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Myofibroblasts and mechano-regulation of connective tissue remodelling

Key Points

  • Myofibroblasts are the predominant cell type that are present in granulation tissue of contracting wounds and fibrocontractive diseases, and are also present in some developing or normal adult tissues.

  • The putative function of myofibroblasts is generating force and altering tissue tension.

  • Myofibroblasts were initially characterized by the presence of microfilament bundles (stress fibres) that are not present in tissue fibroblasts.

  • Two types of myofibroblasts can be characterized: proto-myofibroblasts, which contain stress fibres but lack α-smooth muscle (SM) actin, and differentiated myofibroblasts, which contain both stress fibres and α-SM actin.

  • The formation and maintenance of the proto-myofibroblast is dependent on isometric tension applied onto a non-compliant substratum.

    The expression of α-SM actin that is characteristic of the differentiated myofibroblast is dependent on interaction of ED-A fibronectin with the cell surface and transforming growth factor β1 (TGF-β1).

  • Myofibroblasts in granulation tissue and in in vitro contraction assays generate contractile force in response to certain SM agonists (such as endothelin).

  • Increased expression of α-SM actin is directly correlated with increased force generation by myofibroblasts.

  • We postulate a positive feedback loop in which tension facilitates TGF-β1 production and/or activation and α-SM actin expression. This, in turn, increases force production and tension development.

  • Myofibroblast contraction is regulated by the level of myosin light chain phosphorylation and the key regulatory step seems to be activation of the Rho–Rho-kinase pathway, which results in the inhibition of myosin light chain phosphatase and increased myosin light chain phosphorylation and contraction.

  • Tissue contraction (contracture) depends on collagen remodelling, a process that is dominated by extracellular-matrix reorganization under the mechanical control of myofibroblast contraction.

Abstract

During the past 20 years, it has become generally accepted that the modulation of fibroblastic cells towards the myofibroblastic phenotype, with acquisition of specialized contractile features, is essential for connective-tissue remodelling during normal and pathological wound healing. Yet the myofibroblast still remains one of the most enigmatic of cells, not least owing to its transient appearance in association with connective-tissue injury and to the difficulties in establishing its role in the production of tissue contracture. It is clear that our understanding of the myofibroblast — its origins, functions and molecular regulation — will have a profound influence on the future effectiveness not only of tissue engineering but also of regenerative medicine generally.

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Figure 1: Myofibroblasts in epiretinal membrane.
Figure 2: The two-stage model of myofibroblast differentiation.
Figure 3: Three-dimensional collagen-lattice model.
Figure 4: Mechanical tension induces myofibroblast differentiation in wound granulation tissue.
Figure 5: α-smooth muscle (SM) actin expression correlates with wrinkling on silicone substrates.
Figure 6: Scar contracture across the wrist following a burn injury.
Figure 7: Model of extracellular-matrix-remodelling phase of matrix contracture.
Figure 8: Contracture in three-dimensional collagen lattices.
Figure 9: Model of the role of myofibroblasts during the healing of an open wound.

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Acknowledgements

The authors acknowledge the support of the National Institutes of Health, the Wellcome Foundation, the Swiss National Science Foundation, UCB-Bioproducts and the European Union Framework V awards. We thank Professor D. A. McGrouther (University of Manchester) for his helpful early discussions and E. Homberg for secretarial work. We apologize for the failure to cite many important contributions to this field owing to space limitations.

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DATABASES

LocusLink

TGF-β1

OMIM

Dupuytren's disease

Swiss-Prot

α-actinin

angiotensin II

β-cytoplasmic actin

γ-cytoplasmic actin

decorin

ED-A

ED-B

FAK

fibromodulin

lumican

MLCK

MMP1

MMP2

MMP3

MMP9

PAI-1

paxillin

procollagen N-protease

Rho kinase

ROKα

talin

tensin

vinculin

Glossary

CONNECTIVE TISSUES

Tissues that form the architectural framework of the vertebrate body. In these tissues, the extracellular matrix is plentiful, and cells are sparsely distributed within it.

GRANULATION TISSUE

Tissue that is formed as part of the initial response to a wound during the healing and repair process, so-called because its surface has a granular appearance due to sprouting of neo-capillaries. It also contains abundant fibroblasts and variable numbers of inflammatory cells.

UTERINE INVOLUTION

The degenerative and regenerative process that the tissues that constitute the uterus and oviducts undergo on their return to a non-pregnant state.

