Differentiation of embryonic stem cells (ESCs) into definitive endoderm requires signalling by both growth factors – such as activin A and Wnt3a – and extracellular matrix (ECM) components – such as fibronectin (FN) and laminin. Although ESCs do both, exerting traction forces and responding to the mechanical properties of the ECM, little is currently known about how soluble factors induce biochemical and physical changes in the ESCs and their associated matrix, when added to differentiate ESCs. Here (p. ), Adam Engler and colleagues used a force-sensitive FN matrix assay in mouse ESCs to understand the crosstalk between mechanical factors and chemical signals in ESCs and the ECM in directing developmental cues. Addition of the myosin inhibitor blebbistatin inhibited ESC differentiation, indicating that traction forces are necessary for the formation of definitive endoderm. This effect is possibly exerted through TGF-β signalling because this treatment transiently prevented the nuclear translocation of the TGF-β effector phosphorylated SMAD2. The authors then showed that extracellular laminin-111 regulated differentiation; its binding to α3β1-integrin inhibited the SMAD2 inhibitor SMAD7 and also decreased FN-induced matrix strain that acts through α5β1-integrin. Taken together, this study shows that soluble factors that induce ESC differentiation activate traction forces, which – in turn – utilise integrins and ECM remodelling to feedback and support growth-factor-activated signalling cascades.
