Mechanisms of force generation and transmission by myofibroblasts.

The myofibroblast has been shown to have a key role in tissue reconstruction after injury and pathological changes characterized by fibrosis. Force generation by the myofibroblast depends on the isometric contraction of stress fibers containing alpha-smooth muscle actin, and is mediated through Rho/Rho-kinase. The force is transmitted by vinculin and tensin-containing "supermature" focal adhesions, which connect stress fibers with the extracellular matrix. Force production and transmission by the myofibroblast are modulated by the coordinated action of cytokines, extracellular matrix components and mechanical tension. Regulation of these phenomena will be important for therapeutic strategies aimed at influencing fibrocontractive diseases.

[1]  B. Geiger,et al.  Assembly and mechanosensory function of focal contacts. , 2001, Current opinion in cell biology.

[2]  Benjamin Geiger,et al.  Exploring the Neighborhood Adhesion-Coupled Cell Mechanosensors , 2002, Cell.

[3]  K. Burridge,et al.  Rho-stimulated contractility drives the formation of stress fibers and focal adhesions , 1996, The Journal of cell biology.

[4]  A. Desmoulière,et al.  Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. , 1995, The American journal of pathology.

[5]  T Delhaas,et al.  Differential responses of adult cardiac fibroblasts to in vitro biaxial strain patterns. , 1999, Journal of molecular and cellular cardiology.

[6]  Frederick Grinnell,et al.  Fibroblast biology in three-dimensional collagen matrices. , 2003, Trends in cell biology.

[7]  C. McCulloch,et al.  The compliance of collagen gels regulates transforming growth factor-β induction of α-smooth muscle actin in fibroblasts , 1999 .

[8]  L. Addadi,et al.  Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates , 2001, Nature Cell Biology.

[9]  D. Ingber.  Tensegrity I. Cell structure and hierarchical systems biology , 2003, Journal of Cell Science.

[10]  R. Clark,et al.  In vivo co-distribution of fibronectin and actin fibers in granulation tissue: immunofluorescence and electron microscope studies of the fibronexus at the myofibroblast surface , 1984, The Journal of cell biology.

[11]  S. Phan,et al.  Regulation of alpha-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts. , 2001, The international journal of biochemistry & cell biology.

[12]  Y. Wang,et al.  Cell locomotion and focal adhesions are regulated by substrate flexibility. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Carlson,et al.  Release of mechanical tension triggers apoptosis of human fibroblasts in a model of regressing granulation tissue. , 1999, Experimental cell research.

[14]  K. Sekiguchi,et al.  Modulation of Cell-adhesive Activity of Fibronectin by the Alternatively Spliced EDA Segment , 1997, The Journal of cell biology.

[15]  Benjamin Geiger,et al.  How do microtubules guide migrating cells? , 2002, Nature Reviews Molecular Cell Biology.

[16]  Justin P. Annes,et al.  Making sense of latent TGFβ activation , 2003, Journal of Cell Science.

[17]  R. Day,et al.  Myofibroblast Differentiation by Transforming Growth Factor-β1 Is Dependent on Cell Adhesion and Integrin Signaling via Focal Adhesion Kinase* , 2003, Journal of Biological Chemistry.

[18]  N. Kaminski,et al.  The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. , 1999, Cell.

[19]  A. Harris,et al.  Silicone rubber substrata: a new wrinkle in the study of cell locomotion. , 1980, Science.

[20]  A. Chauhan,et al.  Regulated splicing of the fibronectin EDA exon is essential for proper skin wound healing and normal lifespan , 2003, The Journal of cell biology.

[21]  A. Gressner,et al.  Expression of isoforms and splice variants of the latent transforming growth factor beta binding protein (LTBP) in cultured human liver myofibroblasts. , 2001, Liver.

[22]  G. Gabbiani,et al.  Rat fibroblasts cultured from various organs exhibit differences in alpha-smooth muscle actin expression, cytoskeletal pattern, and adhesive structure organization. , 1998, Experimental cell research.

