Role of the actin cytoskeleton in tuning cellular responses to external mechanical stress
ABSTRACT Mechanical forces are essential for tissue homeostasis. In adherent cells, cell-matrix adhesions connect the extracellular matrix (ECM) with the cytoskeleton and transmit forces in both directions. Integrin receptors and signaling molecules in cell-matrix adhesions transduce mechanical into chemical signals, thereby regulating many cellular processes. This review focuses on how cellular mechanotransduction is tuned by actin-generated cytoskeletal tension that balances external with internal mechanical forces. We point out that the cytoskeleton rapidly responds to external forces by RhoA-dependent actin assembly and contraction. This in turn induces remodeling of cell-matrix adhesions and changes in cell shape and orientation. As a consequence, a cell constantly modulates its response to new bouts of external mechanical stimulation. Changes in actin dynamics are monitored by MAL/MKL-1/MRTF-A, a co-activator of serum response factor. Recent evidence suggests that MAL is also involved in coupling mechanically induced changes in the actin cytoskeleton to gene expression. Compared with other, more rapid and transient signals evoked at the cell surface, this parallel mechanotransduction pathway is more sustained and provides spatial and temporal specificity to the response. We describe examples of genes that are regulated by mechanical stress in a manner depending on actin dynamics, among them the ECM protein, tenascin-C.
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ABSTRACT: Extracellular matrix (ECM) within the vascular network provides both a structural and regulatory role. The ECM is a dynamic composite of multiple proteins that form structures connecting cells within the network. Blood vessels are distended by blood pressure and, therefore, require ECM components with elasticity yet with enough tensile strength to resist rupture. The ECM is involved in conducting mechanical signals to cells. Most importantly, ECM regulates cellular function through chemical signaling by controlling activation and bioavailability of the growth factors. Cells respond to ECM by remodeling their microenvironment which becomes dysregulated in vascular diseases such hypertension, restenosis and atherosclerosis. This review examines the cellular and ECM components of vessels, with specific emphasis on the regulation of collagen type I and implications in vascular disease.01/2014; 28(1):25-39. DOI:10.7555/JBR.27.20130064
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ABSTRACT: To test the hypothesis that the pericellular fibronectin matrix is involved in mechanotransduction, we compared the response of normal and fibronectin-deficient mouse fibroblasts to cyclic substrate strain. Normal fibroblasts seeded on vitronectin in fibronectin-depleted medium deposited their own fibronectin matrix. In cultures exposed to cyclic strain, RhoA was activated, actin-stress fibers became more prominent, MAL/MKL1 shuttled to the nucleus, and mRNA encoding tenascin-C was induced. By contrast, these RhoA-dependent responses to cyclic strain were suppressed in fibronectin knockdown or knockout fibroblasts grown under identical conditions. On vitronectin substrate, fibronectin-deficient cells lacked fibrillar adhesions containing alpha5 integrin. However, when fibronectin-deficient fibroblasts were plated on exogenous fibronectin, their defects in adhesions and mechanotransduction were restored. Studies with fragments indicated that both the RGD-synergy site and the adjacent heparin-binding region of fibronectin were required for full activity in mechanotransduction, but not its ability to self-assemble. In contrast to RhoA-mediated responses, activation of Erk1/2 and PKB/Akt by cyclic strain was not affected in fibronectin-deficient cells. Our results indicate that pericellular fibronectin secreted by normal fibroblasts is a necessary component of the strain-sensing machinery. Supporting this hypothesis, induction of cellular tenascin-C by cyclic strain was suppressed by addition of exogenous tenascin-C, which interferes with fibronectin-mediated cell spreading.Journal of Cell Science 04/2010; 123(Pt 9):1511-21. DOI:10.1242/jcs.060905 · 5.33 Impact Factor
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ABSTRACT: Mechanical forces play important roles in the regulation of cellular functions, including polarization, migration and stem cell differentiation. Tremendous advancement in our understanding of mechanotransduction has been achieved with the recent development of imaging technologies and molecular biosensors. In particular, genetically encoded biosensors based on fluorescence resonance energy transfer (FRET) technology have been widely developed and applied in the field of mechanobiology. In this article, we will provide an overview of the recent progress of FRET application in mechanobiology, specifically mechanotransduction. We first introduce fluorescent proteins and FRET technology. We then discuss the mechanotransduction processes in different cells including stem cells, with a special emphasis on the important signalling molecules involved in mechanotransduction. Finally, we discuss methods that can allow the integration of simultaneous FRET imaging and mechanical stimulation to trigger signalling transduction. In summary, FRET technology has provided a powerful tool for the study of mechanotransduction to advance our systematic understanding of the molecular mechanisms by which cells respond to mechanical stimulation.Journal of The Royal Society Interface 03/2010; 7 Suppl 3:S365-75. DOI:10.1098/rsif.2010.0042.focus · 3.86 Impact Factor