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:

Mechanotransduction and extracellular matrix homeostasis

Nature Reviews Molecular Cell Biology volume 15, pages 802–812 (2014)Cite this article

Subjects

Key Points

  • Under steady state conditions, cells must actively maintain the mechanical properties of the extracellular matrix (ECM) to maintain the normal function of many, if not all, tissues.

  • Cells control ECM mechanics through degradation, synthesis, organization and pre-stress of its components.

  • Mechanical cues from the ECM trigger signalling cascades that alter gene expression and affect various processes, including cell motility and fate.

  • Elucidating the feedback mechanisms between cells and the ECM that maintain mechanical properties is a key question for future work.

Abstract

Soft connective tissues at steady state are dynamic; resident cells continually read environmental cues and respond to them to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix (ECM) that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the ECM by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechanoregulation process, which includes the deposition, rearrangement or removal of the ECM to maintain overall form and function. Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.

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: Key components in mechanical homeostasis of soft connective tissue.
Figure 2: Feedback control loops regulate extracellular matrix structure and function.
Figure 3: Cell–extracellular matrix interactions in health and disease.
Figure 4: Force-mediated regulation of integrin adhesions.

Similar content being viewed by others

References

  1. Lu, P., Takai, K., Weaver, V. M. & Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 3, a005058 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Schwartz, M. A., Schaller, M. D. & Ginsberg, M. H. Integrins: emerging paradigms of signal transduction. Annu. Rev. Cell Dev. Biol. 11, 549–599 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Bissell, M. J. & Aggeler, J. Dynamic reciprocity: how do extracellular matrix and hormones direct gene expression? Prog. Clin. Biol. Res. 249, 251–262 (1987).

    CAS  PubMed  Google Scholar 

  4. Vogel, V. & Sheetz, M. Local force and geometry sensing regulate cell functions. Nature Rev. Mol. Cell Biol. 7, 265–275 (2006).

    Article  CAS  Google Scholar 

  5. Hoffman, B. D., Grashoff, C. & Schwartz, M. A. Dynamic molecular processes mediate cellular mechanotransduction. Nature 475, 316–323 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in development and diseases. Nature Rev. Cell Mol. Biol. http://dx.doi.org/10.1038/nrm3904 (2014)

  7. Mouw, J., Ou, G. & Weaver, V. M. Deconstructing extracellular matrix assembly: a multi-scale road map. Nature Rev. Cell Mol. Biol. http://dx.doi.org/10.1038/nrm3902 (2014)

  8. Hynes, R. O. & Naba, A. Overview of the matrisome—an inventory of extracellular matrix constituents and functions. Cold Spring Harb. Perspect. Biol. 4, a004903 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Arribas, S. M., Hinek, A. & Gonzalez, M. C. Elastic fibres and vascular structure in hypertension. Pharmacol. Ther. 111, 771–791 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Kielty, C. M. Elastic fibres in health and disease. Expert Rev. Mol. Med. 8, 1–23 (2006).

    Article  PubMed  Google Scholar 

  11. Ricard-Blum, S. The collagen family. Cold Spring Harb. Perspect. Biol. 3, a004978 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ferruzzi, J., Collins, M. J., Yeh, A. T. & Humphrey, J. D. Mechanical assessment of elastin integrity in fibrillin-1- deficient carotid arteries: implications for Marfan syndrome. Cardiovasc. Res. 92, 287–295 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Leung, D. Y., Glagov, S. & Mathews, M. B. Cyclic stretching stimulates synthesis of matrix components by arterial smooth muscle cells in vitro. Science 191, 475–477 (1976). The first demonstration that cyclic mechanical loading induced smooth muscle cells to increase their ECM production.

    Article  CAS  PubMed  Google Scholar 

  14. Hinz, B. et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am. J. Pathol. 180, 1340–1355 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nagase, H., Visse, R. & Murphy, G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res. 69, 562–573 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R. A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nature Rev. Mol. Cell Biol. 3, 349–363 (2002).

