Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix

By P. Wipff, D. Rifkin, Jean-Jacques Meister, B. Hinz. Journal of Cell Biology, 2007

1,283 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/c59651083cf3742f37587a17f2a0bdd49b55d2a7

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Citations in the corpus

Integrins (2009, background): “More recently, a mechanical-straindependent contribution of myofibroblast β1 integrins to TGF-β activation has been demonstrated (Wipff et al. 2007).”
TGF-β Activation and Function in Immunity (2013, background): “Wipff and coworkers (170) showed that this effect could be induced in the absence of intact cells, using cytoskeletal preparations from myofibroblasts, and that TGF-β activation clearly required transmission of contractile force, because this effect was also prevented when fibroblasts were plated on”
The myofibroblast: paradigm for a mechanically active cell. (2010, background): “Importantly, mechanical activation of TGFb1 by myofibroblasts is not operational in the context of a compliant ECM with Young’s modulus of r5000kPa (Wipff et al., 2007) (Fig.”
Therapy for Fibrotic Diseases: Nearing the Starting Line (2013, background): “As highly contractile cells, myofibroblasts are well suited to exert physical force on latent TGFb (40).”
Physical traits of cancer (2020, background): “For example, matrix-bound latent TGF-b, inactive upon synthesis and unable to bind to its cognate cell surface receptors, can be activated bymyofibroblast-induced tensile forces onECM (24).”
Fibroblasts: origins, definitions, and functions in health and disease (2021, background): “Sensing of biomechanical inputs promotes fibroblast proliferation and can induce a myofibroblast state (Huang et al., 2012) and acquisition of pro-fibrotic lineage identity (Mascharak et al., 2021), which, in turn, can contract ECM to release ECMbound TGF-b (Wipff et al., 2007), further amplifying t”
TGF-β1 Signaling and Tissue Fibrosis. (2018, background): “…TGF-b activation has been plating cells on polyacrylamide gels of varying stiffness, and showing that cells plated on more deformable substrates have progressively impaired ability to activate TGF-b as the substrate deformability increases (Wipff et al. 2007; Giacomini et al. 2012).”
Transforming growth factor–β in tissue fibrosis (2020, background): “Nonproteolytic activation may involve tractional forces exerted by the actin cytoskeleton that induce conformational changes of the LLC, leading to presentation of active TGF-β to its receptors (Wipff and Hinz, 2008; Margadant and Sonnenberg, 2010; Wipff et al., 2007).”
Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer (2011, positive): “Autocrine TGF signaling and TGF- and SMAD3-independent mechanisms have also been implicated in fibroblast activation (Kaviratne et al., 2004; Moustakas and Heldin, 2005).”