Elsevier

Differentiation

Volume 86, Issue 3, October 2013, Pages 112-120
Differentiation

From tissue mechanics to transcription factors

https://doi.org/10.1016/j.diff.2013.07.004Get rights and content

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.

Introduction

Many cell types are highly sensitive to physical as well as chemical stimuli. Transduction of physical stimuli into biochemical signaling pathways has been well characterized in systems such as the response of retinal cells to the absorption of photons, or the activation of ion channels by deflection of actin bundles in the hair cell due to acoustic waves. However, much less is known about how cells respond when the forces they generate internally are opposed by passive, viscoelastic properties of the extracellular matrix (ECM) or by neighboring cells within tissues. This brief 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 externally applied forces.

Mechanical signals can be generally classified as those that arise from the passive mechanical resistance to forces generated by the cell, and those that arise when a cell is actively subjected to forces applied by other cells, fluid flow, or gravity. In all situations, these forces are resisted by the stiffness of the ECM and the glycocalyx that surrounds cells. Changes in tissue stiffness are frequently associated with diseases such as cancer (Levental et al., 2010), fibrosis (Wells, 2008), and atherosclerosis (Duprez and Cohn, 2007, Kothapalli et al., 2012, Mitchell et al., 2010). Some studies suggest that, in addition to resulting from pathology, mechanical changes may play a role akin to soluble factors in causing the progression of such diseases. For example, measurements of the viscoelasticity of liver in experimentally-induced liver fibrosis in rats showed that the stiffness of liver, as quantified by shear elastic modulus, increased before histologically-detectable increases in ECM deposition or myofibroblast differentiation (Georges et al., 2007) (Perepelyuk et al., 2013). These results suggest that changes in tissue mechanics that can activate liver myofibroblast precursors- hepatic stellate cells (Olsen et al., 2011) and portal fibroblasts (Li et al., 2007) - precede and therefore may cause or at least contribute to development of pathosis. Increased tissue stiffness also appears to contribute to the development and spread of cancer in some models (Levental et al., 2010); the response of cells to abnormal ECM stiffness may then render them resistant to chemotherapeutic agents, possibly because of changes in the cytoskeleton-membrane interface at cell adhesions (Schrader et al., 2011).

Many cell types alter their structure and function in response to the mechanical properties of the materials to which they adhere (Pelham and Wang, 1997) and the type of adhesion receptor by which they bind (Byfield et al., 2009, Chopra et al., 2012, Ganz et al., 2006). Mechanical stimuli can act in concert with or in some cases override or prevent chemical stimulation (Wells and Discher, 2008). In vivo, cells engage their ECM both by mechanosensitive adhesion complexes and by other surface receptors, including those for growth factors and inflammatory mediators, that cannot act as adhesive anchors but that potentially modify the mechanical signals transduced at the cell/ECM interface. The cellular response to substrate stiffness in vitro or to changes in the mechanical properties of tissues during development, injury, or disease can be context-dependent, with different cell types being maximally sensitive to widely different ranges of substrate stiffness (Georges and Janmey, 2005). Substrate stiffness can be sensed by cells within 2 min of their adhesion to substrates with similar surface topologies and adhesion protein densities but different elastic moduli (Yeung et al., 2005). Pioneering studies of substrate stiffness sensing showed that this response does not require protein synthesis (Pelham and Wang, 1997), indicating that the initial response of cells to substrate mechanics requires only signals that are acutely produced in response to tension. There is no obvious universal response to substrate stiffness, but increasing stiffness commonly correlates with increased actomyosin contractility, activation of the small GTPase RhoA, increased tyrosine phosphorylation of numerous proteins, activation of focal adhesion kinase (FAK), and increased Ca2+ influx through mechanosensitive channels. How these initial signals integrate with each other and are translated into changes in cytoskeletal structure such as increased synthesis of α-smooth muscle actin (α-SMA) (Hinz et al., 2001), which is a common downstream effect of increased stiffness, and other morphological and functional responses is currently an active area of research.