    Article  CAS  Google Scholar 

  17. Ciobanasu, C., Faivre, B. & Le Clainche, C. Integrating actin dynamics, mechanotransduction and integrin activation: the multiple functions of actin binding proteins in focal adhesions. Eur. J. Cell Biol. 92, 339–348 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Ingber, D. E. Tensegrity-based mechanosensing from macro to micro. Prog. Biophys. Mol. Biol. 97, 163–179 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Humphrey, J. D. Stress, strain, and mechanotransduction in cells. J. Biomech. Eng. 123, 638–641 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Discher, D. E., Janmey, P. & Wang, Y. L. Tissue cells feel and respond to the stiffness of their substrate. Science 310, 1139–1143 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Humphrey, J. D. Vascular adaptation and mechanical homeostasis at tissue, cellular, and sub-cellular levels. Cell Biochem. Biophys. 50, 53–78 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Bersi, M. R., Ferruzzi, J., Eberth, J. F., Gleason, R. L. & Humphrey, J. D. Consistent biomechanical phenotyping of common carotid arteries from seven genetic, pharmacological, and surgical mouse models. Ann. Biomed. Engineer. 42, 1207–1223 (2014).

    Article  CAS  Google Scholar 

  23. Shadwick, R. E. Mechanical design in arteries. J. Exp. Biol. 202, 3305–3313 (1999).

    CAS  PubMed  Google Scholar 

  24. Wang, J. H. & Thampatty, B. P. An introductory review of cell mechanobiology. Biomech. Model. Mechanobiol. 5, 1–16 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Silver, F. H., Siperko, L. M. & Seehra, G. P. Mechanobiology of force transduction in dermal tissue. Skin Res. Technol. 9, 3–23 (2003).

    Article  PubMed  Google Scholar 

  26. Cook, J. R. et al. Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome. J. Clin. Invest. 124, 1329–1339 (2014). Clear evidence that an organ-level pathology resulted from abnormal mechanosensing related to a genetic mutation in an ECM protein.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ganesh, S. K. et al. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features. FASEB J. 28, 3313–3324 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Humphrey, J. D., Milewicz, D. M., Tellides, G. & Schwartz, M. A. Cell biology. Dysfunctional mechanosensing in aneurysms. Science 344, 477–479 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Gerber, E. E. et al. Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature 503, 126–130 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Agarwal, S. K. Integrins and cadherins as therapeutic targets in fibrosis. Front. Pharmacol. 5, 131 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fung, Y. C. Biomechanics: Mechanical Properties of Living Tissues. (Springer, 1993).

    Book  Google Scholar 

  33. 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). An early demonstration in vitro that fibroblasts establish steady-state endogenous tension when introduced into an initially stress-free collagen gel.

    Article  CAS  PubMed  Google Scholar 

  34. Marenzana, M., Wilson-Jones, N., Mudera, V. & Brown, R. A. The origins and regulation of tissue tension: identification of collagen tension-fixation process in vitro. Exp. Cell Res. 312, 423–433 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. 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 

  36. Legant, W. R. et al. Measurement of mechanical tractions exerted by cells in three-dimensional matrices. Nature Methods 7, 969–971 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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 

  38. Tan, J. L. et al. Cells lying on a bed of microneedles: an approach to isolate mechanical force. Proc. Natl Acad. Sci. USA 100, 1484–1489 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chiu, J. J. & Chien, S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol. Rev. 91, 327–387 (2011).

    Article  PubMed  Google Scholar 

  40. Humphrey, J. D. & Rajagopal, K. R. A constrained mixture model for growth and remodeling of soft tissues. Math. Models Methods Appl. Sci. 12, 407–430 (2002).

    Article  Google Scholar 

  41. Li, Q., Muragaki, Y., Hatamura, I., Ueno, H. & Ooshima, A. Stretch-induced collagen synthesis in cultured smooth muscle cells from rabbit aortic media and a possible involvement of angiotensin II and transforming growth factor-β. J. Vasc. Res. 35, 93–103 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. O'Callaghan, C. J. & Williams, B. Mechanical strain-induced extracellular matrix production by human vascular smooth muscle cells: role of TGF-β1 . Hypertension 36, 319–324 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. 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 

  44. Ruberti, J. W. & Hallab, N. J. Strain-controlled enzymatic cleavage of collagen in loaded matrix. Biochem. Biophys. Res. Commun. 336, 483–489 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Valentin, A. & Humphrey, J. D. Evaluation of fundamental hypotheses underlying constrained mixture models of arterial growth and remodelling. Philos. Trans. A Math. Phys. Eng. Sci. 367, 3585–3606 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cyron, C., Wilson, J. S. & Humphrey, J. D. Mechanobiological stability: a new paradigm to understand the enlargement of aneurysms. J. Roy. Soc. 11, 20140680 (2014).

