Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Cell Biol. 179 (6): 1311-1323

Copyright © 2007 by the Rockefeller University Press.


Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix

Pierre-Jean Wipff1, Daniel B. Rifkin2, Jean-Jacques Meister1, , and Boris Hinz1

1 Laboratory of Cell Biophysics, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
2 Department of Cell Biology, New York University School of Medicine, New York, NY 10016

Correspondence to B. Hinz: boris.hinz{at}

Abstract: The conjunctive presence of mechanical stress and active transforming growth factor β1 (TGF-β1) is essential to convert fibroblasts into contractile myofibroblasts, which cause tissue contractures in fibrotic diseases. Using cultured myofibroblasts and conditions that permit tension modulation on the extracellular matrix (ECM), we establish that myofibroblast contraction functions as a mechanism to directly activate TGF-β1 from self-generated stores in the ECM. Contraction of myofibroblasts and myofibroblast cytoskeletons prepared with Triton X-100 releases active TGF-β1 from the ECM. This process is inhibited either by antagonizing integrins or reducing ECM compliance and is independent from protease activity. Stretching myofibroblast-derived ECM in the presence of mechanically apposing stress fibers immediately activates latent TGF-β1. In myofibroblast-populated wounds, activation of the downstream targets of TGF-β1 signaling Smad2/3 is higher in stressed compared to relaxed tissues despite similar levels of total TGF-β1 and its receptor. We propose activation of TGF-β1 via integrin-mediated myofibroblast contraction as a potential checkpoint in the progression of fibrosis, restricting autocrine generation of myofibroblasts to a stiffened ECM.

Abbreviations used in this paper: {alpha}-SMA, {alpha} smooth muscle actin; AT-II, angiotensin-II; DOC, deoxycholate; ET-1, endothelin-1; FN, fibronectin; LAP, latency associated protein; LLC, large latent complex; LTBP-1, latent TGF-β binding protein 1; Mf, myofibroblast; SLC, small latent complex; TGF-β RII, TGF-β receptor type II; TMLC, transformed mink lung reporter cells; TX-100, Triton X-100.

The fate of the primary cilium during myofibroblast transition.
M. Rozycki, M. Lodyga, J. Lam, M. Z. Miranda, K. Fatyol, P. Speight, and A. Kapus (2014)
Mol. Biol. Cell 25, 643-657
   Abstract »    Full Text »    PDF »
Aortic Carboxypeptidase-like Protein (ACLP) Enhances Lung Myofibroblast Differentiation through Transforming Growth Factor {beta} Receptor-dependent and -independent Pathways.
K. E. Tumelty, B. D. Smith, M. A. Nugent, and M. D. Layne (2014)
J. Biol. Chem. 289, 2526-2536
   Abstract »    Full Text »    PDF »
Engineered Micromechanical Cues Affecting Human Pluripotent Stem Cell Regulations and Fate.
D. Nampe and H. Tsutsui (2013)
Journal of Laboratory Automation 18, 482-493
   Abstract »    Full Text »    PDF »
Hydrogels preserve native phenotypes of valvular fibroblasts through an elasticity-regulated PI3K/AKT pathway.
H. Wang, M. W. Tibbitt, S. J. Langer, L. A. Leinwand, and K. S. Anseth (2013)
PNAS 110, 19336-19341
   Abstract »    Full Text »    PDF »
Fibroblasts and the Ground They Walk On.
D. J. Tschumperlin (2013)
Physiology 28, 380-390
   Abstract »    Full Text »    PDF »
Differential topical susceptibility to TGF{beta} in intact and injured regions of the epithelium: key role in myofibroblast transition.
P. Speight, H. Nakano, T. J. Kelley, B. Hinz, and A. Kapus (2013)
Mol. Biol. Cell 24, 3326-3336
   Abstract »    Full Text »    PDF »
TGF{beta} receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells.
