Increased Plasminogen Activator Inhibitor-1 in Keloid Fibroblasts May Account for their Elevated Collagen Accumulation in Fibrin Gel Cultures

Tuan, Tai‐Lan; Wu, Huayang; Huang, Eunice Y.; Chong, Sheree; Laug, Walter E.; Messadi, Diana V.; Kelly, Paul A.; Le, Anh D.

doi:10.1016/s0002-9440(10)64292-7

Cited by 73 publications

(72 citation statements)

References 67 publications

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“…7 The increased expression of PAI-1 protein is also present in fibroblasts of keloid lesions. 24 Importantly, PAI-1 may cause excessive accumulation of newly synthesized collagen by keloid fibroblasts because reducing PAI-1 activity with PAI-1 neutralizing antibody normalizes collagen accumulation by keloid fibroblasts. 24 This link between PAI-1 and collagen accumulation represents a novel mechanism participating in keloid pathogenesis.…”

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confidence: 99%

Adenoviral Overexpression and Small Interfering RNA Suppression Demonstrate That Plasminogen Activator Inhibitor-1 Produces Elevated Collagen Accumulation in Normal and Keloid Fibroblasts

Tuan

Hwu

et al. 2008

The American Journal of Pathology

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Keloids are tumor-like skin scars that grow as a result of the aberrant healing of skin injuries, with no effective treatment. We provide new evidence that both overexpression of plasminogen activator inhibitor-1 (PAI-1) and elevated collagen accumulation are intrinsic features of keloid fibroblasts and that these characteristics are causally linked. Using seven strains each of early passage normal and keloid fibroblasts, the keloid strains exhibited inherently elevated collagen accumulation and PAI-1 expression in serumfree, 0.1% ITS؉ culture; larger increases in these parameters occurred when cells were cultured in 3% serum. To demonstrate a causal relationship between PAI-1 overexpression and collagen accumulation, normal fibroblasts were infected with PAI-1-expressing adenovirus. Such cells exhibited a two-to fourfold increase in the accumulation of newly synthesized collagen in a viral dose-dependent fashion in both monolayers and fibrin gel, provisional matrix-like cultures. Three different PAI-1-targeted small interfering RNAs, alone or in combination, produced greater than an 80% PAI-1 knockdown and reduced collagen accumulation in PAI-1-overexpressing normal or keloid fibroblasts. A vitronectin-binding mutant of PAI-1 was equipotent with wild-type PAI-1 in inducing collagen accumulation, whereas a complete protease inhibitor mutant retained approximately 50% activity. Thus, PAI-1 may use more than its protease inhibitory activity to control keloid collagen accumulation. PAI-1-targeted interventions , such as small interfering RNA and lentiviral short hairpin RNA-containing microRNA sequence suppression reported here , may have therapeutic utility in the prevention of keloid scarring.

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confidence: 99%

Adenoviral Overexpression and Small Interfering RNA Suppression Demonstrate That Plasminogen Activator Inhibitor-1 Produces Elevated Collagen Accumulation in Normal and Keloid Fibroblasts

Tuan

Hwu

et al. 2008

The American Journal of Pathology

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“…In vitro studies have demonstrated that the rate of collagen synthesis increases when fibroblasts are grown within a three-dimensional fibrin matrix as opposed to a collagen matrix. 15,16 Tuan and colleagues 17,18 found that keloid fibroblasts deposited an increased amount of collagen when grown in fibrin gel culture compared with control fibroblasts and that they also displayed a decreased fibrinolytic activity. The group suggested that reduced fibrinolysis may in part mediate the fibrotic phenotype displayed by these overactive scars.…”

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confidence: 99%

Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator

Giorgio-Miller

Bottoms

Laurent

et al. 2005

The American Journal of Pathology

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The deposition of fibrin is an integral part of the tissue repair process, but its persistence is also associated with a number of fibrotic conditions. This study addressed the hypothesis that reduced fibrinolysis and fibrin persistence are associated with an enhanced accumulation of collagen and the development of skin fibrosis. Decreased fibrinolysis was confirmed in fibrin gel cultures that contained human dermal fibroblasts plus the specific plasmin inhibitor ␣ 2 -antiplasmin or dermal fibroblasts isolated from plasminogen activator (PA)-deficient mice. Collagen accumulation was significantly increased in the presence of inhibitor and in tPA-deficient, but not uPAdeficient, fibroblasts compared with controls. These findings were also confirmed using a skin fibrosis model in which multiple injections of fibrin were given subcutaneously to PA-deficient mice. Injection sites from tPA-deficient mice displayed significantly increased collagen levels compared with uPA-deficient mice and wild-type controls. Up-regulation of fibroblast procollagen gene expression and reduced activation of pro-MMP-1 appeared to mediate the increase in collagen by human dermal fibroblasts in the presence of ␣2-antiplasmin. These findings suggest that persistent fibrin is associated with enhanced collagen accumulation that may result in the development of fibrotic skin disorders in which reduced fibrinolysis is a feature.

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“…1,2 More recent studies have identified phenotypic differences in growth factor production, receptor expression, and intracellular signal transduction between normal, keloid, and hypertrophic scar fibroblasts. [3][4][5][6][7] These investigations have focused on studying fibroblast behavior using cell proliferation assays and biochemical assays such as tririated proline incorporation, procollagen…”

Section: Arch Facial Plastmentioning

confidence: 99%

“…Recently, the RAFT organotypic culture model 4,[9][10][11] has been developed to study wound healing. A RAFT is an artificial tissue model consisting of fibroblasts embedded in a collagen gel with or without keratinocytes seeded on the surface.…”

Section: Original Articlementioning

confidence: 99%

“…The data presented are in accord with previous work using conventional methods that have shown that keloid-derived fibroblasts exhibit phenotypic differences resulting in increased collagen production. [1][2][3][4][5][6][7] The advantage of the present system is that it incorporates a biologically active wound model resembling human skin with an imaging device that allows serial measurements of the same specimen over time. Furthermore, since MPM provides a quantitative measurement of collagen second harmonic signal generation, it can be used to estimate matrix collagen density without fixation or exogenous dyes that could cause disruption of the native physiologic environment.…”

Section: Commentmentioning

confidence: 99%

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Modeling Aberrant Wound Healing Using Tissue-Engineered Skin Constructs and Multiphoton Microscopy

Torkian

Yeh

Engel

et al. 2004

Archives of Facial Plastic Surgery

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Increased Plasminogen Activator Inhibitor-1 in Keloid Fibroblasts May Account for their Elevated Collagen Accumulation in Fibrin Gel Cultures

Abstract: Keloids are scars that show exuberant growth beyond the margins of the original wound that rarely regress throughout time. It is estimated that ϳ15 to 20% of AfricanAmericans, Hispanics, and Asians develop keloids with a suggested genetic predisposition to keloid formation.

Cited by 73 publications

References 67 publications

Adenoviral Overexpression and Small Interfering RNA Suppression Demonstrate That Plasminogen Activator Inhibitor-1 Produces Elevated Collagen Accumulation in Normal and Keloid Fibroblasts

Adenoviral Overexpression and Small Interfering RNA Suppression Demonstrate That Plasminogen Activator Inhibitor-1 Produces Elevated Collagen Accumulation in Normal and Keloid Fibroblasts

Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator

Modeling Aberrant Wound Healing Using Tissue-Engineered Skin Constructs and Multiphoton Microscopy

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