAS  PubMed  Google Scholar 

  2. Muellner, T. et al. Light and electron microscopic study of stress-shielding effects on rat patellar tendon. Arch. Orthop. Trauma Surg. 121, 561–565 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Brown, R. A. in Future Strategies for Tissue and Organ Replacement (eds Polak, J. M., Hench, L. L. & Kemp, P.) 51–78 (World Scientific Publishing, Singapore, 2002).

    Book  Google Scholar 

  4. Eastwood, M., Mudera, V. C., McGrouther, D. A. & Brown, R. A. Effect of precise mechanical loading on fibroblast populated collagen lattices: morphological changes. Cell Motil. Cytoskeleton 40, 13–21 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Serini, G. & Gabbiani, G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp. Cell Res. 250, 273–283 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Powell, D. W. et al. Myofibroblasts. I. Paracrine cells important in health and disease. Am. J. Physiol. 277, C1–C9 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Grinnell, F. Fibroblast-collagen-matrix contraction: growth-factor signalling and mechanical loading. Trends Cell Biol. 10, 362–365 (2000).Describes fibroblast collagen matrix-contraction models and recent evidence that indicates that the state of cellular mechanical loading determines the mechanism that cells use to regulate contraction.

    Article  CAS  PubMed  Google Scholar 

  8. Carrel, A. & Hartmann, A. Cicatrization of wounds. I. The relation between the size and the rate of its cicatrization. J. Exp. Med. 24, 429–450 (1916).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Payling Wright, G. An Introduction to Pathology 2nd Edition (Longmans Green and Co., London, 1954).

    Google Scholar 

  10. Abercrombie, M., Flint, M. H. & James, D. W. Wound contraction in relation to collagen formation in scorbutic guinea pigs. J. Embryol. Exp. Morph. 4, 167 (1956).

    Google Scholar 

  11. Gabbiani, G., Ryan, G. B. & Majno, G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 27, 549–550 (1971).

    Article  CAS  PubMed  Google Scholar 

  12. Walker, G. A., Guerrero, I. A. & Leinwand, L. A. Myofibroblasts: molecular crossdressers. Curr. Top. Dev. Biol. 51, 91–107 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Darby, I., Skalli, O. & Gabbiani, G. α-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab. Invest. 63, 21–29 (1990).

    CAS  PubMed  Google Scholar 

  14. Skalli, O. et al. A monoclonal antibody against α-smooth muscle actin: a new probe for smooth muscle differentiation. J. Cell Biol. 103, 2787–2796 (1986).The specific antibody for α-SM actin shows that this protein is expressed temporarily in granulation-tissue fibroblasts.

    Article  CAS  PubMed  Google Scholar 

  15. Desmouliere, A., Geinoz, A., Gabbiani, F. & Gabbiani, G. Transforming growth factor-β1 induces α-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Cell Biol. 122, 103–111 (1993).The first demonstration that TGF-β1 is involved in the induction of α-SM actin in normal fibroblasts and myofibroblasts.

    Article  CAS  PubMed  Google Scholar 

  16. Burridge, K. & Chrzanowska-Wodnicka, M. Focal adhesions, contractility, and signaling. Annu. Rev. Cell Dev. Biol. 12, 463–518 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Kreis, T. E. & Birchmeier, W. Stress fiber sarcomeres of fibroblasts are contractile. Cell 22, 555–561 (1980).

    Article  CAS  PubMed  Google Scholar 

  18. 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. 114, 3285–3296 (2001).Demonstration that focal adhesion size and composition are modulated by intracellular and extracellular factors that regulate the myofibroblast phenotype.

    Article  CAS  PubMed  Google Scholar 

  19. Singer, I. I., Kawka, D. W., Kazazis, D. M. & Clark, R. A. 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. 98, 2091–2106 (1984).

    Article  CAS  PubMed  Google Scholar 

  20. Chicurel, M. E., Chen, C. S. & Ingber, D. E. Cellular control lies in the balance of forces. Curr. Opin. Cell Biol. 10, 232–239 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Geiger, B. & Bershadsky, A. Assembly and mechanosensory function of focal contacts. Curr. Opin. Cell Biol. 13, 584–592 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Gabbiani, G., Chaponnier, C. & Huttner, I. Cytoplasmic filaments and gap junctions in epithelial cells and myofibroblasts during wound healing. J. Cell Biol. 76, 561–568 (1978).

    Article  CAS  PubMed  Google Scholar 

  23. Spanakis, S. G., Petridou, S. & Masur, S. K. Functional gap junctions in corneal fibroblasts and myofibroblasts. Invest. Ophthalmol. Vis. Sci. 39, 1320–1328 (1998).

    CAS  PubMed  Google Scholar 

  24. Jamieson, S., Going, J. J., D'Arcy, R. & George, W. D. Expression of gap junction proteins connexin 26 and connexin 43 in normal human breast and in breast tumours. J. Pathol. 184, 37–43 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Harris, A. K., Stopak, D. & Wild, P. Fibroblast traction as a mechanism for collagen morphogenesis. Nature 290, 249–251 (1981).