    Article  CAS  Google Scholar 

  47. Kadler, K. E., Hill, A. & Canty-Laird, E. G. Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators. Curr. Opin. Cell Biol. 20, 495–501 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Velling, T., Risteli, J., Wennerberg, K., Mosher, D. F. & Johansson, S. Polymerization of type I and III collagens is dependent on fibronectin and enhanced by integrins α 11β 1 and α 2β 1. J. Biol. Chem. 277, 37377–37381 (2002). This work showed that cells actively contribute, in vivo , to collagen fibrillogenesis via an integrin-mediated process.

    Article  CAS  PubMed  Google Scholar 

  49. Li, S., Van Den Diepstraten, C., D'Souza, S. J., Chan, B. M. & Pickering, J. G. Vascular smooth muscle cells orchestrate the assembly of type I collagen via α2β1 integrin, RhoA, and fibronectin polymerization. Am. J. Pathol. 163, 1045–1056 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Meshel, A. S., Wei, Q., Adelstein, R. S. & Sheetz, M. P. Basic mechanism of three-dimensional collagen fibre transport by fibroblasts. Nature Cell Biol. 7, 157–164 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Dahlmann-Noor, A. H., Martin-Martin, B., Eastwood, M., Khaw, P. T. & Bailly, M. Dynamic protrusive cell behaviour generates force and drives early matrix contraction by fibroblasts. Exp. Cell Res. 313, 4158–4169 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Huelsz-Prince, G., Belkin, A. M., VanBavel, E. & Bakker, E. N. Activation of extracellular transglutaminase 2 by mechanical force in the arterial wall. J. Vasc. Res. 50, 383–395 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Baneyx, G., Baugh, L. & Vogel, V. Fibronectin extension and unfolding within cell matrix fibrils controlled by cytoskeletal tension. Proc. Natl Acad. Sci. USA 99, 5139–5143 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mao, Y. & Schwarzbauer, J. E. Fibronectin fibrillogenesis, a cell-mediated matrix assembly process. Matrix Biol. 24, 389–399 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Canty, E. G. et al. Coalignment of plasma membrane channels and protrusions (fibripositors) specifies the parallelism of tendon. J. Cell Biol. 165, 553–563 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Czirok, A. et al. Elastic fiber macro-assembly is a hierarchical, cell motion-mediated process. J. Cell. Physiol. 207, 97–106 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Ramirez, F. & Dietz, H. C. Fibrillin-rich microfibrils: Structural determinants of morphogenetic and homeostatic events. J. Cell. Physiol. 213, 326–330 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Bax, D. V. et al. Cell adhesion to fibrillin-1 molecules and microfibrils is mediated by α 5 β 1 and α v β 3 integrins. J. Biol. Chem. 278, 34605–34616 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Chiquet, M., Gelman, L., Lutz, R. & Maier, S. From mechanotransduction to extracellular matrix gene expression in fibroblasts. Biochim. Biophys. Acta 1793, 911–920 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Peyton, S. R. & Putnam, A. J. Extracellular matrix rigidity governs smooth muscle cell motility in a biphasic fashion. J. Cell. Physiol. 204, 198–209 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Wang, H. B., Dembo, M. & Wang, Y. L. Substrate flexibility regulates growth and apoptosis of normal but not transformed cells. Am. J. Physiol. Cell Physiol. 279, C1345–1350 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Plotnikov, S. V., Pasapera, A. M., Sabass, B. & Waterman, C. M. Force fluctuations within focal adhesions mediate ECM-rigidity sensing to guide directed cell migration. Cell 151, 1513–1527 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Lo, C. M., Wang, H. B., Dembo, M. & Wang, Y. L. Cell movement is guided by the rigidity of the substrate. Biophys. J. 79, 144–152 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Klein, E. A. et al. Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening. Curr. Biol. 19, 1511–1518 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Meredith, J. E. Jr., Fazeli, B. & Schwartz, M. A. The extracellular matrix as a cell survival factor. Mol. Biol. Cell 4, 953–961 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Frisch, S. M. & Francis, H. Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124, 619–626 (1994).