G. Chen, X. Chen, A. Sukumar, B. Gao, J. Curley, H. W. Schnaper, A. J. Ingram, and J. C. Krepinsky (2013)
J. Cell Sci. 126, 3697-3712
   Abstract »    Full Text »    PDF »
Hemodynamic and Cellular Response Feedback in Calcific Aortic Valve Disease.
S. T. Gould, S. Srigunapalan, C. A. Simmons, and K. S. Anseth (2013)
Circ. Res. 113, 186-197
   Abstract »    Full Text »    PDF »
miR-145 regulates myofibroblast differentiation and lung fibrosis.
S. Yang, H. Cui, N. Xie, M. Icyuz, S. Banerjee, V. B. Antony, E. Abraham, V. J. Thannickal, and G. Liu (2013)
FASEB J 27, 2382-2391
   Abstract »    Full Text »    PDF »
Therapy for Fibrotic Diseases: Nearing the Starting Line.
S. L. Friedman, D. Sheppard, J. S. Duffield, and S. Violette (2013)
Science Translational Medicine 5, 167sr1
   Full Text »    PDF »
Production of Gastrointestinal Tumors in Mice by Modulating Latent TGF-{beta}1 Activation.
K. Shibahara, M. Ota, M. Horiguchi, K. Yoshinaga, J. Melamed, and D. B. Rifkin (2013)
Cancer Res. 73, 459-468
   Abstract »    Full Text »    PDF »
Neuronal Wiskott-Aldrich syndrome protein (N-WASP) is critical for formation of {alpha}-smooth muscle actin filaments during myofibroblast differentiation.
G.-Q. Cai, C.-F. Chou, M. Hu, A. Zheng, L. F. Reichardt, J.-L. Guan, H. Fang, T. R. Luckhardt, Y. Zhou, V. J. Thannickal, et al. (2012)
Am J Physiol Lung Cell Mol Physiol 303, L692-L702
   Abstract »    Full Text »    PDF »
Matrix control of transforming growth factor-{beta} function.
M. Horiguchi, M. Ota, and D. B. Rifkin (2012)
J. Biochem. 152, 321-329
   Abstract »    Full Text »    PDF »
ECM stiffness primes the TGF{beta} pathway to promote chondrocyte differentiation.
J. L. Allen, M. E. Cooke, and T. Alliston (2012)
Mol. Biol. Cell 23, 3731-3742
   Abstract »    Full Text »    PDF »
Modelling the interaction of keratinocytes and fibroblasts during normal and abnormal wound healing processes.
S. N. Menon, J. A. Flegg, S. W. McCue, R. C. Schugart, R. A. Dawson, and D. L. S. McElwain (2012)
Proc R Soc B 279, 3329-3338
   Abstract »    Full Text »    PDF »
Cells Lacking {beta}-Actin are Genetically Reprogrammed and Maintain Conditional Migratory Capacity.
D. Tondeleir, A. Lambrechts, M. Muller, V. Jonckheere, T. Doll, D. Vandamme, K. Bakkali, D. Waterschoot, M. Lemaistre, O. Debeir, et al. (2012)
Mol. Cell. Proteomics 11, 255-271
   Abstract »    Full Text »    PDF »
Improved throughput traction microscopy reveals pivotal role for matrix stiffness in fibroblast contractility and TGF-{beta} responsiveness.
A. Marinkovic, J. D. Mih, J.-A. Park, F. Liu, and D. J. Tschumperlin (2012)
Am J Physiol Lung Cell Mol Physiol 303, L169-L180
   Abstract »    Full Text »    PDF »
uPA Binding to PAI-1 Induces Corneal Myofibroblast Differentiation on Vitronectin.
L. Wang, C. M. Ly, C.-Y. Ko, E. E. Meyers, D. A. Lawrence, and A. M. Bernstein (2012)
Invest. Ophthalmol. Vis. Sci. 53, 4765-4775
   Abstract »    Full Text »    PDF »
Interstitial Fluid and Lymph Formation and Transport: Physiological Regulation and Roles in Inflammation and Cancer.
