Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix

J Cell Biol. 2007 Dec 17;179(6):1311-23. doi: 10.1083/jcb.200704042.

Abstract

The conjunctive presence of mechanical stress and active transforming growth factor beta1 (TGF-beta1) 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-beta1 from self-generated stores in the ECM. Contraction of myofibroblasts and myofibroblast cytoskeletons prepared with Triton X-100 releases active TGF-beta1 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-beta1. In myofibroblast-populated wounds, activation of the downstream targets of TGF-beta1 signaling Smad2/3 is higher in stressed compared to relaxed tissues despite similar levels of total TGF-beta1 and its receptor. We propose activation of TGF-beta1 via integrin-mediated myofibroblast contraction as a potential checkpoint in the progression of fibrosis, restricting autocrine generation of myofibroblasts to a stiffened ECM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytoskeleton / physiology
  • Extracellular Matrix / metabolism*
  • Fibroblasts / physiology*
  • Fibroblasts / ultrastructure
  • Integrins / physiology
  • Muscle Contraction / physiology*
  • Myoblasts, Smooth Muscle / physiology*
  • Myoblasts, Smooth Muscle / ultrastructure
  • Phosphorylation
  • Rats
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism
  • Stress, Mechanical
  • Transforming Growth Factor beta1 / metabolism*
  • Wound Healing / physiology

Substances

  • Integrins
  • Smad2 Protein
  • Smad2 protein, rat
  • Smad3 Protein
  • Smad3 protein, rat
  • Transforming Growth Factor beta1