    Article  CAS  PubMed  Google Scholar 

  70. Abraham, D. J., Eckes, B., Rajkumar, V. & Krieg, T. New developments in fibroblast and myofibroblast biology: implications for fibrosis and scleroderma. Curr. Rheumatol Rep. 9, 136–143 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Yeung, T. et al. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell. Motil. Cytoskeleton 60, 24–34 (2005).

    Article  PubMed  Google Scholar 

  72. Kong, H. J., Polte, T. R., Alsberg, E. & Mooney, D. J. FRET measurements of cell-traction forces and nano-scale clustering of adhesion ligands varied by substrate stiffness. Proc. Natl Acad. Sci. USA 102, 4300–4305 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chopra, A. et al. Augmentation of integrin-mediated mechanotransduction by hyaluronic acid. Biomaterials 35, 71–82 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Mih, J. D., Marinkovic, A., Liu, F., Sharif, A. S. & Tschumperlin, D. J. Matrix stiffness reverses the effect of actomyosin tension on cell proliferation. J. Cell Sci. 125, 5974–5983 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Prager-Khoutorsky, M. et al. Fibroblast polarization is a matrix-rigidity-dependent process controlled by focal adhesion mechanosensing. Nature Cell Biol. 13, 1457–1465 (2011). This siRNA screen identified genes linked to Tyr kinase signalling that alter cell rigidity sensing, demonstrating that these responses involve active signalling rather than purely mechanical mechanisms.

    Article  CAS  PubMed  Google Scholar 

  76. Yoshigi, M., Hoffman, L. M., Jensen, C. C., Yost, H. J. & Beckerle, M. C. Mechanical force mobilizes zyxin from focal adhesions to actin filaments and regulates cytoskeletal reinforcement. J. Cell Biol. 171, 209–215 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tamada, M., Sheetz, M. P. & Sawada, Y. Activation of a signaling cascade by cytoskeleton stretch. Dev. Cell 7, 709–718 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Iyer, K. V., Pulford, S., Mogilner, A. & Shivashankar, G. V. Mechanical activation of cells induces chromatin remodeling preceding MKL nuclear transport. Biophys. J. 103, 1416–1428 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lambert, C. A., Colige, A. C., Munaut, C., Lapiere, C. M. & Nusgens, B. V. Distinct pathways in the over-expression of matrix metalloproteinases in human fibroblasts by relaxation of mechanical tension. Matrix Biol. 20, 397–408 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Chiquet-Ehrismann, R. et al. Tenascin-C expression by fibroblasts is elevated in stressed collagen gels. J. Cell Biol. 127, 2093–2101 (1994).

    Article  CAS  PubMed  Google Scholar 

  81. Mackie, E. J., Thesleff, I. & Chiquet-Ehrismann, R. Tenascin is associated with chondrogenic and osteogenic differentiation in vivo and promotes chondrogenesis in vitro. J. Cell Biol. 105, 2569–2579 (1987).