H. Wiig and M. A. Swartz (2012)
Physiol Rev 92, 1005-1060
   Abstract »    Full Text »    PDF »
Deconstructing the third dimension - how 3D culture microenvironments alter cellular cues.
B. M. Baker and C. S. Chen (2012)
J. Cell Sci. 125, 3015-3024
   Abstract »    Full Text »    PDF »
GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGF{beta} signaling.
A. Willaert, S. Khatri, B. L. Callewaert, P. J. Coucke, S. D. Crosby, J. G. H. Lee, E. C. Davis, S. Shiva, M. Tsang, A. De Paepe, et al. (2012)
Hum. Mol. Genet. 21, 1248-1259
   Abstract »    Full Text »    PDF »
GARP regulates the bioavailability and activation of TGF{beta}.
R. Wang, J. Zhu, X. Dong, M. Shi, C. Lu, and T. A. Springer (2012)
Mol. Biol. Cell 23, 1129-1139
   Abstract »    Full Text »    PDF »
Integrin {alpha}v{beta}5-Mediated TGF-{beta} Activation by Airway Smooth Muscle Cells in Asthma.
A. L. Tatler, A. E. John, L. Jolly, A. Habgood, J. Porte, C. Brightling, A. J. Knox, L. Pang, D. Sheppard, X. Huang, et al. (2011)
J. Immunol. 187, 6094-6107
   Abstract »    Full Text »    PDF »
Cross Talk among TGF-{beta} Signaling Pathways, Integrins, and the Extracellular Matrix.
J. S. Munger and D. Sheppard (2011)
Cold Spring Harb Perspect Biol 3, a005017
   Abstract »    Full Text »    PDF »
Hepatic stellate cells require a stiff environment for myofibroblastic differentiation.
A. L. Olsen, S. A. Bloomer, E. P. Chan, M. D. A. Gaca, P. C. Georges, B. Sackey, M. Uemura, P. A. Janmey, and R. G. Wells (2011)
Am J Physiol Gastrointest Liver Physiol 301, G110-G118
   Abstract »    Full Text »    PDF »
SPARC promotes pericyte recruitment via inhibition of endoglin-dependent TGF-{beta}1 activity.
L. B. Rivera and R. A. Brekken (2011)
J. Cell Biol. 193, 1305-1319
   Abstract »    Full Text »    PDF »
The lens as a model for fibrotic disease.
J. A. Eldred, L. J. Dawes, and I. M. Wormstone (2011)
Phil Trans R Soc B 366, 1301-1319
   Abstract »    Full Text »    PDF »
Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer.
T. R. Cox and J. T. Erler (2011)
Dis. Model. Mech. 4, 165-178
   Abstract »    Full Text »    PDF »
Getting Physical With the Aortic Valve.
P. F. Davies and M. A. Guerraty (2011)
Arterioscler Thromb Vasc Biol 31, 474-475
   Full Text »    PDF »
Tumor Cell Invasion Is Promoted by Interstitial Flow-Induced Matrix Priming by Stromal Fibroblasts.
A. C. Shieh, H. A. Rozansky, B. Hinz, and M. A. Swartz (2011)
Cancer Res. 71, 790-800
   Abstract »    Full Text »    PDF »
Altered dynamics of transforming growth factor {beta} (TGF-{beta}) receptors in scleroderma fibroblasts.
Y. Asano, H. Ihn, M. Jinnin, K. Tamaki, and S. Sato (2011)
Ann Rheum Dis 70, 384-387
   Abstract »    Full Text »    PDF »
Mammary Gland ECM Remodeling, Stiffness, and Mechanosignaling in Normal Development and Tumor Progression.
P. Schedin and P. J. Keely (2011)
Cold Spring Harb Perspect Biol 3, a003228
   Abstract »    Full Text »    PDF »
The extracellular matrix at a glance.
C. Frantz, K. M. Stewart, and V. M. Weaver (2010)
J. Cell Sci. 123, 4195-4200
   Full Text »    PDF »
The pathogenesis of idiopathic pulmonary fibrosis.
W. R. Coward, G. Saini, and G. Jenkins (2010)
Therapeutic Advances in Respiratory Disease 4, 367-388
   Abstract »    PDF »
Defective granulation tissue formation in mice with specific ablation of integrin-linked kinase in fibroblasts - role of TGF{beta}1 levels and RhoA activity.
K. Blumbach, M. C. Zweers, G. Brunner, A. S. Peters, M. Schmitz, J.-N. Schulz, A. Schild, C. P. Denton, T. Sakai, R. Fassler, et al. (2010)
J. Cell Sci. 123, 3872-3883
   Abstract »    Full Text »    PDF »
Expression of integrin {beta}1 by fibroblasts is required for tissue repair in vivo.
S. Liu, X. Shi-wen, K. Blumbach, M. Eastwood, C. P. Denton, B. Eckes, T. Krieg, D. J. Abraham, and A. Leask (2010)
J. Cell Sci. 123, 3674-3682
   Abstract »    Full Text »    PDF »
Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression.
F. Liu, J. D. Mih, B. S. Shea, A. T. Kho, A. S. Sharif, A. M. Tager, and D. J. Tschumperlin (2010)
J. Cell Biol. 190, 693-706
   Abstract »    Full Text »    PDF »
Thy-1-Integrin {alpha}v{beta}5 Interactions Inhibit Lung Fibroblast Contraction-induced Latent Transforming Growth Factor-{beta}1 Activation and Myofibroblast Differentiation.
Y. Zhou, J. S. Hagood, B. Lu, W. D. Merryman, and J. E. Murphy-Ullrich (2010)
J. Biol. Chem. 285, 22382-22393
   Abstract »    Full Text »    PDF »
FAK mediates the activation of cardiac fibroblasts induced by mechanical stress through regulation of the mTOR complex.
A. P. Dalla Costa, C. F. M. Z. Clemente, H. F. Carvalho, J. B. Carvalheira, W. Nadruz Jr, and K. G. Franchini (2010)
Cardiovasc Res 86, 421-431
   Abstract »    Full Text »    PDF »
Pericellular fibronectin is required for RhoA-dependent responses to cyclic strain in fibroblasts.
R. Lutz, T. Sakai, and M. Chiquet (2010)
J. Cell Sci. 123, 1511-1521
   Abstract »    Full Text »    PDF »
Fibrinogen Triggers Astrocyte Scar Formation by Promoting the Availability of Active TGF-{beta} after Vascular Damage.
C. Schachtrup, J. K. Ryu, M. J. Helmrick, E. Vagena, D. K. Galanakis, J. L. Degen, R. U. Margolis, and K. Akassoglou (2010)
J. Neurosci. 30, 5843-5854
   Abstract »    Full Text »    PDF »
The Fibroblast Integrin {alpha}11{beta}1 Is Induced in a Mechanosensitive Manner Involving Activin A and Regulates Myofibroblast Differentiation.
S. Carracedo, N. Lu, S. N. Popova, R. Jonsson, B. Eckes, and D. Gullberg (2010)
J. Biol. Chem. 285, 10434-10445
   Abstract »    Full Text »    PDF »
Nanoscale Topography-Induced Modulation of Fundamental Cell Behaviors of Rabbit Corneal Keratocytes, Fibroblasts, and Myofibroblasts.
S. A. Pot, S. J. Liliensiek, K. E. Myrna, E. Bentley, J. V. Jester, P. F. Nealey, and C. J. Murphy (2010)
Invest. Ophthalmol. Vis. Sci. 51, 1373-1381
   Abstract »    Full Text »    PDF »
Integrin-TGF-{beta} crosstalk in fibrosis, cancer and wound healing.
C. Margadant and A. Sonnenberg (2010)
EMBO Rep. 11, 97-105
   Abstract »    Full Text »    PDF »
Transforming growth factor beta (TGFB) signaling is activated during porcine implantation: proposed role for latency-associated peptide interactions with integrins at the conceptus-maternal interface.