    Article  CAS  PubMed  Google Scholar 

  26. Grinnell, F. Fibroblasts, myofibroblasts, and wound contraction. J. Cell Biol. 124, 401–404 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Bell, E., Ivarsson, B. & Merrill, C. Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc. Natl Acad. Sci. USA 76, 1274–1278 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ehrlich, H. P. & Rajaratnam, J. B. Cell locomotion forces versus cell contraction forces for collagen lattice contraction: an in vitro model of wound contraction. Tissue Cell 22, 407–417 (1990).

    Article  CAS  PubMed  Google Scholar 

  29. Hinz, B., Mastrangelo, D., Iselin, C. E., Chaponnier, C. & Gabbiani, G. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am. J. Pathol. 159, 1009–1020 (2001).This paper showed that the myofibroblastic phenotype is regulated by mechanical tension in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gross, J., Farinelli, W., Sadow, P., Anderson, R. & Bruns, R. On the mechanism of skin wound 'contraction': a granulation tissue 'knockout' with a normal phenotype. Proc. Natl Acad. Sci. USA 92, 5982–5986 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Berry, D. P., Harding, K. G., Stanton, M. R., Jasani, B. & Ehrlich, H. P. Human wound contraction: collagen organization, fibroblasts, and myofibroblasts. Plast. Reconstr. Surg. 102, 124–131 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Kapanci, Y., Ribaux, C., Chaponnier, C. & Gabbiani, G. Cytoskeletal features of alveolar myofibroblasts and pericytes in normal human and rat lung. J. Histochem. Cytochem. 40, 1955–1963 (1992).

    Article  CAS  PubMed  Google Scholar 

  33. Lindahl, P. & Betsholtz, C. Not all myofibroblasts are alike: revisiting the role of PDGF-A and PDGF-B using PDGF-targeted mice. Curr. Opin. Nephrol. Hypertens. 7, 21–26 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Martin, P. Wound healing — aiming for perfect skin regeneration. Science 276, 75–81 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Lindahl, P., Johansson, B. R., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Bostrom, H. et al. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 85, 863–873 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Desmouliere, A., Rubbia-Brandt, L., Grau, G. & Gabbiani, G. Heparin induces α-smooth muscle actin expression in cultured fibroblasts and in granulation tissue myofibroblasts. Lab. Invest. 67, 716–726 (1992).

    CAS  PubMed  Google Scholar 

  38. Rubbia-Brandt, L., Sappino, A. P. & Gabbiani, G. Locally applied GM-CSF induces the accumulation of α-smooth muscle actin containing myofibroblasts. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 60, 73–82 (1991).

    Article  CAS  PubMed  Google Scholar 

  39. Ffrench-Constant, C., Van de Water, L., Dvorak, H. F. & Hynes, R. O. Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat. J. Cell Biol. 109, 903–914 (1989).

    Article  CAS  PubMed  Google Scholar 

  40. Serini, G. et al. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor- β1. J. Cell Biol. 142, 873–881 (1998).Shows that the ED-A domain of cellular fibronectin is required for α-SM actin stimulating activity of TGF-β1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Burridge, K. Are stress fibres contractile? Nature 294, 691–692 (1981).

    Article  CAS  PubMed  Google Scholar 

  42. Pelham, R. J. Jr & Wang, Y. Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl Acad. Sci. USA 94, 13661–13665 (1997).This paper shows the ability of cells to survey the mechanical properties of their surrounding environment, and the effect this has on focal adhesion formation. This indicates the possible involvement of both protein tyrosine phosphorylation and myosin-generated cortical forces in this process.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tomasek, J. J., Haaksma, C. J., Eddy, R. J. & Vaughan, M. B. Fibroblast contraction occurs on release of tension in attached collagen lattices: dependency on an organized actin cytoskeleton and serum. Anat. Rec. 232, 359–368 (1992).Shows that fibroblasts in stressed collagen lattices acquire the myofibroblast phenotype and that these cells can generate contractile force, which results in rapid contraction of the collagen lattices.

    Article  CAS  PubMed  Google Scholar 

  44. Elsdale, T. & Bard, J. Collagen substrata for studies on cell behavior. J. Cell Biol. 54, 626–637 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mochitate, K., Pawelek, P. & Grinnell, F. Stress relaxation of contracted collagen gels: disruption of actin filament bundles, release of cell surface fibronectin, and down-regulation of DNA and protein synthesis. Exp. Cell Res. 193, 198–207 (1991).

    Article  CAS  PubMed  Google Scholar 

  46. Halliday, N. L. & Tomasek, J. J. Mechanical properties of the extracellular matrix influence fibronectin fibril assembly in vitro. Exp. Cell Res. 217, 109–117 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. Porter, R. A., Brown, R. A., Eastwood, M., Occleston, N. L. & Khaw, P. T. Ultrastructural changes during contraction of collagen lattices by ocular fibroblasts. Wound Repair Regen. 6, 157–166 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Tomasek, J. J. et al. Gelatinase A activation is regulated by the organization of the polymerized actin cytoskeleton. J. Biol. Chem. 272, 7482–7487 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Kasugai, S. et al. Measurements of the isometric contractile forces generated by dog periodontal ligament fibroblasts in vitro. Arch. Oral Biol. 35, 597–601 (1990).