    Article  CAS  PubMed  Google Scholar 

  82. Chiquet-Ehrismann, R. & Chiquet, M. Tenascins: regulation and putative functions during pathological stress. J. Pathol. 200, 488–499 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Carey, W. A., Taylor, G. D., Dean, W. B. & Bristow, J. D. Tenascin-C deficiency attenuates TGF-ss-mediated fibrosis following murine lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 299, L785–L793 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. El-Karef, A. et al. Deficiency of tenascin-C attenuates liver fibrosis in immune-mediated chronic hepatitis in mice. J. Pathol. 211, 86–94 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Nishioka, T. et al. Tenascin-C may aggravate left ventricular remodeling and function after myocardial infarction in mice. Am. J. Physiol. Heart Circ. Physiol. 298, H1072–H1078 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Mizuno, D., Tardin, C., Schmidt, C. F. & Mackintosh, F. C. Nonequilibrium mechanics of active cytoskeletal networks. Science 315, 370–373 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Wachsstock, D. H., Schwarz, W. H. & Pollard, T. D. Cross-linker dynamics determine the mechanical properties of actin gels. Biophys. J. 66, 801–809 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Trepat, X. et al. Viscoelasticity of human alveolar epithelial cells subjected to stretch. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L1025–L1034 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Webster, K. D., Ng, W. P. & Fletcher, D. A. Tensional homeostasis in single fibroblasts. Biophys. J. 107, 146–155 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Jungbauer, S., Gao, H. J., Spatz, J. P. & Kemkemer, R. Two characteristic regimes in frequency-dependent dynamic reorientation of fibroblasts on cyclically stretched substrates. Biophys. J. 95, 3470–3478 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Faust, U. et al. Cyclic stress at mHz frequencies aligns fibroblasts in direction of zero strain. PLoS ONE 6, 16 (2011).

    Article  CAS  Google Scholar 

  92. Gawlak, G. et al. Paxillin mediates stretch-induced Rho signaling and endothelial permeability via assembly of paxillin-p42/44MAPK-GEF-H1 complex. FASEB J. 28, 3249–3260 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Verma, S. K. et al. Rac1 and RhoA differentially regulate angiotensinogen gene expression in stretched cardiac fibroblasts. Cardiovasc. Res. 90, 88–96 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. De, R., Zemel, A. & Safran, S. A. Dynamics of cell orientation. Nature Phys. 3, 655–659 (2007).

    Article  CAS  Google Scholar 

  95. Schwarz, U. S. & Safran, S. A. Physics of adherent cells. Rev. Modern Phys. 85, 1327–1381 (2013).

    Article  CAS  Google Scholar 

  96. Livne, A., Bouchbinder, E. & Geiger, B. Cell orientation under cyclic stretching. Nature Comm. 5, 3938 (2014).

    Article  CAS  Google Scholar 

  97. Karnik, S. K. et al. A critical role for elastin signaling in vascular morphogenesis and disease. Development 130, 411–423 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Brooke, B. S., Bayes-Genis, A. & Li, D. Y. New insights into elastin and vascular disease. Trends Cardiovasc. Med. 13, 176–181 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Koyama, H., Raines, E. W., Bornfeldt, K. E., Roberts, J. M. & Ross, R. Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors. Cell 87, 1069–1078 (1996).

    Article  CAS  PubMed  Google Scholar 

  100. Katsumi, A., Orr, A. W., Tzima, E. & Schwartz, M. A. Integrins in mechanotransduction. J. Biol. Chem. 279, 12001–12004 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Davis, G. E. Affinity of integrins for damaged extracellular matrix: α v β 3 binds to denatured collagen type I through RGD sites. Biochem. Biophys. Res. Commun. 182, 1025–1031 (1992).

    Article  CAS  PubMed  Google Scholar 

  102. Altrock, E., Muth, C. A., Klein, G., Spatz, J. P. & Lee-Thedieck, C. The significance of integrin ligand nanopatterning on lipid raft clustering in hematopoietic stem cells. Biomaterials 33, 3107–3118 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Cavalcanti-Adam, E. A., Aydin, D., Hirschfeld-Warneken, V. C. & Spatz, J. P. Cell adhesion and response to synthetic nanopatterned environments by steering receptor clustering and spatial location. HFSP J. 2, 276–285 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Trappmann, B. et al. Extracellular-matrix tethering regulates stem-cell fate. Nature Mater. 11, 642–649 (2012).

    Article  CAS  Google Scholar 

  105. Storm, C., Pastore, J. J., MacKintosh, F. C., Lubensky, T. C. & Janmey, P. A. Nonlinear elasticity in biological gels. Nature 435, 191–194 (2005). The origin and implications of strain-dependent stiffness in biological gels.

