Fig. 4.

Model of the mechanical control of cell fate switching. Mechanical forces generated by acto-myosin interactions within the cytoskeleton are resisted by integrin adhesions to the ECM, cadherin adhesions to neighboring cells and internal cytoskeletal struts (e.g. microtubules and cross-linked actin bundles as in filopodia), thereby establishing a tensional prestress that stabilizes cell and tissue structure through a tensegrity mechanism (reviewed by Ingber, 2006). Alterations in the mechanical forces that are balanced between the ECM, neighboring cells and opposing cytoskeletal elements modulate intracellular biochemistry and gene expression (Ingber, 2006; Stamenovic and Ingber, 2009). Molecules involved in cytoskeletal tension generation, including actin, myosin II, Rho, ROCK and the Rho modulator p190RhoGAP, play a central role in this form of mechanical signaling. External forces (e.g. fluid shear stress) also can modulate gene transcription, for example through changes in nitric oxide (NO) signaling. The binding of growth factors and ECM ligands to their respective cell surface receptors can alter cellular biochemistry and gene expression independently of changes in cell prestress or external forces; however, mechanical stresses govern the final biochemical response and determine cell fate (e.g. whether stem cells differentiate into bone, muscle, nerve, blood or other cells). Physical forces exerted on surface adhesion receptors are also transmitted directly to the nucleus along cytoskeletal filaments and molecules that connect the cytoskeleton to the nucleus, such as nesprin (Wang et al., 2009). Nuclear envelope molecules, such as lamin, stabilize nuclear architecture under mechanical strain, and defects in nuclear mechanical signaling can lead to developmental abnormalities.