While attachment of connective tissue cells to the ECM is generally reliant on the formation and remodeling of integrin-mediated, actomyosin-linked adhesions, connective tissue cells can also adhere to each other by intercellular adhesive molecules (e.g. cadherins) that may act as force (Ko et al., 2001) and stiffness (Chopra et al., 2011, Ganz et al., 2006) sensors and regulate gene expression. N-cadherin-mediated adherens junctions are influenced by integrins; fibroblasts may therefore integrate mechanical signals from intercellular and matrix adhesion systems to coordinate gene responses that are involved in differentiation, organogenesis, and wound healing (Linask et al., 2005). Mechanotransduction may not be a single isolated process involving integrins or cadherins (Ko et al., 2001, Potard et al., 1997) but instead may result from a concatenation of processes that require the recruitment of attachment, cytoskeletal, and signaling proteins. Conceivably these proteins then form docking/signaling complexes that are arranged in time and space to regulate transcription.

Section snippets

Models of transcriptional response to tissue mechanics

Most studies and models of mechanically triggered transcriptional changes suggest that the transition from physical to biochemical events occurs at the plasma membrane or within the cytoplasm and leads to biochemical changes in transcription factors or regulators that cause their entry into the nucleus to regulate gene expression. While the molecular identity of specific mechanotransducers in mammals has not been clearly defined, analysis of Caenorhabditis elegans (Syntichaki and Tavernarakis,

Substrate stiffness effects on cell proliferation and differentiation in vitro

One of the major downstream effects of mechanical signaling is altered proliferation. Indeed, the proliferation of many cell types increases with ECM stiffness. This effect is clearly seen by measuring entry into the S phase of the cell cycle or by determining the transcriptional activation of mechanosensitive cell cycle genes as described below. Proximally, these transcriptional changes result from mechanosensitive alterations in the assembly and/or phosphorylation of focal adhesion proteins

Mechanotranscription and differentiation in tissues in response to external stress

Forces affect the metabolic responses and gene expression repertoires of many tissues. Altered gene expression in response to physical signals can manifest as stimulation of bone formation (Martin, 2007, Skerry and Suva, 2003, Turner and Robling, 2004), enhanced turnover of connective tissue matrices (Ozaki et al., 2005), remodeling of the periodontium during orthodontic treatment and dental occlusal trauma (Krishnan and Davidovitch, 2009, Rygh, 1973), induction of cardiac hypertrophy by volume

Conclusion

The physical environment of a cell is as rich a source of potential signals and information as its chemical environment, and the responses of cells to physical stimuli are also likely to be as complex as their biochemical and genetic signaling pathways. Since many cells are embedded within materials composed of ECM molecules populated by neighboring force-generating cells, the homeostatic state of any single cell depends on inputs from multiple mechanosensitive signaling systems. Perturbations

References (120)

  • F. Drees et al.

    Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly

    Cell

    (2005)
  • K. Franze et al.

    Neurite branch retraction is caused by a threshold-dependent mechanical impact

    Biophysical Journal

    (2009)
  • J. Fringer et al.

    Fibroblast quiescence in floating or released collagen matrices: contribution of the ERK signaling pathway and actin cytoskeletal organization

    Journal of Biological Chemistry

    (2001)
  • P.A. Galie et al.

    Reduced serum content and increased matrix stiffness promote the cardiac myofibroblast transition in 3D collagen matrices

    Cardiovascular Pathology

    (2011)
  • P.C. Georges et al.

    Matrices with compliance comparable to that of brain tissue select neuronal over glial growth in mixed cortical cultures

    Biophysical Journal

    (2006)
  • M.B. Hautmann et al.

    A transforming growth factor beta (TGFbeta) control element drives TGFbeta-induced stimulation of smooth muscle alpha-actin gene expression in concert with two CArG elements

    Journal of Biological Chemistry

    (1997)
  • B.P. Helmke et al.

    Putting the squeeze on mechanotransduction

    Developmental Cell

    (2004)
  • G.J. Her et al.

    Control of three-dimensional substrate stiffness to manipulate mesenchymal stem cell fate toward neuronal or glial lineages

    Acta Biomaterialia

    (2013)
  • B. Hinz

    Masters and servants of the force: the role of matrix adhesions in myofibroblast force perception and transmission

    European Journal of Cell Biology

    (2006)
  • A. Katsumi et al.

    Integrins in mechanotransduction

    Journal of Biological Chemistry

    (2004)
  • E.A. Klein et al.

    Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening

    Current Biology

    (2009)
  • K.S. Ko et al.

    Cadherins mediate intercellular mechanical signaling in fibroblasts by activation of stretch-sensitive calcium-permeable channels

    Journal of Biological Chemistry

    (2001)
  • D. Kothapalli et al.