    Article  CAS  PubMed  Google Scholar 

  50. Delvoye, P., Wiliquet, P., Leveque, J. L., Nusgens, B. V. & Lapiere, C. M. Measurement of mechanical forces generated by skin fibroblasts embedded in a three-dimensional collagen gel. J. Invest. Dermatol. 97, 898–902 (1991).

    Article  CAS  PubMed  Google Scholar 

  51. Kolodney, M. S. & Wysolmerski, R. B. Isometric contraction by fibroblasts and endothelial cells in tissue culture: a quantitative study. J. Cell Biol. 117, 73–82 (1992).

    Article  CAS  PubMed  Google Scholar 

  52. Eastwood, M., McGrouther, D. A. & Brown, R. A. A culture force monitor for measurement of contraction forces generated in human dermal fibroblast cultures: evidence for cell-matrix mechanical signalling. Biochim. Biophys. Acta 1201, 186–192 (1994).

    Article  CAS  PubMed  Google Scholar 

  53. Chrzanowska-Wodnicka, M. & Burridge, K. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J. Cell Biol. 133, 1403–1415 (1996).Shows that activated Rho stimulates contractility, drives the formation of stress fibres and focal adhesions, and elevates tyrosine phosphorylation.

    Article  CAS  PubMed  Google Scholar 

  54. Vaughan, M. B., Howard, E. W. & Tomasek, J. J. Transforming growth factor-β1 promotes the morphological and functional differentiation of the myofibroblast. Exp. Cell Res. 257, 180–189 (2000).Shows that TGF-β1 will promote the formation of stress fibres, focal adhesions and fibronectin fibrils by fibroblasts that are cultured in stressed collagen lattices, and that this correlates with increased generation of contractile force.

    Article  CAS  PubMed  Google Scholar 

  55. Ronnov-Jessen, L. & Petersen, O. W. Induction of α-smooth muscle actin by transforming growth factor-β1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab. Invest. 68, 696–707 (1993).

    CAS  PubMed  Google Scholar 

  56. Roberts, A. B. & Sporn, M. B. in The Molecular and Cellular Biology of Wound Repair (ed. Clark, R. A. F.) 275–308 (Plenum Press, New York, 1996).

    Google Scholar 

  57. O'Kane, S. & Ferguson, M. W. Transforming growth factor-βs and wound healing. Int. J. Biochem. Cell Biol. 29, 63–78 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Massague, J. The transforming growth factor-β family. Annu. Rev. Cell Biol. 6, 597–641 (1990).

    Article  CAS  PubMed  Google Scholar 

  59. Border, W. A. & Noble, N. A. Transforming growth factorβ in tissue fibrosis. N. Engl. J. Med. 331, 1286–1292 (1994).

    Article  CAS  PubMed  Google Scholar 

  60. Schmid, P., Itin, P., Cherry, G., Bi, C. & Cox, D. A. Enhanced expression of transforming growth factor-β type I and type II receptors in wound granulation tissue and hypertrophic scar. Am. J. Pathol. 152, 485–493 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kim, S. J. et al. Autoinduction of transforming growth factor β1 is mediated by the AP-1 complex. Mol. Cell. Biol. 10,1492–1497 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Yang, L. et al. Healing of burn wounds in transgenic mice overexpressing transforming growth factor-β1 in the epidermis. Am. J. Pathol. 159, 2147–2157 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Roberts, A. B. et al. Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl Acad. Sci. USA 83, 4167–4171 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lund, L. R. et al. Transforming growth factor-β is a strong and fast acting positive regulator of the level of type-1 plasminogen activator inhibitor mRNA in WI-38 human lung fibroblasts. EMBO J. 6, 1281–1286 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Borsi, L., Castellani, P., Risso, A. M., Leprini, A. & Zardi, L. Transforming growth factor-β regulates the splicing pattern of fibronectin messenger RNA precursor. FEBS Lett. 261, 175–178 (1990).

    Article  CAS  PubMed  Google Scholar 

  66. Miyazono, K., Ichijo, H. & Heldin, C. H. Transforming growth factor-β: latent forms, binding proteins and receptors. Growth Factors 8, 11–22 (1993).

    Article  CAS  PubMed  Google Scholar 

  67. Khalil, N. TGF-β: from latent to active. Microbes Infect. 1, 1255–1263 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Massague, J. & Wotton, D. Transcriptional control by the TGF-β/Smad signaling system. EMBO J. 19, 1745–1754 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Heldin, C. H., Miyazono, K. & ten Dijke, P. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465–471 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Schnabl, B. et al. The role of Smad3 in mediating mouse hepatic stellate cell activation. Hepatology 34, 89–100 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Tomasek, J. J., Flanders, K. C. & Haaksma, C. J. Smad3 signaling is not required for TGF-β1 promoted myofibroblast differentiation. Wound Repair Regen. (in the press).

