Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation

J Cell Biol. 2014 Oct 27;207(2):283-97. doi: 10.1083/jcb.201402006. Epub 2014 Oct 20.

Abstract

Integrin-mediated force application induces a conformational change in latent TGF-β1 that leads to the release of the active form of the growth factor from the extracellular matrix (ECM). Mechanical activation of TGF-β1 is currently understood as an acute process that depends on the contractile force of cells. However, we show that ECM remodeling, preceding the activation step, mechanically primes latent TGF-β1 akin to loading a mechanical spring. Cell-based assays and unique strain devices were used to produce a cell-derived ECM of controlled organization and prestrain. Mechanically conditioned ECM served as a substrate to measure the efficacy of TGF-β1 activation after cell contraction or direct force application using magnetic microbeads. The release of active TGF-β1 was always higher from prestrained ECM as compared with unorganized and/or relaxed ECM. The finding that ECM prestrain regulates the bioavailability of TGF-β1 is important to understand the context of diseases that involve excessive ECM remodeling, such as fibrosis or cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Extracellular Matrix / metabolism*
  • HEK293 Cells
  • Humans
  • Integrins / metabolism
  • Integrins / physiology
  • Mechanotransduction, Cellular
  • Myofibroblasts / cytology
  • Myofibroblasts / metabolism
  • Rats, Wistar
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • Integrins
  • Transforming Growth Factor beta1