Article

Dermal transforming growth factor-beta responsiveness mediates wound contraction and epithelial closure

Vanderbilt-Ingram Cancer Center and Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
American Journal Of Pathology (Impact Factor: 4.6). 12/2009; 176(1):98-107. DOI: 10.2353/ajpath.2010.090283
Source: PubMed

ABSTRACT Stromal-epithelial interactions are important during wound healing. Transforming growth factor-beta (TGF-beta) signaling at the wound site has been implicated in re-epithelization, inflammatory infiltration, wound contraction, and extracellular matrix deposition and remodeling. Ultimately, TGF-beta is central to dermal scarring. Because scarless embryonic wounds are associated with the lack of dermal TGF-beta signaling, we studied the role of TGF-beta signaling specifically in dermal fibroblasts through the development of a novel, inducible, conditional, and fibroblastic TGF-beta type II receptor knockout (Tgfbr2(dermalKO)) mouse model. Full thickness excisional wounds were studied in control and Tgfbr2(dermalKO) back skin. The Tgfbr2(dermalKO) wounds had accelerated re-epithelization and closure compared with controls, resurfacing within 4 days of healing. The loss of TGF-beta signaling in the dermis resulted in reduced collagen deposition and remodeling associated with a reduced extent of wound contraction and elevated macrophage infiltration. Tgfbr2(dermalKO) and control skin had similar numbers of myofibroblastic cells, suggesting that myofibroblastic differentiation was not responsible for reduced wound contraction. However, several mediators of cell-matrix interaction were reduced in the Tgfbr2(dermalKO) fibroblasts, including alpha1, alpha2, and beta1 integrins, and collagen gel contraction was diminished. There were associated deficiencies in actin cytoskeletal organization of vasodilator-stimulated phosphoprotein-containing lamellipodia. This study indicated that paracrine and autocrine TGF-beta dermal signaling mechanisms mediate macrophage recruitment, re-epithelization, and wound contraction.

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    • "As the reproducibility of macroscopic findings is low and not strong enough to hold in court, there is a need for additional methods to determine wound age in living subjects [1– 4]. In forensic autopsies several immunohistochemical markers are applied to determine wound age more precisely, in addition to more traditional histological characteristics of wound healing [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]. To this end skin excisions are made in which the actual damage (e.g. "
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    ABSTRACT: Wound age determination in living subjects is important in routine diagnostics in forensic medicine. Macroscopical description of a wound to determine wound age however is inadequate. The aim of this study was to assess whether it would be feasible to determine wound age via analysis of morphological characteristics and extracellular matrix proteins in skin biopsies of living subjects referred to a forensic outpatient clinic. Skin biopsies (n=101), representing the border area of the wound, were taken from skin injuries of known wound age (range: 4.5h-25days) in living subjects. All biopsies were analyzed for 3 morphological features (ulceration, parakeratosis and hemorrhage) and 3 extracellular matrix markers (collagen III, collagen IV and α-SMA). For quantification, biopsies were subdivided in 4 different timeframes: 0.2-2 days, 2-4 days, 4-10 days and 10-25 days old wounds. Subsequently, a probability scoring system was developed. For hemorrhage, collagen III, collagen IV and α-SMA expression no relation with wound age was found. Ulceration was only found in wounds of 0.2-2, 2-4 and 4-10 days old, implying that the probability that a wound was more than 10 days old in case of ulceration is equal to 0%. Also parakeratosis was almost exclusively found in wounds of 0.2-2, 2-4 and 4-10 days old, except for one case with a wound age of 15 days old. The probability scoring system of all analyzed markers, as depicted above, however can be used to calculate individual wound age probabilities in biopsies of skin wounds of living subjects. We have developed a probability scoring system, analysing morphological characteristics and extracellular matrix proteins in superficial skin biopsies of wounds in living subjects that can be applied in forensic medicine for wound age determination. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Forensic Science International 11/2014; 246C. DOI:10.1016/j.forsciint.2014.11.013 · 2.12 Impact Factor
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    • "of endothelial cells also a few minutes after wound infliction. Like CD62p, Factor VIII has not been described in wound hemorrhage yet [18] [24] [25] [27]. "
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    ABSTRACT: PURPOSE OF THE STUDY: In forensic autopsies it is important to determine the age of early vital skin wounds as accurate as possible. In addition to inflammation, coagulation is also induced in vital wounds. Analysis of blood coagulation markers in wound hemorrhage could therefore be an important additional discriminating factor in wound age determination. The aim of this study was to develop a wound age probability scoring system, based on the immunohistochemical expression levels of Fibronectin, CD62p and Factor VIII in wound hemorrhage. METHODS: Tissue samples of (A) non injured control skin (n=383), and samples of mechanically induced skin injuries of known wound age, (B) injuries inflicted shortly before death (up to a few minutes old) (n=382), and (C) injuries inflicted 15-30min before death (n=42) were obtained at autopsy in order to validate wound age estimation. Tissue slides were stained for Fibronectin, CD62p and Factor VIII and were subsequently scored for staining intensity (IHC score) in wound hemorrhage (1=minor, 2=moderate, 3=strong positive). Finally, probability scores of these markers were calculated. RESULTS: In at most 14% of the non-injured control samples, hemorrhage was found, with mean±standard deviation IHC scores of 0.1±0.4, 0.2±0.4 and 0.2±0.5 for Fibronectin, CD62p, and Factor VIII, respectively. Expression of these markers significantly increased to mean IHC scores 1.4±0.8 (Fibronectin), 1.2±0.6 (CD62p), and 1.6±0.8 (Factor VIII) in wounds inflicted shortly before death (few minutes old) and to 2.6±0.5 (Fibronectin), 2.5±0.6 (CD62p), and 2.8±0.4 (Factor VIII) in 15-30min old wounds. The probabilities that a wound was non vital in case of an IH score 0 were 87%, 88% and 90% for Fibronectin, CD62p, and Factor VIII, respectively. In case of an IHC score 1 or 2, the probabilities that a wound was a few minutes old were 82/90%, 82/83% and 72/93%. Finally, in case of an IHC score 3, the probabilities that a wound was 15-30min old were 65%, 76% and 55%. CONCLUSIONS: Based on the expression of Fibronectin, CD62p and Factor VIII in wound hemorrhage, we developed a probability scoring system that can be used in forensic autopsies to improve wound age estimation in early skin injuries.
    Forensic Science International 08/2014; 28(244C):128-135. DOI:10.1016/j.forsciint.2014.08.015. · 2.12 Impact Factor
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    • "of endothelial cells also a few minutes after wound infliction. Like CD62p, Factor VIII has not been described in wound hemorrhage yet [18] [24] [25] [27]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In forensic autopsies it is important to determine the age of early vital skin wounds as accurate as possible. In addition to inflammation, coagulation is also induced in vital wounds. Analysis of blood coagulation markers in wound hemorrhage could therefore be an important additional discriminating factor in wound age determination. The aim of this study was to develop a wound age probability scoring system, based on the immunohistochemical expression levels of Fibronectin, CD62p and Factor VIII in wound hemorrhage.
    Forensic Science International 08/2014; 244:128–135. DOI:10.1016/j.forsciint.2014.08.015 · 2.12 Impact Factor