  72. Hautmann, M. B., Madsen, C. S. & Owens, G. K. A transforming growth factor β (TGFβ) control element drives TGFβ-induced stimulation of smooth muscle α-actin gene expression in concert with two CArG elements. J. Biol. Chem. 272, 10948–10956 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Roy, S. G., Nozaki, Y. & Phan, S. H. Regulation of α-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts. Int. J. Biochem. Cell Biol. 33, 723–734 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Sullivan, K. M., Lorenz, H. P., Meuli, M., Lin, R. Y. & Adzick, N. S. A model of scarless human fetal wound repair is deficient in transforming growth factor β. J. Pediatr. Surg. 30, 198–202 (1995).

    Article  CAS  PubMed  Google Scholar 

  75. Mack, C. P. & Owens, G. K. Regulation of smooth muscle α-actin expression in vivo is dependent on CArG elements within the 5′ and first intron promoter regions. Circ. Res. 84, 852–861 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Swartz, E. A., Johnson, A. D. & Owens, G. K. Two MCAT elements of the SM α-actin promoter function differentially in SM versus non-SM cells. Am. J. Physiol. 275, C608–C618 (1998).

  77. Schurch, W., Skalli, O. & Gabbiani, G. in Dupuytren's Disease (eds McFarlane, R., McGrouther, D. A. & Flint, M. H.) 31–47 (Churchill Livingston, Edinburgh, 1990).

    Google Scholar 

  78. Van der Loop, F. T., Gabbiani, G., Kohnen, G., Ramaekers, F. C. & van Eys, G. J. Differentiation of smooth muscle cells in human blood vessels as defined by smoothelin, a novel marker for the contractile phenotype. Arterioscler. Thromb. Vasc. Biol. 17, 665–671 (1997).

    Article  CAS  PubMed  Google Scholar 

  79. Christen, T. et al. Mechanisms of neointima formation and remodeling in the porcine coronary artery. Circulation 103, 882–888 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Van der Loop, F. T., Schaart, G., Timmer, E. D., Ramaekers, F. C. & van Eys, G. J. Smoothelin, a novel cytoskeletal protein specific for smooth muscle cells. J. Cell Biol. 134, 401–411 (1996).

    Article  CAS  PubMed  Google Scholar 

  81. Jones, R. C. & Jacobson, M. Angiogenesis in the hypertensive lung: response to ambient oxygen tension. Cell Tissue Res. 300, 263–284 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Higton, D. I. R. & James, D. W. The force of contraction of full-thickness wounds of rabbit skin. Br. J. Surg. 51, 462–466 (1964).

    Article  CAS  PubMed  Google Scholar 

  83. Majno, G., Gabbiani, G., Hirschel, B. J., Ryan, G. B. & Statkov, P. R. Contraction of granulation tissue in vitro: similarity to smooth muscle. Science 173, 548–550 (1971).

    Article  CAS  PubMed  Google Scholar 

  84. Gabbiani, G., Hirschel, B. J., Ryan, G. B., Statkov, P. R. & Majno, G. Granulation tissue as a contractile organ. A study of structure and function. J. Exp. Med. 135, 719–734 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Appleton, I., Tomlinson, A., Chander, C. L. & Willoughby, D. A. Effect of endothelin-1 on croton oil-induced granulation tissue in the rat. A pharmacologic and immunohistochemical study. Lab. Invest. 67, 703–710 (1992).

    CAS  PubMed  Google Scholar 

  86. Hinz, B., Celetta, G., Tomasek, J. J., Gabbiani, G. & Chaponnier, C. α-smooth muscle actin expression upregulates fibroblast contractile activity. Mol. Biol. Cell 12, 2730–2741 (2001).This shows that a correlation exists between α-SM actin expression and contractile activity of fibroblast in vitro.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Arora, P. D. & McCulloch, C. A. Dependence of collagen remodelling on α-smooth muscle actin expression by fibroblasts. J. Cell Physiol. 159, 161–175 (1994).

    Article  CAS  PubMed  Google Scholar 

  88. Arora, P. D., Narani, N. & McCulloch, C. A. The compliance of collagen gels regulates transforming growth factor-β induction of α-smooth muscle actin in fibroblasts. Am. J. Pathol. 154, 871–882 (1999).Shows that TGF-β1-induced increases of α-SM actin content are dependent on the resistance of the substrate to deformation and that the generation of intracellular tension is a central determinant of contractile cytoskeletal gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ronnov-Jessen, L. & Petersen, O. W. A function for filamentous α-smooth muscle actin: retardation of motility in fibroblasts. J. Cell Biol. 134, 67–80 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Chaponnier, C. et al. The specific NH2-terminal sequence Ac-EEED of α-smooth muscle actin plays a role in polymerization in vitro and in vivo. J. Cell Biol. 130, 887–895 (1995).

    Article  CAS  PubMed  Google Scholar 

  91. Hinz, B., Gabbiani, G. & Chaponnier, C. The N-terminal peptide of α-smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo. J. Cell Biol. (in the press).This shows that the amino-terminal sequence of α-SM actin inhibits myofibroblast contraction in vitro and in vivo , which indicates a new therapeutic strategy.

