Fibroblast Differentiation in Wound Healing and Fibrosis

doi:10.1016/S0074-7696(07)57004-X

International Review of Cytology

Volume 257, 2007, Pages 143-179

https://doi.org/10.1016/S0074-7696(07)57004-X Get rights and content

The contraction of granulation tissue from skin wounds was first described in the 1960s. Later it was discovered that during tissue repair, fibroblasts undergo a change in phenotype from their normal relatively quiescent state in which they are involved in slow turnover of the extracellular matrix, to a proliferative and contractile phenotype termed myofibroblasts. These cells show some of the phenotypic characteristics of smooth muscle cells and have been shown to contract in vitro. In the 1990s, a number of researchers in different fields showed that myofibroblasts are present during tissue repair or response to injury in a variety of other tissues, including the liver, kidney, and lung. During normal repair processes, the myofibroblastic cells are lost as repair resolves to form a scar. This cell loss is via apoptosis. In pathological fibroses, myofibroblasts persist in the tissue and are responsible for fibrosis via increased matrix synthesis and for contraction of the tissue. In many cases this expansion of the extracellular matrix impedes normal function of the organ. For this reason much interest has centered on the derivation of myofibroblasts and the factors that influence their differentiation, proliferation, extracellular matrix synthesis, and survival. Further understanding of how fibroblast differentiation and myofibroblast phenotype is controlled may provide valuable insights into future therapies that can control fibrosis and scarring.

Introduction

Fibroblasts are present in many tissues in the body, normally in a relatively quiescent state and are mainly responsible for the production and turnover of extracellular matrix (ECM) molecules. It has been approximately 35 years since it was first reported that fibroblasts are also capable of changing during tissue repair processes to a contractile phenotype involved both in increased extracellular matrix production and contraction during the repair process. Since that time, much interest has centered on the control of this cell and, in particular, the factors that control fibroblast phenotype, proliferation, extracellular matrix production, and their disappearance as tissue repair resolves. It is now apparent that the fibroblast and the differentiated cell it gives rise to, the myofibroblast, is involved in tissue repair or the response to injury in many tissues in the body and is also an important cell in numerous pathological settings, particularly pathological fibrosis and scarring in a number of organs and in the stromal response around tumors. In this review we will discuss the various roles of the myofibroblast, its derivation, control of its phenotype, and its disappearance during scar resolution.

Section snippets

Inflammation

Tissue repair in all organs begins with inflammation, which represents the defining biological response to trauma in adults. Inflammatory reactions are triggered by a diverse range of events including, among others, physical injury, infection, and exposure to toxins. In the case of physical trauma, platelet aggregation forms a hemostatic plug and blood coagulation forms the provisional matrix. Platelets release growth factors and adhesive proteins that stimulate the inflammatory response and

Fibroblasts

The fibroblasts present in various connective tissues represent a heterogeneous population of cells. Other than the myofibroblast, first described by Gabbiani (Gabbiani 1971, Majno 1971), there is no formal nomenclature to define fibroblast subphenotypes (Trelstad and Birk, 1985). An important question is therefore, what is a fibroblast?

Ultrastructurally, fibroblasts are identified on the basis of their stellate appearance with elongated, branching processes (Takahashi‐Iwanaga, 1994). They have

Fibrogenic Mediators

The activity of fibroblasts and their subsequent differentiation into myofibroblasts is dependent on a combination of the action of growth factors and other soluble mediators, extracellular matrix components, and mechanical stress.

Resolution or Progression

Resolution of inflammation represents an important step in limiting the chronicity of inflammation (Kuncio et al., 1991). Fibrogenesis continues as long as permissive conditions exist. The persistent accumulation of inflammatory cells is associated with the continued destruction of renal tissue and deposition of scar tissue. If unchecked this leads to progression of scarring and ultimately in the case of internal organs, organ failure. Abscess formation is an extreme example of uncontrolled

Concluding Remarks

In many respects, the pathologic process of fibrosis in internal organs resembles disordered wound healing in the skin. If we define fibrosis by the presence of an increased density of interstitial collagenous matrix (especially collagens type I and III), the histological picture of fibrosis could be produced by increased production and/or reduced breakdown of collagen, or by the loss of normal cellular content leaving behind the interstitial reticulin (Gonzalez‐Avila 1988, Hewitson 1998, Jones

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Fibroblast Differentiation in Wound Healing and Fibrosis

Introduction

Section snippets

Inflammation

Fibroblasts

Fibrogenic Mediators

Resolution or Progression

Concluding Remarks

J. Biol. Chem.

Curr. Opin. Cell Biol.

J. Biol. Chem.

Kidney Int.

Kidney Int.

Kidney Int.

Biochem. Biophys. Res. Commun.

Mut.Res.

Pathology

J. Biol. Chem.

Am. J. Pathol.

Matrix Biol

Matrix Biol.

Curr. Opin. Cell Biol.

Am. J. Med. Sci.

Int. J. Biochem. Cell Biol.

Lab. Invest.

Adv. Chronic Kidney Dis.

Exp. Cell Res.

Am. J. Pathol.

Kidney Int.

Am. J. Pathol.

Kidney Int.

Int. J. Biochem. Cell Biol.

Kidney Int.

Int. J. Biochem. Cell Biol.

J. Biol. Chem.

Kidney Int.

Dermatol. Clin.

J. Lab. Clin. Med.

Cell

Kidney Int.

Kidney Int.

Biochem. Biophys. Res. Commun.

Mol. Ther.

Kidney Int.

Peripheral blood fibrocytes: Differentiation pathway and migration to wound sites

J. Immunol.

Collagen formation and wound contraction during repair of small excised wounds in the skin of rats

J. Embryol. Exp. Morphol.

Wound contraction in relation to collagen formation in scorbutic guinea pigs

J. Embryol. Exp. Morphol.

The role of interstitial infiltrates in IgA nephropathy: A study with monoclonal antibodies

Nephrol. Dial. Transplant.

Human renal cortical interstitial cells with some features of smooth muscle cells participate in tubulointerstitial and crescentic glomerular injury

J. Am. Soc. Nephrol.

Expression and secretion of type beta transforming growth factor by activated human macrophages

Proc. Natl. Acad. Sci. USA

Interleukin‐1 in crescentic glomerulonephritis

Kidney Int.

Co‐localization of erythropoietin mRNA and ecto‐5′‐nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin

J. Histochem. Cytochem.

Liver fibrosis

J. Clin. Invest.

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Proc. Natl. Acad. Sci. USA

The myofibroblast. Possible derivation from macrophages in xanthogranuloma

Am. J. Dermatopathol.

Comparison of properties of four inhibitors of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase

Am. J. Cardiol.

Natural inhibitor of transforming growth factor‐b protects against scarring in experimental kidney disease

Nature

Suppression of experimental glomerulonephritis by antiserum against transforming growth factor b1

Nature