FIBROSIS

The production of fibrous connective tissue as a consequence of chronic inflammation or healing. Its function is to replace lost parenchymal tissue.

PARENCHYMA

The essential or functional elements of an organ as distinguished from its stroma or framework.

EXTRACELLULAR MATRIX

(ECM). A complex, three-dimensional network of very large macromolecules that provides contextual information and an architectural scaffold for cellular adhesion and migration.

STRESS FIBRES

Intracellular axial bundles of filamentous-actin and actin-associated proteins.

FIBRONECTIN FIBRILS

Extracellular fibrils that are composed of fibronectin, and are found primarily in tissues that undergo active morphogenesis, such as embryonic tissue and granulation tissue.

GAP JUNCTION

A junction between two cells that consists of pores that allow passage of molecules (up to 9 kDa).

CORNEA

The transparent, curved part of the front of the eyeball. It is made up of many layers (in particular a thick stromal layer), and refracts incident light onto the lens.

CONNEXIN

The main protein component of a connexon, the structural subunit of a gap junction. Six connexins make up one connexon.

EPIRETINAL MEMBRANE

A membrane that can sometimes form on the surface of the central portion of the retina when the vitreous gel that fills the central eye cavity shrinks away from the retina.

DIFFERENTIATION

The elaboration of particular characteristics that are expressed by an end-stage cell type or by a cell en route to becoming an end-stage cell. This term is not synonymous with commitment, but differentiation features are used to determine when a cell is committed.

FIBROCONTRACTIVE DISEASES

Connective tissue disorders, such as Dupuytren's disease, that involve both tissue contracture and fibrosis.

GRANULOMA POUCH

A fluid-filled pouch that is created by subcutaneous injection of air and a necrotizing agent, such as croton oil, which later fills with fluid and becomes surrounded by granulation tissue.

PERICYTES

Support cells of capillaries (referred to as smooth muscle cells in larger vessels).

FOCAL ADHESIONS

Cellular structures that link the extracellular matrix on the outside of the cell, through integrin receptors, to the actin cytoskeleton inside the cell.

DERMIS

The innermost layer of the vertebrate skin that lies beneath the epidermis and is responsible for the tensile strength of skin. It comprises loose connective tissue that contains blood capillaries, smooth-muscle fibres, sweat glands and sebaceous glands with their ducts, hair follicles and sensory nerve endings.

MESENCHYMAL STEM CELL

A cell from immature connective tissue — tissue that consists of cells embedded in extracellular matrix — that has the potential to divide and reproduce a replica cell as well as a differentiated progeny.

PLATELETS

The smallest blood cells, which are important in haemostasis and blood coagulation.

MACROPHAGES

Any cells of the mononuclear phagocyte system that are characterized by their ability to phagocytose foreign particulate and colloidal material.

SMADS

A family of transcription factors that mediate transforming factor β (TGF-β) signals. The term SMAD is derived from the founding members of this family, the Drosophila protein MAD (Mothers Against Decapentaplegic) and the Caenorhabditis elegans protein SMA (small body size).

HEPATIC STELLATE CELLS

Also known as perisinusoidal cells, these cells are normally quiescent, but when they are stimulated by several toxins, they differentiate into myofibroblasts, which results in liver fibrosis.

CArG BOX MOTIF

A CArG box motif — CC(A+T-rich)6GG — is a DNA element that is required for muscle-specific gene transcription.

ISOMETRIC TENSION

A condition in which contraction of muscle, non-muscle cells or the actomyosin network is opposed by an equal load that prevents net shortening, even though tension increases.

ISOTONIC CONTRACTION

A condition in which contraction results in a shortening of muscle, nonmuscle, or the actomyosin network in order that tension remains constant.

RHO FAMILY GTPASES

Ras-related GTPases that are involved in controlling the polymerization of actin.

LYSOPHOSPHATIDIC ACID

Any phosphatidic acid that is deacylated at positions 1 or 2. It binds to a G-protein-coupled receptor, which results in the activation of the small GTP-binding protein Rho and the induction of stress fibres.

CYTOCHALASIN D

A fungal compound that specifically interferes with actin polymerization.

METALLOPROTEINASE

A proteinase that has a metal ion at its active site.

PROTEOGLYCAN

Any glycoprotein that contains glycosaminoglycans as the carbohydrate unit.

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Tomasek, J., Gabbiani, G., Hinz, B. et al. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3, 349–363 (2002). https://doi.org/10.1038/nrm809

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