  92. Nobes, C. D. & Hall, A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81, 53–62 (1995).

    Article  CAS  PubMed  Google Scholar 

  93. Balaban, N. Q. et al. Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates. Nature Cell Biol. 3, 466–472 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Geiger, B., Bershadsky, A., Pankov, R. & Yamada, K. M. Transmembrane crosstalk between the extracellular matrix–cytoskeleton crosstalk. Nature Rev. Mol. Cell Biol. 2, 793–805 (2001).

    Article  CAS  Google Scholar 

  95. Zamir, E. & Geiger, B. Molecular complexity and dynamics of cell-matrix adhesions. J. Cell Sci. 114, 3583–3590 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Cukierman, E., Pankov, R., Stevens, D. R. & Yamada, K. M. Taking cell-matrix adhesions to the third dimension. Science 294, 1708–1712 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Heino, J., Ignotz, R. A., Hemler, M. E., Crouse, C. & Massague, J. Regulation of cell adhesion receptors by transforming growth factor-β. Concomitant regulation of integrins that share a common β1 subunit. J. Biol. Chem. 264, 380–388 (1989).

    Article  CAS  PubMed  Google Scholar 

  98. Ignotz, R. A., Heino, J. & Massague, J. Regulation of cell adhesion receptors by transforming growth factor-β. Regulation of vitronectin receptor and LFA-1. J. Biol. Chem. 264, 389–392 (1989).

    Article  CAS  PubMed  Google Scholar 

  99. Brown, R. A. et al. Enhanced fibroblast contraction of 3D collagen lattices and integrin expression by TGF-β1 and β3: mechanoregulatory growth factors? Exp. Cell Res. 274, 310–322 (2002).Study shows very rapid stimulation of traction force by TGF-β1 and TGF-β3, which is consistent with activated cytoskeletal contraction.

    Article  CAS  PubMed  Google Scholar 

  100. Katoh, K., Kano, Y., Masuda, M., Onishi, H. & Fujiwara, K. Isolation and contraction of the stress fiber. Mol. Biol. Cell 9, 1919–1938 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Leung, T., Manser, E., Tan, L. & Lim, L. A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J. Biol. Chem. 270, 29051–29054 (1995).

    Article  CAS  PubMed  Google Scholar 

  102. Ishizaki, T. et al. The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J. 15, 1885–1893 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chihara, K. et al. Cytoskeletal rearrangements and transcriptional activation of c-fos serum response element by Rho-kinase. J. Biol. Chem. 272, 25121–25127 (1997).

    Article  CAS  PubMed  Google Scholar 

  104. Amano, M. et al. Myosin II activation promotes neurite retraction during the action of Rho and Rho-kinase. Genes Cells 3, 177–188 (1998).

    Article  CAS  PubMed  Google Scholar 

  105. Amano, M. et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J. Biol. Chem. 271, 20246–20249 (1996).

    Article  CAS  PubMed  Google Scholar 

  106. Kimura, K. et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273, 245–248 (1996).

    Article  CAS  PubMed  Google Scholar 

  107. Kawano, Y. et al. Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo. J. Cell Biol. 147, 1023–1038 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Katoh, K. et al. Rho-kinase-mediated contraction of isolated stress fibers. J. Cell Biol. 153, 569–584 (2001).Describes an isolated reactivatable stress fibre contraction model in which actomyosin-based nonmuscle contractility is regulated by two kinase systems: MLCK, which promotes rapid contraction, and Rho kinase, which maintains a sustained contraction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gong, M. C. et al. Role of guanine nucleotide-binding proteins–ras-family or trimeric proteins or both in Ca2+ sensitization of smooth muscle. Proc. Natl Acad. Sci. USA 93, 1340–1345 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tomasek, J. J., Martin, M. D., Vaughan, M. B., Cowan, R. & Kropp, B. P. Myofibroblast contraction in granulation tissue is dependent on Rho kinase. Mol. Biol. Cell 11, 88a (2000).

  111. Parizi, M., Howard, E. W. & Tomasek, J. J. Regulation of LPA-promoted myofibroblast contraction: role of Rho, myosin light chain kinase, and myosin light chain phosphatase. Exp. Cell Res. 254, 210–220 (2000).Shows that LPA-promoted contraction of myofibroblasts occurs through the Rho–Rho kinase pathway, probably by inhibiting myosin light chain phosphatase.

    Article  CAS  PubMed  Google Scholar 

  112. Glimcher, M. J. in Pathobiology (eds Kang, A. H. & Nimni, M. E.) 137–165 (CRC Press, Boca Ratton, 1992).

    Google Scholar 

  113. Glimcher, M. J. & Peabody, H. M. in Dupuytren's Disease (eds McFarlane, R., McGrouther, D. A. & Flint, M. H.) 72–85 (Churchill Livingston, Edinburgh, 1990).

