Matrix elasticity, cytoskeletal tension, and TGF-beta: the insoluble and soluble meet

Abstract

Soluble growth factors are potent regulators of normal and pathological processes. Mechanical factors are emerging as similarly important, but there has been no obvious mechanism linking the different factors. A recent report now demonstrates that cell-generated mechanical tension results in release of active transforming growth factor-beta from stiff extracellular matrix, providing a mechanism for differentiation and maintenance of myofibroblasts in processes like fibrosis. More broadly, the work suggests that matrix stiffness could regulate the equilibrium between storage and release of a host of matrix-bound growth factors.

Fig. 1

Mechanical tension results in TGF-β release and maintenance of the myofibroblast phenotype through a “feed-forward” loop. Myofibroblasts behave differently on soft versus stiff matrices. On soft extracellular matrices (ECMs), cell-generated tension on the TGF-β latent complex (through α-SMA stress fibers and integrins) results in deformation of the ECM. The latent complex remains intact, keeping TGF-β sequestered in the matrix and preventing its release (left). Without release of TGF-β, there is no active TGF-β to bind to its receptor and Smads remain cytoplasmic. Existing α-SMA degrades and cells synthesize less new α-SMA, resulting in loss of the contractile, myofibroblast phenotype. When myofibroblasts are on stiff matrices, cell-generated tension meets resistance from the matrix, with deformation of the TGF-β latent complex and release of soluble TGF-β (right). This bioactive TGF-β binds its receptor, resulting in phosphorylation and nuclear localization of the Smads with synthesis of ECM, the TGF-β latent complex itself, and α-SMA, which maintains the myofibroblast phenotype or even makes it more contractile.