Fibroblast Differentiation in Wound Healing and Fibrosis
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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