    Google Scholar 

  114. Ryan, G. B. et al. Myofibroblasts in human granulation tissue. Hum. Pathol. 5, 55–67 (1974).

    Article  CAS  PubMed  Google Scholar 

  115. Grinnell, F. & Ho, C. H. Transforming growth factorβ stimulates fibroblast–collagen matrix contraction by different mechanisms in mechanically loaded and unloaded matrices. Exp. Cell Res. 273, 248–255 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Brown, R. A. & Byers, P. D. Swelling of cartilage and expansion of the collagen network. Calcif. Tissue Int. 45, 260–261 (1989).

    Article  CAS  PubMed  Google Scholar 

  117. Nemetschek, T. et al. [Functional properties of parallel fibred connective tissue with special regard to viscoelasticity (author's transl)]. Virchows Arch. A Pathol. Anat. Histol. 386, 125–151 (1980).

    Article  CAS  PubMed  Google Scholar 

  118. Woessner, J. F. in Collagen in Health and Disease (eds Jayson, M. I. V. & Weiss, J. B.) 506–527 (Churchill Livingston, Edinburgh, 1982).

    Google Scholar 

  119. Byers, P. D. & Brown, R. A. in Methods in Cartilage Research (eds Maroudas, A. & Kuettner, K. E.) 318–321 (Academic, London, 1990).

    Google Scholar 

  120. Gabbiani, G., Le Lous, M., Bailey, A. J., Bazin, S. & Delaunay, A. Collagen and myofibroblasts of granulation tissue. A chemical, ultrastructural and immunologic study. Virchows Archiv. B Cell Pathol. 21, 133–145 (1976).

    Article  CAS  Google Scholar 

  121. Graham, H. K., Holmes, D. F., Watson, R. B. & Kadler, K. E. Identification of collagen fibril fusion during vertebrate tendon morphogenesis. The process relies on unipolar fibrils and is regulated by collagen–proteoglycan interaction. J. Mol. Biol. 295, 891–902 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Danielson, K. G. et al. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J. Cell Biol. 136, 729–743 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kypreos, K. E., Birk, D., Trinkaus-Randall, V., Hartmann, D. J. & Sonenshein, G. E. Type V collagen regulates the assembly of collagen fibrils in cultures of bovine vascular smooth muscle cells. J. Cell Biochem. 80, 146–155 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Young, B. B., Gordon, M. K. & Birk, D. E. Expression of type XIV collagen in developing chicken tendons: association with assembly and growth of collagen fibrils. Dev. Dyn. 217, 430–439 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. Watson, R. B., Holmes, D. F., Graham, H. K., Nusgens, B. V. & Kadler, K. E. Surface located procollagen N-propeptides on dermatosparactic collagen fibrils are not cleaved by procollagen N-proteinase and do not inhibit binding of decorin to the fibril surface. J. Mol. Biol. 278, 195–204 (1998).

    Article  CAS  PubMed  Google Scholar 

  126. Ezura, Y., Chakravarti, S., Oldberg, A., Chervoneva, I. & Birk, D. E. Differential expression of lumican and fibromodulin regulate collagen fibrillogenesis in developing mouse tendons. J. Cell Biol. 151, 779–788 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Prajapati, R. T., Chavally-Mis, B., Herbage, D., Eastwood, M. & Brown, R. A. Mechanical loading regulates protease production by fibroblasts in three-dimensional collagen substrates. Wound Repair Regen. 8, 226–237 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Desmouliere, A., Redard, M., Darby, I. & Gabbiani, G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am. J. Pathol. 146, 56–66 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Grinnell, F., Zhu, M., Carlson, M. A. & Abrams, J. M. Release of mechanical tension triggers apoptosis of human fibroblasts in a model of regressing granulation tissue. Exp. Cell Res. 248, 608–619 (1999).

    Article  CAS  PubMed  Google Scholar 

  130. Mudera, V. C. et al. Molecular responses of human dermal fibroblasts to dual cues: contact guidance and mechanical load. Cell Motil. Cytoskeleton 45, 1–9 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Wakatsuki, T., Kolodney, M. S., Zahalak, G. I. & Elson, E. L. Cell mechanics studied by a reconstituted model tissue. Biophys. J. 79, 2353–2368 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Schurch, W., Seemayer, T. A. & Gabbiani, G. in Histology for Pathologists (ed. Sternberg, S. S.) 129–165 (Raven Press, Ltd, New York, 1997).

    Google Scholar 

  133. Garana, R. M. et al. Radial keratotomy. II. Role of the myofibroblast in corneal wound contraction. Invest. Ophthalmol. Vis. Sci. 33, 3271–3282 (1992).

    CAS  PubMed  Google Scholar 

  134. Jester, J. V., Petroll, W. M., Barry, P. A. & Cavanagh, H. D. Expression of α-smooth muscle (α-SM) actin during corneal stromal wound healing. Invest. Ophthalmol. Vis. Sci. 36, 809–819 (1995).

    CAS  PubMed  Google Scholar 

  135. Jester, J. V. et al. Corneal keratocytes: in situ and in vitro organization of cytoskeletal contractile proteins. Invest. Ophthalmol. Vis. Sci. 35, 730–743 (1994).