    Article  CAS  PubMed  Google Scholar 

  106. Sawhney, R. K. & Howard, J. Slow local movements of collagen fibers by fibroblasts drive the rapid global self-organization of collagen gels. J. Cell Biol. 157, 1083–1091 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Winer, J. P., Oake, S. & Janmey, P. A. Non-linear elasticity of extracellular matrices enables contractile cells to communicate local position and orientation. PLoS ONE 4, e6382 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Bershadsky, A. D., Balaban, N. Q. & Geiger, B. Adhesion-dependent cell mechanosensitivity. Annu. Rev. Cell Dev. Biol. 19, 677–695 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Moore, S. W., Roca-Cusachs, P. & Sheetz, M. P. Stretchy proteins on stretchy substrates: the important elements of integrin-mediated rigidity sensing. Dev. Cell 19, 194–206 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhong, C. et al. Rho-mediated contractility exposes a cryptic site in fibronectin and induces fibronectin matrix assembly. J. Cell Biol. 141, 539–551 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. del Rio, A. et al. Stretching single talin rod molecules activates vinculin binding. Science 323, 638–641 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Patel, B. et al. The activity of the vinculin binding sites in talin is influenced by the stability of the helical bundles that make up the talin rod. J. Biol. Chem. 281, 7458–7467 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Grashoff, C. et al. Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature 466, 263–266 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Dumbauld, D. W. et al. Contractility modulates cell adhesion strengthening through focal adhesion kinase and assembly of vinculin-containing focal adhesions. J. Cell. Physiol. 223, 746–756 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Ehrlicher, A. J., Nakamura, F., Hartwig, J. H., Weitz, D. A. & Stossel, T. P. Mechanical strain in actin networks regulates FilGAP and integrin binding to filamin A. Nature 478, 260–263 (2011). Identification of tension-dependent changes in the interactions of filamin with other proteins that may mediate cytoskeletal strengthening and signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Katsumi, A. et al. Effects of cell tension on the small GTPase Rac. J. Cell Biol. 158, 153–164 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Rognoni, L., Stigler, J., Pelz, B., Ylanne, J. & Rief, M. Dynamic force sensing of filamin revealed in single-molecule experiments. Proc. Natl Acad. Sci. USA 109, 19679–19684 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Meng, F., Suchyna, T. M., Lazakovitch, E., Gronostajski, R. M. & Sachs, F. Real Time, F. R.E. T. Based detection of mechanical stress in cytoskeletal and extracellular matrix proteins. Cell. Mol. Bioeng. 4, 148–159 (2011).

    Article  PubMed  Google Scholar 

  119. Chen, W., Lou, J., Evans, E. A. & Zhu, C. Observing force-regulated conformational changes and ligand dissociation from a single integrin on cells. J. Cell Biol. 199, 497–512 (2012). Single-molecule techniques demonstrated that integrins show force and loading rate-dependent changes in conformation and stability of the integrin–ligand interaction that may underlie mechanotransduction by these receptors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kong, F. et al. Cyclic mechanical reinforcement of integrin-ligand interactions. Mol. Cell 49, 1060–1068 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Pasapera, A. M., Schneider, I. C., Rericha, E., Schlaepfer, D. D. & Waterman, C. M. Myosin II activity regulates vinculin recruitment to focal adhesions through FAK-mediated paxillin phosphorylation. J. Cell Biol. 188, 877–890 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lee, C. Y. et al. Actin depolymerization under force is governed by lysine 113:glutamic acid 195-mediated catch-slip bonds. Proc. Natl Acad. Sci. USA 110, 5022–5027 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Hayakawa, K., Tatsumi, H. & Sokabe, M. Actin filaments function as a tension sensor by tension-dependent binding of cofilin to the filament. J. Cell Biol. 195, 721–727 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Marshall, T. W., Aloor, H. L. & Bear, J. E. Coronin 2A regulates a subset of focal-adhesion-turnover events through the cofilin pathway. J. Cell Sci. 122, 3061–3069 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Gardel, M. L. et al. Traction stress in focal adhesions correlates biphasically with actin retrograde flow speed. J. Cell Biol. 183, 999–1005 (2008). This study described the relationship between traction stress and actin retrograde flow within focal adhesions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hu, K., Ji, L., Applegate, K. T., Danuser, G. & Waterman-Storer, C. M. Differential transmission of actin motion within focal adhesions. Science 315, 111–115 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Brown, C. M. et al. Probing the integrin-actin linkage using high-resolution protein velocity mapping. J. Cell Sci. 119, 5204–5214 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Ponti, A., Machacek, M., Gupton, S. L., Waterman-Storer, C. M. & Danuser, G. Two distinct actin networks drive the protrusion of migrating cells. Science 305, 1782–1786 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Chan, C. E. & Odde, D. J. Traction dynamics of filopodia on compliant substrates. Science 322, 1687–1691 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Edwards, C. M. & Schwarz, U. S. Force localization in contracting cell layers. Phys. Rev. Lett. 107, 5 (2011). Theory and experiments linked matrix compliance to loading rate of ECM–integrin–cytoskeletal bonds.