[23]  J. Molloy,et al.  Contractility of single human dermal myofibroblasts and fibroblasts. , 2002, Cell motility and the cytoskeleton.

[24]  C. McCulloch,et al.  Dependence of collagen remodelling on α‐smooth muscle actin expression by fibroblasts , 1994 .

[25]  K. Burridge.  Are stress fibres contractile? , 1981, Nature.

[26]  R. Silver,et al.  Contractile activity and smooth muscle alpha-actin organization in thrombin-induced human lung myofibroblasts. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[27]  K. Miyazono,et al.  Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein , 1994, The Journal of cell biology.

[28]  C. McCulloch,et al.  Intercellular mechanotransduction: cellular circuits that coordinate tissue responses to mechanical loading. , 2001, Biochemical and biophysical research communications.

[29]  P. Harding,et al.  Regulation of the mesangial cell myofibroblast phenotype by actin polymerization , 2003, Journal of cellular physiology.

[30]  B. Hinz,et al.  Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. , 2001, The American journal of pathology.

[31]  M Eastwood,et al.  Tensional homeostasis in dermal fibroblasts: Mechanical responses to mechanical loading in three‐dimensional substrates , 1998, Journal of cellular physiology.

[32]  A. Geinoz,et al.  The Fibronectin Domain ED-A Is Crucial for Myofibroblastic Phenotype Induction by Transforming Growth Factor-β1 , 1998, Journal of Cell Biology.

[33]  F. Grinnell,et al.  Transforming growth factor beta stimulates fibroblast-collagen matrix contraction by different mechanisms in mechanically loaded and unloaded matrices. , 2002, Experimental cell research.

[34]  B. Hinz,et al.  Cell-matrix and cell-cell contacts of myofibroblasts: role in connective tissue remodeling , 2003, Thrombosis and Haemostasis.

[35]  B. Hinz,et al.  Myofibroblasts and mechano-regulation of connective tissue remodelling , 2002, Nature Reviews Molecular Cell Biology.

[36]  Paul Martin,et al.  Wound Healing--Aiming for Perfect Skin Regeneration , 1997, Science.

[37]  F. Hirche,et al.  Fibroblasts in Mechanically Stressed Collagen Lattices Assume a “Synthetic” Phenotype* , 2001, The Journal of Biological Chemistry.

[38]  Albert K. Harris,et al.  Fibroblast traction as a mechanism for collagen morphogenesis , 1981, Nature.

[39]  Frederick Grinnell,et al.  Modulation of fibroblast morphology and adhesion during collagen matrix remodeling. , 2002, Molecular biology of the cell.

[40]  D. Sheppard,et al.  The EIIIA Segment of Fibronectin Is a Ligand for Integrins α9β1 and α4β1Providing a Novel Mechanism for Regulating Cell Adhesion by Alternative Splicing* , 2002, The Journal of Biological Chemistry.

[41]  B. Hinz,et al.  Alpha-smooth muscle actin is crucial for focal adhesion maturation in myofibroblasts. , 2003, Molecular biology of the cell.

[42]  David A. Cheresh,et al.  Get a ligand, get a life: integrins, signaling and cell survival , 2002, Journal of Cell Science.

[43]  A. Bershadsky,et al.  The state of actin assembly regulates actin and vinculin expression by a feedback loop. , 1995, Journal of cell science.

[44]  B. Hinz,et al.  Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. , 2001, Molecular biology of the cell.

[45]  M. Chiquet,et al.  Regulation of extracellular matrix gene expression by mechanical stress. , 1999, Matrix biology : journal of the International Society for Matrix Biology.

[46]  Benjamin Geiger,et al.  Focal Contacts as Mechanosensors Externally Applied Local Mechanical Force Induces Growth of Focal Contacts by an Mdia1-Dependent and Rock-Independent Mechanism , 2001 .

[47]  M Eastwood,et al.  Molecular responses of human dermal fibroblasts to dual cues: contact guidance and mechanical load. , 2000, Cell motility and the cytoskeleton.