    CAS  PubMed  Google Scholar 

  136. Masur, S. K., Conors, R. J. Jr, Cheung, J. K. & Antohi, S. Matrix adhesion characteristics of corneal myofibroblasts. Invest. Ophthalmol. Vis. Sci. 40, 904–910 (1999).

    CAS  PubMed  Google Scholar 

  137. Jester, J. V., Petroll, W. M. & Cavanagh, H. D. Corneal stromal wound healing in refractive surgery: the role of myofibroblasts. Prog. Retin. Eye Res. 18, 311–356 (1999).

    Article  CAS  PubMed  Google Scholar 

  138. Masur, S. K., Dewal, H. S., Dinh, T. T., Erenburg, I. & Petridou, S. Myofibroblasts differentiate from fibroblasts when plated at low density. Proc. Natl Acad. Sci. USA 93, 4219–4223 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Glasser, S. R. & Julian, J. Intermediate filament protein as a marker of uterine stromal cell decidualization. Biol. Reprod. 35, 463–474 (1986).

    Article  CAS  PubMed  Google Scholar 

  140. Toccanier-Pelte, M.-F., Skalli, O., Kapanci, Y. & Gabbiani, G. Characterization of stromal cells with myoid features in lymph nodes and spleen in normal and pathological conditions. Am. J. Pathol. 129, 109–118 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Sappino, A. P., Dietrich, P. Y., Skalli, O., Widgren, S. & Gabbiani, G. Colonic pericryptal fibroblasts. Differentiation pattern in embryogenesis and phenotypic modulation in epithelial proliferative lesions. Virchows Arch. A Pathol. Anat. Histopathol. 415, 551–557 (1989).

    Article  CAS  PubMed  Google Scholar 

  142. Kaye, G. I., Lane, N. & Pascal, P. R. Colonic pericryptal fibroblast sheath: replication, migration and cytodifferentiation of a mesenchymal cell-system in adult tissue. II. Fine structural aspects of normal rabbit and human colon. Gastroenterology 54, 852–865 (1968).

    Article  CAS  PubMed  Google Scholar 

  143. Czernobilsky, B. et al. α smooth muscle actin (α-SM actin) in normal human ovaries, in ovarian stromal hyperplasia and in ovarian neoplasms. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 57, 55–61 (1989).

    Article  CAS  PubMed  Google Scholar 

  144. Beertsen, W., Everts, V. & van den Hooff, A. Fine structure of fibroblasts in the periodontal ligament of the rat incisor and their possible role in tooth eruption. Arch. Oral Biol. 19, 1087–1098 (1974).

    Article  CAS  PubMed  Google Scholar 

  145. Bressler, R. S. Myoid cells in the capsule of the adrenal gland and in monolayers derived from cultured adrenal capsules. Anat. Rec. 177, 525–531 (1973).

    Article  CAS  PubMed  Google Scholar 

  146. Yokoi, Y. et al. Immunocytochemical detection of desmin in fat-storing cells (Ito cells). Hepatology 4, 709–714 (1984).

    Article  CAS  PubMed  Google Scholar 

  147. Kapanci, Y., Ribaux, C., Chaponnier, C. & Gabbiani, G. Cytoskeletal features of alveolar myofibroblasts and pericytes in normal human and rat lung. J. Histochem. Cytochem. 40, 1955–1963 (1992).

    Article  CAS  PubMed  Google Scholar 

  148. Charbord, P. et al. The cytoskeleton of stromal cells from human bone marrow cultures resembles that of cultured smooth muscle cells. Exp. Hematol. 18, 276–282 (1990).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the support of the National Institutes of Health, the Wellcome Foundation, the Swiss National Science Foundation, UCB-Bioproducts and the European Union Framework V awards. We thank Professor D. A. McGrouther (University of Manchester) for his helpful early discussions and E. Homberg for secretarial work. We apologize for the failure to cite many important contributions to this field owing to space limitations.

Author information

Authors and Affiliations

  1. Department of Cell Biology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, 73190, OK, USA

    James J. Tomasek

  2. Department of Pathology, Centre Médical Universitaire, University of Geneva, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland

    Giulio Gabbiani, Boris Hinz & Christine Chaponnier

  3. Tissue Repair & Engineering Centre, University College London, Institute of Orthopaedics, Royal National Orthopaedic Hospital, Stanmore, HA7 4LP, Middlesex, UK

    Robert A. Brown

Authors
  1. James J. Tomasek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giulio Gabbiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Boris Hinz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christine Chaponnier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert A. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James J. Tomasek.

Related links

Related links

DATABASES

LocusLink

TGF-β1

OMIM

Dupuytren's disease

Swiss-Prot

α-actinin

angiotensin II

β-cytoplasmic actin

γ-cytoplasmic actin

decorin

ED-A

ED-B

FAK

fibromodulin

lumican

MLCK

MMP1

MMP2

MMP3

MMP9

PAI-1

paxillin

procollagen N-protease

Rho kinase

ROKα

talin

tensin

vinculin

Glossary

CONNECTIVE TISSUES

Tissues that form the architectural framework of the vertebrate body. In these tissues, the extracellular matrix is plentiful, and cells are sparsely distributed within it.

