Fibroblasts can condense a hydrated collagen lattice to a tissue-like structure 1/28th the area of the starting gel in 24 hr. The rate of the process can be regulated by varying the protein content of the lattice, the cell number, or the con- centration of an inhibitor such as Colcemid. Fibroblasts of high population doubling level propagated in vitro, which have left the cell cycle, can carry out the contraction at least as efficiently as cycling cells. The potential uses of the system as an immu- nologically tolerated "tissue" for wound hea ing and as a model for studying fibroblast function are discussed.

Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative

Excessive scars form as a result of aberrations of physiologic wound healing and may arise following any Insult to the deep dermis. By causing pain, pruritus and contractures, excessive scarring significantly affects the patient’s quality of life, both physically and psychologically. Multiple studies on hypertrophic scar and keloid formation have been conducted for decades and have led to a plethora of therapeutic strategies to prevent or attenuate excessive scar formation. However, most therapeutic approaches remain clinically unsatisfactory, most likely owing to poor understanding of the complex mechanisms underlying the processes of scarring and wound contraction. In this review we summarize the current understanding of the pathophysiology underlying keloid and hypertrophic scar formation and discuss established treatments and novel therapeutic strategies.

Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies

It is estimated worldwide that over 6 million people per annum experience a burn injury. Despite advances in management and improved survival rates, the incidence of hypertrophic scarring remains high. These scars are particularly common after burns and are often raised, red, hard and may cause abnormal sensations. Such pathological scarring can lead to severe functional impairment, psychological morbidity, and costly long term healthcare. Wound healing is an inherent process which restores the integrity of the skin after injury and although scarring is a frequent by-product, the scarless wound healing observed in early human gestational fetuses suggests that it is not an essential component of the response. This has lead to a large body of research attempting to understand the mechanisms behind scarring and in turn prevent it. One of the main focuses of recent research has been the role played by the growth factor TGF-β in the process of both wound healing and scar formation. The three isoforms (TGF-β1, TGF-β2 and TGF-β3) appear to have overlapping functions and predominantly mediate their effects through the intracellular SMAD pathway. Initial research suggested that TGF-β1 was responsible for the fibrotic scarring response whereas the scarless wound healing seen in fetal wounds was due to increased levels of TGF-β3. However, the reality appears to be far more complex and it is unlikely that simply altering the ratio of TGF-β isoforms will lead to scarless wound healing. Other aspects of the TGF-β system that appear promising include the downstream mediator CTGF, the proteoglycan decorin and the binding protein p311. Other putative mechanisms which may underlie the pathogenesis of hypertrophic scars include excessive inflammation, excessive angiogenesis, altered levels of matrix metalloproteinases, growth factors, and delayed apoptosis of fibrotic myofibroblasts either due to p53 genetic alterations or tensile forces across the wound. If an effective treatment for hypertrophic scars following burns injury is to be developed then further work must be carried out to understand the basic mechanisms of pathological scarring.

The role of the TGF-β family in wound healing, burns and scarring: a review.

Scar formation, with persistent alteration of the normal tissue structure, is an undesirable and significant result of both wound healing and fibrosing disorders. There are few strategies to prevent or to treat scarring. The transforming growth factor beta (TGF-β) superfamily is an important mediator of tissue repair. Each TGF-β isoform may exert a different effect on wound healing, which may be context-dependent. In particular, TGF-β1 may mediate fibrosis in adults' wounds, while TGF-β3 may promote scarless healing in the fetus and reduced scarring in adults. Thus, TGF-β3 may offer a scar-reducing therapy for acute and chronic wounds and fibrosing disorders.

Transforming growth factor beta (TGF-β) isoforms in wound healing and fibrosis.

Fibrous connective tissues provide mechanical support and frameworks for other tissues of the body and play an integral role in normal tissue physiology and pathology. Three-dimensional collagen matrices exhibit mechanical and structural features that resemble fibrous connective tissue and have become an important model system to study cell behavior in a tissue-like environment. This review focuses on motile and mechanical interactions between cells—especially fibroblasts—and collagen matrices. We describe several matrix contraction models, the interactions between fibroblasts and collagen fibrils at global and subcellular levels, unique features of mechanical feedback between cells and the matrix, and the impact of the cell-matrix tension state on cell morphology and mechanical behavior. We develop a conceptual framework to explain the balance between cell migration and collagen translocation including the concept of promigratory and procontractile growth factor environments. Finally, we review the significance of these concepts for the physiology of wound repair.

Cell Motility and Mechanics in Three-Dimensional Collagen Matrices

Recombinant human decorin inhibits TGF-β1-induced contraction of collagen lattice by hypertrophic scar fibroblasts

﻿While wound contraction plays an important role in healing, it may lead to excessive scar formation and pathological wound contracture in extreme conditions. To date, the key regulator of wound contraction and keloid formation is transforming growth factor-beta (TGF-b1). Decorin has been reported to bind TGF-b1 and neutralize some of its activities. The present study investigated whether decorin affected TGF-b1-induced fibroblast contractile activity by using fibroblast-populated collagen lattice (FPCL), which has been generally used as an in-vitro model thought to mimic wound contraction in vivo, modified by the incorporation of recombinant human decorin into collagen gel. As expected, TGF-b1 significantly enhanced the contraction of collagen gel at hour 12, 24, 48, 72, and 96 (P < 0.05). Recombinant human decorin inhibited both the basal and TGF-b1-enhanced contraction of collagen gel by keloid fibroblasts (P < 0.05). These inhibitory effects of recombinant human decorin were associated with suppression of TGF-b1-induced filamentous actin (F-actin) expression in keloid fibroblasts. Furthermore, recombinant human decorin inhibited TGF-b1 induced a-smooth muscle actin (a-SMA), PAI-1 (plasminogen activator inhibitor-1) protein, and mRNA expressions in keloid fibroblasts (P < 0.05). These data indicate that recombinant human decorin can suppress TGF-b1-induced contraction of collagen gel by keloid fibroblasts. Moreover, decorin can inhibit basal contraction of collagen gel by keloid fibroblasts. These results suggest that decorin may have therapeutic potential for excessive skin contraction as observed in a keloid. ﻿.

Wei-Shi Xu

Papers

Recombinant human decorin inhibits TGF-β1-induced contraction of collagen lattice by hypertrophic scar fibroblasts

Recombinant Human Decorin Inhibits TGF-b1 Induced Contraction of Collagen Lattice by Keloid Fibroblasts