Role of the actin cytoskeleton in tuning cellular responses to external mechanical stress

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Scandinavian Journal of Medicine and Science in Sports (Impact Factor: 3.17). 05/2009; 19(4):490-9. DOI: 10.1111/j.1600-0838.2009.00928.x
Source: PubMed

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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    • "Translocation to the nucleus occurs following Rho family activation and polymerization of actin cytoskeleton into stress fibers linking actin dynamics to transcription [73] . These related factors are the proteins that respond to stretching or force [80] . MRTF-B is required for vascular development and differentiation of smooth muscle cell [81] . "
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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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    • "Mechanical forces stimulate cell differentiation and control/maintain tissue function via membrane associated " mechanoreceptor " mechanisms, activation of second messengers and downstream gene regulation in various mammalian systems like musculoskeletal and cardiovascular tissues (Hahn and Schwartz, 2009; Jani and Schock, 2009; Papachroni et al., 2009). Cell adhesion molecules like integrins, membrane associated receptors and strain sensitive channels have been described to transmit mechanical forces to intracellular structures like the actin cytoskeleton and second messengers like calcium flux (Asparuhova et al., 2009; Huveneers and Danen, 2009; Kiselyov and Patterson, 2009; Puklin-Faucher and Sheetz, 2009; Sharif-Naeini et al., 2010). Mechanobiochemical transformation in single cells is elicited by the stimulation of ERK1/2 kinase phosphorylation cascades, activation and nuclear translocation of transcription factors and modulation of gene expression (Khatiwala et al., 2009; Klossner et al., 2009; Liu et al., 2009; Rangaswami et al., 2009; Young et al., 2009). "
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    ABSTRACT: Mechanical forces are translated into biochemical signals and contribute to cell differentiation and phenotype maintenance. Mesenchymal stem cells and their tissue-specific offspring, as osteoblasts and chondrocytes, cells of cardiovascular tissues and lung cells are sensitive to mechanical loading but molecules and mechanisms involved have to be unraveled. It is well established that cellular mechanotransduction is mediated e.g. by activation of the transcription factor SP1 and by kinase signaling cascades resulting in the activation of the AP1 complex. To investigate cellular mechanisms involved in mechanotransduction and to analyze substances, which modulate cellular mechanosensitivity reporter gene constructs, which can be transfected into cells of interest might be helpful. Suitable small-scale bioreactor systems and mechanosensitive reporter gene constructs are lacking. To analyze the molecular mechanisms of mechanotransduction and its crosstalk with biochemically induced signal transduction, AP1 and SP1 luciferase reporter gene constructs were cloned and transfected into various cell lines and primary cells. A newly developed bioreactor and small-scale 24-well polyurethane dishes were used to apply cyclic stretching to the transfected cells. 1 Hz cyclic stretching for 30 min in this system resulted in a significant stimulation of AP1 and SP1 mediated luciferase activity compared to unstimulated cells. In summary we describe a small-scale cell culture/bioreactor system capable of analyzing subcellular crosstalk mechanisms in mechanotransduction, mechanosensitivity of primary cells and of screening the activity of putative mechanosensitizers as new targets, e.g. for the treatment of bone loss caused by both disuse and signal transduction related alterations of mechanotransduction.
    European cells & materials 07/2010; 20:344-55. · 4.89 Impact Factor
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    • "MAL (MKL-1; MRTF-A) is a transcriptional co-activator of serum response factor (SRF) that cycles between the cytoplasm and the nucleus under the control of RhoA-dependent actin dynamics (Asparuhova et al., 2009; Miralles et al., 2003). Mechanical strain stimulates actin reorganization and was shown to promote a shift of MAL from the cytoplasm to the nucleus in serum-starved cells (Maier et al., 2008; Zhao et al., 2007). "
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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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