GRANULATION TISSUE

Tissue that is formed as part of the initial response to a wound during the healing and repair process, so-called because its surface has a granular appearance due to sprouting of neo-capillaries. It also contains abundant fibroblasts and variable numbers of inflammatory cells.

UTERINE INVOLUTION

The degenerative and regenerative process that the tissues that constitute the uterus and oviducts undergo on their return to a non-pregnant state.

FIBROSIS

The production of fibrous connective tissue as a consequence of chronic inflammation or healing. Its function is to replace lost parenchymal tissue.

PARENCHYMA

The essential or functional elements of an organ as distinguished from its stroma or framework.

EXTRACELLULAR MATRIX

(ECM). A complex, three-dimensional network of very large macromolecules that provides contextual information and an architectural scaffold for cellular adhesion and migration.

STRESS FIBRES

Intracellular axial bundles of filamentous-actin and actin-associated proteins.

FIBRONECTIN FIBRILS

Extracellular fibrils that are composed of fibronectin, and are found primarily in tissues that undergo active morphogenesis, such as embryonic tissue and granulation tissue.

GAP JUNCTION

A junction between two cells that consists of pores that allow passage of molecules (up to 9 kDa).

CORNEA

The transparent, curved part of the front of the eyeball. It is made up of many layers (in particular a thick stromal layer), and refracts incident light onto the lens.

CONNEXIN

The main protein component of a connexon, the structural subunit of a gap junction. Six connexins make up one connexon.

EPIRETINAL MEMBRANE

A membrane that can sometimes form on the surface of the central portion of the retina when the vitreous gel that fills the central eye cavity shrinks away from the retina.

DIFFERENTIATION

The elaboration of particular characteristics that are expressed by an end-stage cell type or by a cell en route to becoming an end-stage cell. This term is not synonymous with commitment, but differentiation features are used to determine when a cell is committed.

FIBROCONTRACTIVE DISEASES

Connective tissue disorders, such as Dupuytren's disease, that involve both tissue contracture and fibrosis.

GRANULOMA POUCH

A fluid-filled pouch that is created by subcutaneous injection of air and a necrotizing agent, such as croton oil, which later fills with fluid and becomes surrounded by granulation tissue.

PERICYTES

Support cells of capillaries (referred to as smooth muscle cells in larger vessels).

FOCAL ADHESIONS

Cellular structures that link the extracellular matrix on the outside of the cell, through integrin receptors, to the actin cytoskeleton inside the cell.

DERMIS

The innermost layer of the vertebrate skin that lies beneath the epidermis and is responsible for the tensile strength of skin. It comprises loose connective tissue that contains blood capillaries, smooth-muscle fibres, sweat glands and sebaceous glands with their ducts, hair follicles and sensory nerve endings.

MESENCHYMAL STEM CELL

A cell from immature connective tissue — tissue that consists of cells embedded in extracellular matrix — that has the potential to divide and reproduce a replica cell as well as a differentiated progeny.

PLATELETS

The smallest blood cells, which are important in haemostasis and blood coagulation.

MACROPHAGES

Any cells of the mononuclear phagocyte system that are characterized by their ability to phagocytose foreign particulate and colloidal material.

SMADS

A family of transcription factors that mediate transforming factor β (TGF-β) signals. The term SMAD is derived from the founding members of this family, the Drosophila protein MAD (Mothers Against Decapentaplegic) and the Caenorhabditis elegans protein SMA (small body size).

HEPATIC STELLATE CELLS

Also known as perisinusoidal cells, these cells are normally quiescent, but when they are stimulated by several toxins, they differentiate into myofibroblasts, which results in liver fibrosis.

CArG BOX MOTIF

A CArG box motif — CC(A+T-rich)6GG — is a DNA element that is required for muscle-specific gene transcription.

ISOMETRIC TENSION

A condition in which contraction of muscle, non-muscle cells or the actomyosin network is opposed by an equal load that prevents net shortening, even though tension increases.

ISOTONIC CONTRACTION

A condition in which contraction results in a shortening of muscle, nonmuscle, or the actomyosin network in order that tension remains constant.

RHO FAMILY GTPASES

Ras-related GTPases that are involved in controlling the polymerization of actin.

LYSOPHOSPHATIDIC ACID

Any phosphatidic acid that is deacylated at positions 1 or 2. It binds to a G-protein-coupled receptor, which results in the activation of the small GTP-binding protein Rho and the induction of stress fibres.

CYTOCHALASIN D

A fungal compound that specifically interferes with actin polymerization.

METALLOPROTEINASE

A proteinase that has a metal ion at its active site.

PROTEOGLYCAN

Any glycoprotein that contains glycosaminoglycans as the carbohydrate unit.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tomasek, J., Gabbiani, G., Hinz, B. et al. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3, 349–363 (2002). https://doi.org/10.1038/nrm809

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm809

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing