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Published online
doi:10.1083/jcb.200704042
The Journal of Cell Biology, Vol. 179, No. 6, 1311-1323
The Rockefeller University Press, 0021-9525 $30.00
© Wipff et al.
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Article

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}epfl.ch

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.


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