From tissue mechanics to transcription factors

Abstract

Changes in tissue stiffness are frequently associated with diseases such as cancer, fibrosis, and atherosclerosis. Several recent studies suggest that, in addition to resulting from pathology, mechanical changes may play a role akin to soluble factors in causing the progression of disease, and similar mechanical control might be essential for normal tissue development and homeostasis. Many cell types alter their structure and function in response to exogenous forces or as a function of the mechanical properties of the materials to which they adhere. This review summarizes recent progress in identifying intracellular signaling pathways, and especially transcriptional programs, that are differentially activated when cells adhere to materials with different mechanical properties or when they are subject to tension arising from external forces. Several cytoplasmic or cytoskeletal signaling pathways involving small GTPases, focal adhesion kinase and transforming growth factor beta as well as the transcriptional regulators MRTF-A, NFκB, and Yap/Taz have emerged as important mediators of mechanical signaling.

Keywords: Mechanical stress; Mechanosensing; Mechanotransduction; Substrate stiffness.

Fig. 1

Signaling pathways that are regulated by matrix stiffness and alter internal tension, proliferation, differentiation, or other transcriptional programs. (A) Rigid substrates lead to inhibition of p120-RhoGAP, and therefore increased activity of signals that depend on GTP-Rho. Substrate rigidity also increases FAK phosphorylation, Rac activity and processes such as proliferation that lie downstream of these signals. Cytoskeletal contractility due to increased Rho and Rac activity can transmit tension from the rigid substrate to the nuclear membrane or chromatin to directly alter gene accessibility or reaction with transcriptional complexes. (B) Two different proposed mechanisms linking substrate mechanics to transcription. Transcription activated by MAL/MRTF and SRF depends on changes in actin assembly that are regulated by substrate stiffness, and not necessarily to the physical stimuli directly. Yap/Taz/Yorkie, in contrast, appear to respond directly to intracellular tension, perhaps mediated by attachment to the cytoskeleton or its membrane linkages but not to biochemical changes in the actin network.

Fig. 2

Signaling pathways activated by external force. (A) Cell stretching model for analyzing mechanotranscriptional signaling pathways. Focal adhesions are depicted on the ventral surface but adhesions also form in response to collagen beads attached to the dorsal cell surface. Collagen beads are attached to the dorsal surfaces of cells by β1 integrins. Stretching forces are applied (0.5–2 pN/mm² surface area of cell). The stretching forces can be adjusted in terms of amplitude, direction and duration, to suit the desired experimental condition. (B) RhoA and MRTF-A as actin-related regulators of cellular response to external mechanical stress. When forces are imposed on integrins bound to collagen coated bead substrates, actin assembly regulation is initiated by changes in RhoA activity. In parallel, changes in the state of actin assembly alter the degree to which the transcription regulator MRTF-A is sequestered in the cytoplasm by its interaction with G-actin. Liberation of MRTF-A when actin polymerization increases leads to SRF activation and expression of gene products such as α-SMA that are characteristic of mesenchymal cell adhesion to rigid substrates and a more contractile phenotype.