Figure 3.

Mechanisms of mechanotransduction implicated in myofibroblast differentiation and function. TGF-β1 stimulates an increased expression of EDA–FN. The EDA segment contains the EDGIHEL motif, which binds to the integrin α4β1/α4β7 receptor cleft, initiating signalling through RhoA/MLCK and FAK. RhoA signalling results in myosin light chain (MLC) promotion of myosin (MYH)/actin assembly and stress fibre polymerisation, which is augmented by HYAL2 that relocates from the membrane to the cytoplasm. RGD motif containing ligands, such as FN and collagens, bind integrins and facilitate the formation of focal adhesion sites, increasing contractile force and α-SMA incorporation into actin stress fibres. In addition, the increased matrix stress generated by EDA–FN and increased MMP activation from CD147 recruitment exacerbates active TGF-β1 release from the extracellular LAP complex.