    Article  CAS  Google Scholar 

  131. Mertz, A. F. et al. Scaling of traction forces with the size of cohesive cell colonies. Phys. Rev. Lett. 108, 5 (2012).

    Article  CAS  Google Scholar 

  132. Marcq, P., Yoshinaga, N. & Prost, J. Rigidity sensing explained by active matter theory. Biophys. J. 101, L33–L35 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Zemel, A., Rehfeldt, F., Brown, A. E. X., Discher, D. E. & Safran, S. A. Optimal matrix rigidity for stress-fibre polarization in stem cells. Nature Phys. 6, 468–473 (2010).

    Article  CAS  Google Scholar 

  134. Trichet, L. et al. Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness. Proc. Natl Acad. Sci. USA 109, 6933–6938 (2012). A combined experimental and theoretical approach suggested that rigidity sensing may not be localized to focal adhesions.

    Article  PubMed  PubMed Central  Google Scholar 

  135. von Wichert, G. et al. RPTP-α acts as a transducer of mechanical force on αv/β3-integrin-cytoskeleton linkages. J. Cell Biol. 161, 143–153 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jiang, G., Huang, A. H., Cai, Y., Tanase, M. & Sheetz, M. P. Rigidity sensing at the leading edge through αvβ3 integrins and RPTPα. Biophys. J. 90, 1804–1809 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Roca-Cusachs, P., Gauthier, N. C., Del Rio, A. & Sheetz, M. P. Clustering of α5β1 integrins determines adhesion strength whereas αvβ3 and talin enable mechanotransduction. Proc. Natl Acad. Sci. USA 106, 16245–16250 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Schiller, H. B. et al. β1- and αv-class integrins cooperate to regulate myosin II during rigidity sensing of fibronectin-based microenvironments. Nature Cell Biol. 15, 625–636 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Wang, H. B., Dembo, M., Hanks, S. K. & Wang, Y. Focal adhesion kinase is involved in mechanosensing during fibroblast migration. Proc. Natl Acad. Sci. USA 98, 11295–11300 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Suriawinata, A. & Fiel, M. I. Liver pathology in obesity. Semin. Liver Dis. 24, 363–370 (2004).

    Article  PubMed  Google Scholar 

  141. Yu, J. et al. Peroxisome proliferator-activated receptors gamma reverses hepatic nutritional fibrosis in mice and suppresses activation of hepatic stellate cells in vitro. Int. J. Biochem. Cell Biol. 42, 948–957 (2010).

    Article  CAS  PubMed  Google Scholar 

  142. Boutouyrie, P., Beaussier, H., Achouba, A., Laurent, S. & EXPLOR trialists. Destiffening effect of valsartan and atenolol: influence of heart rate and blood pressure. J. Hypertens. 32, 108–114 (2014).

    Article  CAS  PubMed  Google Scholar 

  143. O'Rourke, M. F. & Hashimoto, J. Mechanical factors in arterial aging: a clinical perspective. J. Am. Coll. Cardiol 50, 1–13 (2007).

    Article  PubMed  Google Scholar 

  144. Kothapalli, D. et al. Apolipoprotein E-mediated cell cycle arrest linked to p27 and the Cox2-dependent repression of miR221/222. Atherosclerosis 227, 65–71 (2013).