D. A Massuto, E. C Kneese, G. A Johnson, R. C Burghardt, R N. Hooper, N. H Ing, and L. A Jaeger (2010)
Reproduction 139, 465-478
   Abstract »    Full Text »    PDF »
Incorporation of Tenascin-C into the Extracellular Matrix by Periostin Underlies an Extracellular Meshwork Architecture.
I. Kii, T. Nishiyama, M. Li, K.-i. Matsumoto, M. Saito, N. Amizuka, and A. Kudo (2010)
J. Biol. Chem. 285, 2028-2039
   Abstract »    Full Text »    PDF »
TGF-{beta} suppresses the upregulation of MMP-2 by vascular smooth muscle cells in response to PDGF-BB.
G. M. Risinger Jr., D. L. Updike, E. C. Bullen, J. J. Tomasek, and E. W. Howard (2010)
Am J Physiol Cell Physiol 298, C191-C201
   Abstract »    Full Text »    PDF »
Plasminogen Activator Inhibitor-1 Regulates Integrin {alpha}v{beta}3 Expression and Autocrine Transforming Growth Factor {beta} Signaling.
B. S. Pedroja, L. E. Kang, A. O. Imas, P. Carmeliet, and A. M. Bernstein (2009)
J. Biol. Chem. 284, 20708-20717
   Abstract »    Full Text »    PDF »
Growth Factors, Matrices, and Forces Combine and Control Stem Cells.
D. E. Discher, D. J. Mooney, and P. W. Zandstra (2009)
Science 324, 1673-1677
   Abstract »    Full Text »    PDF »
Overview of pathogenesis of systemic sclerosis.
D. J. Abraham, T. Krieg, J. Distler, and O. Distler (2009)
Rheumatology 48, iii3-iii7
   Abstract »    Full Text »    PDF »
Sustained activation of STAT5 is essential for chromatin remodeling and maintenance of mammary-specific function.
R. Xu, C. M. Nelson, J. L. Muschler, M. Veiseh, B. K. Vonderhaar, and M. J. Bissell (2009)
J. Cell Biol. 184, 57-66
   Abstract »    Full Text »    PDF »
Perturbation of transforming growth factor (TGF)-ss1 association with latent TGF-{beta} binding protein yields inflammation and tumors.
K. Yoshinaga, H. Obata, V. Jurukovski, R. Mazzieri, Y. Chen, L. Zilberberg, D. Huso, J. Melamed, P. Prijatelj, V. Todorovic, et al. (2008)
PNAS 105, 18758-18763
   Abstract »    Full Text »    PDF »
Lkb1 is required for TGF{beta}-mediated myofibroblast differentiation.
K. Vaahtomeri, E. Ventela, K. Laajanen, P. Katajisto, P.-J. Wipff, B. Hinz, T. Vallenius, M. Tiainen, and T. P. Makela (2008)
J. Cell Sci. 121, 3531-3540
   Abstract »    Full Text »    PDF »
In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-{beta}1.
J. Ahamed, N. Burg, K. Yoshinaga, C. A. Janczak, D. B. Rifkin, and B. S. Coller (2008)
Blood 112, 3650-3660
   Abstract »    Full Text »    PDF »
Myofibroblast communication is controlled by intercellular mechanical coupling.
L. Follonier, S. Schaub, J.-J. Meister, and B. Hinz (2008)
J. Cell Sci. 121, 3305-3316
   Abstract »    Full Text »    PDF »
Focal Adhesion Kinase (FAK)-related Non-kinase Inhibits Myofibroblast Differentiation through Differential MAPK Activation in a FAK-dependent Manner.
Q. Ding, C. L. Gladson, H. Wu, H. Hayasaka, and M. A. Olman (2008)
J. Biol. Chem. 283, 26839-26849
   Abstract »    Full Text »    PDF »
Matrix Elasticity, Cytoskeletal Tension, and TGF-{beta}: The Insoluble and Soluble Meet.
R. G. Wells and D. E. Discher (2008)
Science Signaling 1, pe13
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882