[48]  Kenneth M. Yamada,et al.  Transmembrane crosstalk between the extracellular matrix and the cytoskeleton , 2001, Nature Reviews Molecular Cell Biology.

[49]  Jonathon Howard,et al.  Slow local movements of collagen fibers by fibroblasts drive the rapid global self-organization of collagen gels , 2002, The Journal of cell biology.

[50]  E Ruoslahti,et al.  Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activation by mechanical stretch is integrin-dependent and matrix-specific in rat cardiac fibroblasts. , 1998, The Journal of clinical investigation.

[51]  A. Seth,et al.  Mechanical force regulation of myofibroblast differentiation in cardiac fibroblasts. , 2003, American journal of physiology. Heart and circulatory physiology.

[52]  Micah Dembo,et al.  Focal adhesion kinase is involved in mechanosensing during fibroblast migration , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[53]  Frederick Grinnell,et al.  Dendritic fibroblasts in three-dimensional collagen matrices. , 2003, Molecular biology of the cell.

[54]  M. Longaker,et al.  Granulation tissue regression induced by musculocutaneous advancement flap coverage. , 2002, Surgery.

[55]  F. Silver,et al.  Mechanobiology of force transduction in dermal tissue , 2003, Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging.

[56]  Michael P. Sheetz,et al.  Force transduction by Triton cytoskeletons , 2002, The Journal of cell biology.

[57]  B. Hinz,et al.  The NH2-terminal peptide of α–smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo , 2002, The Journal of cell biology.

[58]  K. Beningo,et al.  Nascent Focal Adhesions Are Responsible for the Generation of Strong Propulsive Forces in Migrating Fibroblasts , 2001, The Journal of cell biology.

[59]  E. Howard,et al.  Regulation of LPA-promoted myofibroblast contraction: role of Rho, myosin light chain kinase, and myosin light chain phosphatase. , 2000, Experimental cell research.

[60]  Christopher S. Chen,et al.  Cells lying on a bed of microneedles: An approach to isolate mechanical force , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[61]  Richard Treisman,et al.  Signal-Regulated Activation of Serum Response Factor Is Mediated by Changes in Actin Dynamics , 1999, Cell.

[62]  Kenneth M. Yamada,et al.  Physical state of the extracellular matrix regulates the structure and molecular composition of cell-matrix adhesions. , 2000, Molecular biology of the cell.

[63]  F. Grinnell,et al.  Stress relaxation of contracted collagen gels: disruption of actin filament bundles, release of cell surface fibronectin, and down-regulation of DNA and protein synthesis. , 1991, Experimental cell research.

[64]  Michael P. Sheetz,et al.  The relationship between force and focal complex development , 2002, The Journal of cell biology.

[65]  Kenneth M. Yamada,et al.  Cell interactions with three-dimensional matrices. , 2002, Current opinion in cell biology.

[66]  K. Kaibuchi,et al.  Rho-Kinase–Mediated Contraction of Isolated Stress Fibers , 2001, The Journal of cell biology.

[67]  K. Burridge,et al.  Rho-mediated Contractility Exposes a Cryptic Site in Fibronectin and Induces Fibronectin Matrix Assembly , 1998, The Journal of cell biology.

[68]  Daniel Choquet,et al.  Extracellular Matrix Rigidity Causes Strengthening of Integrin–Cytoskeleton Linkages , 1997, Cell.

[69]  K. Preissner,et al.  Molecular Interactions and Functional Interference between Vitronectin and Transforming Growth Factor-β , 2002, Laboratory Investigation.

[70]  G. Owens,et al.  Smooth Muscle Differentiation Marker Gene Expression Is Regulated by RhoA-mediated Actin Polymerization* , 2001, The Journal of Biological Chemistry.

[71]  G. Gabbiani,et al.  Focal adhesion features during myofibroblastic differentiation are controlled by intracellular and extracellular factors. , 2001, Journal of cell science.

[72]  J. Fluck,et al.  Normal human primary fibroblasts undergo apoptosis in three-dimensional contractile collagen gels. , 1998, The Journal of investigative dermatology.