    Article  CAS  PubMed  Google Scholar 

  145. Liu, F. et al. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J. Cell Biol. 190, 693–706 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Grinnell, F. Fibroblast biology in three-dimensional collagen matrices. Trends Cell Biol. 13, 264–269 (2003).

    Article  CAS  PubMed  Google Scholar 

  147. Gineyts, E. et al. Racemization and isomerization of type I collagen C-telopeptides in human bone and soft tissues: assessment of tissue turnover. Biochem. J. 345, 481–485 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Humphrey, J. D., Eberth, J. F., Dye, W. W. & Gleason, R. L. Fundamental role of axial stress in compensatory adaptations by arteries. J. Biomech. 42, 1–8 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work in the authors' laboratories was supported, in part, by grants from the US National Institutes of Health (R01 HL105297 to J.D.H. and PO1 GM98412 to M.A.S.), US National Science Foundation (CMMI-116142 to J.D.H.), Sackler Program at Yale University (to E.R.D. and J.D.H.) and the Connecticut Stem Cell Fund grant 12SCA09 (to E.R.D.).

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Yale University,

    Jay D. Humphrey & Martin A. Schwartz

  2. Department of Mechanical Engineering, Yale University,

    Eric R. Dufresne

  3. Department of Cell Biology, Yale University,

    Eric R. Dufresne & Martin A. Schwartz

  4. Department of Medicine, Yale University, New Haven, 06520, Connecticut, USA

    Martin A. Schwartz

Authors
  1. Jay D. Humphrey
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Eric R. Dufresne
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Martin A. Schwartz
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Martin A. Schwartz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Homeostasis

An active promotion of equilibrium by biological systems. Homeostasis is a process, not a state. It requires both a sensor and an effector mechanism.

Integrins

Heterodimeric transmembrane protein complexes that are fundamental to mechanically linking the extracellular matrix to the cytoskeleton, and particularly to actin filaments.

Integrin linker proteins

Intracellular proteins, such as talin, filamin, α-actinin, PINCH, parvin, vinculin and paxillin, that provide vital links between the cytosolic domain of integrins and the cytoskeleton.

Williams syndrome

A genetic disorder resulting from the deletion of multiple genes on chromosome 7, including the gene encoding elastin, that results in cardiovascular disease and neurodevelopmental problems.

Marfan syndrome

A genetic disorder that affects connective tissues throughout the body, particularly in the heart, blood vessels, bones, joints and eyes. The affected extracellular matrix glycoprotein is fibrillin 1.

Osteogenesis imperfecta

A genetic disorder that presents as eight types, having mild to lethal consequences. It results primarily from mutations that affect collagen type I and leads to brittle bones, among other effects.

Ehlers–Danlos syndrome

A group of six heritable disorders caused by different defects in the synthesis of collagen, all of which exhibit joint laxity, fragile skin and easy bruising.

Mechanotransduction

Conversion of mechanical stimuli into biochemical information by cells.

Actomyosin

Combination of thin (actin) and thick (myosin) cytoskeletal filaments that enable forceful contractions powered by ATP. Inclusion of smooth muscle β-actin into actomyosin structures based on non-muscle myosin results in stress fibres that contract more forcefully.

Fibropositors

Membrane-associated structures in embryonic cells that aid in the organized deposition of collagen within the extracellular space. They depend on actomyosin activity.

Catch bond

A small fraction of molecular bonds that strengthen under force. Most molecular bonds, covalent or non-covalent, increase their off rates under tension, exhibiting so-called 'slip bond' behaviour, with the bond weakening under force. In the case of catch bonds, off rates decrease under tension (within a certain range), thus strengthening under force.

Quasi-static

A dynamic process that nevertheless occurs slowly enough that it can be considered as a series of equilibria.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Humphrey, J., Dufresne, E. & Schwartz, M. Mechanotransduction and extracellular matrix homeostasis. Nat Rev Mol Cell Biol 15, 802–812 (2014). https://doi.org/10.1038/nrm3896

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3896

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