Effect of adenoviral mediated overexpression of fibromodulin on human dermal fibroblasts and scar formation in full-thickness incisional wounds

Stoff, Alexander; Rivera, Angel A.; Mathis, J. Michael; Moore, Steven T.; Banerjee, N. Sanjib; Everts, Maaike; Espinosa-de-los-Monteros, Antonio; Novák, Zdeněk; Vásconez, Luis O.; Broker, Thomas R.; Richter, Dirk F.; Feldman, Dale; Siegal, Gene P.; Stoff-Khalili, Mariam A.; Curiel, David T.

doi:10.1007/s00109-006-0148-z

Cited by 52 publications

(33 citation statements)

References 48 publications

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“…20,23 In addition, adenovirus-mediated FM overexpression decreased TGF-b1 expression in human dermal fibroblasts. 35 In this study, we observed an inverse correlation between FM and Tgf-b1 with its downstream fibrosis target, type I collagen, in fetal cutaneous wound models: High FM levels correlated with decreased Tgf-b1 expression and scarless repair, while low FM levels correlated with increased Tgf-b1 expression and scar formation. Therefore, our current finding strongly suggests that FM plays crucial regulatory roles in TGF-b signaling during cutaneous wound repair.…”

Section: Discussionmentioning

confidence: 51%

Fibromodulin Is Essential for Fetal-Type Scarless Cutaneous Wound Healing

Zheng

Zhang

Dang

et al. 2016

The American Journal of Pathology

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In contrast to adult and late-gestation fetal skin wounds, which heal with scar, early-gestation fetal skin wounds display a remarkable capacity to heal scarlessly. Although the underlying mechanism of this transition from fetal-type scarless healing to adult-type healing with scar has been actively investigated for decades, in utero restoration of scarless healing in late-gestation fetal wounds has not been reported. In this study, using loss-and gain-of-function rodent fetal wound models, we identified that fibromodulin (Fm) is essential for fetal-type scarless wound healing. In particular, we found that loss of Fm can eliminate the ability of early-gestation fetal rodents to heal without scar. Meanwhile, administration of fibromodulin protein (FM) alone was capable of restoring scarless healing in lategestation rat fetal wounds, which naturally heal with scar, as characterized by dermal appendage restoration and organized collagen architectures that were virtually indistinguishable from those in age-matched unwounded skin. High Fm levels correlated with decreased transforming growth factor (TGF)-b1 expression and scarless repair, while low Fm levels correlated with increased TGF-b1 expression and scar formation. This study represents the first successful in utero attempt to induce scarless repair in late-gestation fetal wounds by using a single protein, Fm, and highlights the crucial role that the FMeTGF-b1 nexus plays in fetal-type scarless skin repair. (Am J Pathol 2016 http://dx

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Section: Discussionmentioning

confidence: 51%

Fibromodulin Is Essential for Fetal-Type Scarless Cutaneous Wound Healing

Zheng

Zhang

Dang

et al. 2016

The American Journal of Pathology

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“…Previous studies have used only the width of the fibrotic area as a measure of scar size and did not delineate the entire scar area. 29,30 By dividing the scar area by the corresponding average scar thickness, our methodology not only measures the entire scar area but is also able to account for variability in skin thickness. Using this approach, we demonstrated that in addition to anatomic regional differences, various other factors such as age, sex, and scar age could influence dermal thickness.…”

Section: Discussionmentioning

confidence: 99%

A Quantitative Approach to Scar Analysis

Khorasani

Zheng

Nguyen

et al. 2011

The American Journal of Pathology

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Analysis of collagen architecture is essential to wound healing research. However, to date no consistent methodologies exist for quantitatively assessing dermal collagen architecture in scars. In this study, we developed a standardized approach for quantitative analysis of scar collagen morphology by confocal microscopy using fractal dimension and lacunarity analysis. Full-thickness wounds were created on adult mice, closed by primary intention, and harvested at 14 days after wounding for morphometrics and standard Fourier transform-based scar analysis as well as fractal dimension and lacunarity analysis. In addition, transmission electron microscopy was used to evaluate collagen ultrastructure. We demonstrated that fractal dimension and lacunarity analysis were superior to Fourier transform analysis in discriminating scar versus unwounded tissue in a wild-type mouse model. To fully test the robustness of this scar analysis approach, a fibromodulin-null mouse model that heals with increased scar was also used. Fractal dimension and lacunarity analysis effectively discriminated unwounded fibromodulin-null versus wild-type skin as well as healing fibromodulin-null versus wild-type wounds, whereas Fourier transform analysis failed to do so. Furthermore, fractal dimension and lacunarity data also correlated well with transmission electron microscopy collagen ultrastructure analysis, adding to their validity. These results demonstrate that fractal dimension and lacunarity are more sensitive than Fourier transform analysis for quantification of scar morphology. Cutaneous scarring can lead to major cosmetic, psychological, and functional consequences in patients with hypertrophic scars from burn injuries or keloid scars. To gain further insight into scar formation, it is essential to be able to better correlate the molecular events during wound repair with changes in collagen architecture. Because 85% of the dermis consists of collagen, 1 dermal elasticity and strength are primarily determined by collagen with lesser contributions from elastin and other extracellular matrix constituents. 2,3 At present, no consistent methodologies exist for quantitatively assessing dermal collagen architecture. Despite the integral nature of collagen ultrastructure and architecture to wound healing research, few studies have been conducted on evaluation of collagen architecture, with most studies published decades ago. 4 Qualitative histopathologic studies of cutaneous scar tissue show more tightly packed collagen bundles with orientations parallel to the epidermis rather than the loose, random, basket-weave-like organization of collagen bundles in normal dermis. 5 Currently traditional scar morphology and collagen architectural analyses are performed by one or two observers, using conventional light microscopy in combination with polarized light. 6,7 More objective methods such as X-ray diffraction, 8,9 laser scattering, 10,11 and Fourier transform analysis 3,4,12 also have been recently described. Head-to-head comparisons of these mo...

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“…146 Decorin has also been shown to block the activity of connective tissue growth factor (CCN2), a downstream mediator of pro-fibrotic TGF-b action, 147 suggesting that its antiscarring activity may extend beyond its effects on TGF-b neutralization. Fibromodulin has also been shown to promote wound healing and to reduce scarring in animal models 148,149 and may represent a therapeutic target for the treatment of HTS. 150,151 TGF-b co-receptors represent a unique class of molecules that are starting to receive attention for their potential as TGF-b ligand neutralizing agents.…”

Section: Strategies Used For Targeting the Tgf-b Signaling Pathway Tomentioning

confidence: 99%