    Cardiovascular protection by ApoE and ApoE-HDL linked to suppression of ECM gene expression and arterial stiffening

    Cell Reports

    (2012)
  • N.D. Leipzig et al.

    The effect of substrate stiffness on adult neural stem cell behavior

    Biomaterials

    (2009)
  • Q. Li et al.

    The density of extracellular matrix proteins regulates inflammation and insulin signaling in adipocytes

    FEBS Letters

    (2010)
  • F. Miralles et al.

    Actin dynamics control SRF activity by regulation of its coactivator MAL

    Cell

    (2003)
  • J.A. Robinson et al.

    Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone

    Journal of Biological Chemistry

    (2006)
  • P. Roca-Cusachs et al.

    Micropatterning of single endothelial cell shape reveals a tight coupling between nuclear volume in G1 and proliferation

    Biophysical Journal

    (2008)
  • H. Rosenfeldt et al.

    Fibroblast quiescence and the disruption of ERK signaling in mechanically unloaded collagen matrices

    Journal of Biological Chemistry

    (2000)
  • M.S. Samuel et al.

    Actomyosin-mediated cellular tension drives increased tissue stiffness and beta-catenin activation to induce epidermal hyperplasia and tumor growth

    Cancer Cell

    (2011)
  • G. Tarone et al.

    Molecular interplay between mechanical and humoral signalling in cardiac hypertrophy

    Trends in Molecular Medicine

    (2003)
  • T. Tetsunaga et al.

    Regulation of mechanical stress-induced MMP-13 and ADAMTS-5 expression by RUNX-2 transcriptional factor in SW1353 chondrocyte-like cells

    Osteoarthritis and Cartilage

    (2011)
  • S.M. Thomasy et al.

    Substratum stiffness and latrunculin B modulate the gene expression of the mechanotransducers YAP and TAZ in human trabecular meshwork cells

    Experimental Eye Research

    (2013)
  • J.L. Balestrini et al.

    The mechanical memory of lung myofibroblasts

    Integrative Biology

    (2012)
  • T. Betz et al.

    Growth cones as soft and weak force generators

    Proceedings of the National Academy of Sciences of United States America

    (2011)
  • A.J. Booth et al.

    Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation

    American Journal of Respiratory and Critical Care Medicine

    (2012)
  • D. Catalucci et al.

    Physiological myocardial hypertrophy: how and why?

    Frontiers in Bioscience

    (2008)
  • C.S. Chen et al.

    Mechanotransduction at cell-matrix and cell-cell contacts

    Proceedings of the National Academy of Sciences of United States of America

    (2004)
  • J.H. Chen et al.

    beta-catenin mediates mechanically regulated, transforming growth factor-beta1-induced myofibroblast differentiation of aortic valve interstitial cells

    Arteriosclerosis, Thrombosis, and Vascular Biology

    (2011)
  • J. Cheng et al.

    The mechanical stress-activated serum-, glucocorticoid-regulated kinase 1 contributes to neointima formation in vein grafts

    Circulation Research

    (2010)
  • A. Chopra et al.

    Cardiac myocyte remodeling mediated by N-cadherin-dependent mechanosensing

    American Journal of Physiology—Heart and Circulatory Physiology

    (2011)
  • J.T. Connelly et al.

    Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisions

    Nature Cell Biology

    (2010)
  • P.F. Davies

    Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology

    Nature Clinical Practice Cardiovascular Medicine

    (2009)
  • E. Demicheva et al.

    Stretch-induced activation of the transcription factor activator protein-1 controls monocyte chemoattractant protein-1 expression during arteriogenesis

    Circulation Research

    (2008)
  • S. Dupont et al.

    Role of YAP/TAZ in mechanotransduction

    Nature

    (2011)
  • D.A. Duprez et al.

    Arterial stiffness as a risk factor for coronary atherosclerosis

    Current Atherosclerosis Reports

    (2007)
  • G. Elberg et al.

    MKL1 mediates TGF-beta1-induced alpha-smooth muscle actin expression in human renal epithelial cells

    American Journal of Physiology

    (2008)
  • A.M. Elsharkawy et al.

    Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis

    Hepatology

    (2007)
  • L.A. Flanagan et al.

    Neurite branching on deformable substrates

    Neuroreport

    (2002)
  • A. Ganz et al.

    Traction forces exerted through N-cadherin contacts

    Biology of the Cell

    (2006)
  • Cited by (0)

    View full text