Transforming growth factor beta (TGF-β) induces fibrosis in a fetal wound model

Krummel, Thomas M.; Michna, Barbara A.; Thomas, Brian L.; Sporn, Michael B.; Nelson, Jeffrey M.; Salzberg, A.M.; Cohen, I. Kelman; Diegelmann, Robert F.

doi:10.1016/s0022-3468(88)80638-9

Cited by 214 publications

(108 citation statements)

References 24 publications

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“…48,49 In addition, fetal studies have shown that factors capable of inducing angiogenesis, such as transforming growth factor-b (TGF-b), 50 platelet-derived growth factor, 51 basic fibroblast growth factor, 52 interleukin-8, 53 and prostaglandin E 2 , 54 are either present at lower levels during scarless healing or can induce scarring when added to these wounds. 10,48,[55][56][57] In line with these previous reports, our studies indicate that scarless fetal wounds heal without a robust increase in vascularity or VEGF levels, in contrast to fibrotic fetal wounds. Although several studies have suggested lower levels of angiogenesis in scarless fetal wounds, one recent study reported increased VEGF mRNA levels and angiogenesis in scarless compared to fibrotic fetal wounds.…”

Section: Discussionsupporting

confidence: 92%

Regulation of scar formation by vascular endothelial growth factor

Wilgus

Ferreira

Oberyszyn

et al. 2008

Laboratory Investigation

276

216

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Section: Discussionsupporting

confidence: 92%

Regulation of scar formation by vascular endothelial growth factor

Wilgus

Ferreira

Oberyszyn

et al. 2008

Laboratory Investigation

276

216

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“…Indeed, induction of TGF-␤ in fetal dermis produces precocious scarring. 42 We developed transgenic mice that have an inducible, conditional knockout of the TGF-␤ type II receptor in dermal fibroblasts in the hope of mimicking the embryonic wound healing phenotype. The Tgfbr2 dermalKO adult mice exhibited accelerated re-epithelization, reduced inflammatory cell recruitment, and deficient dermal collagen re-organization (Figures 2-4).…”

Section: Discussionmentioning

confidence: 99%

Dermal Transforming Growth Factor-β Responsiveness Mediates Wound Contraction and Epithelial Closure

Martínez‐Ferrer

Afshar-Sherif

Uwamariya

et al. 2010

The American Journal of Pathology

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Stromal-epithelial interactions are important during wound healing. Transforming growth factor-␤ (TGF-␤) signaling at the wound site has been implicated in re-epithelization , inflammatory infiltration, wound contraction , and extracellular matrix deposition and remodeling. Ultimately , TGF-␤ is central to dermal scarring. Because scarless embryonic wounds are associated with the lack of dermal TGF-␤ signaling , we studied the role of TGF-␤ signaling specifically in dermal fibroblasts through the development of a novel , inducible , conditional , and fibroblastic TGF-␤ 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-␤ 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 ␣1 , ␣2 , and ␤1 integrins , and collagen gel contraction was diminished. There were associated deficiencies in actin cytoskeletal organization of vasodilatorstimulated phosphoprotein-containing lamellipodia. This study indicated that paracrine and autocrine TGF-␤ dermal signaling mechanisms mediate macrophage recruitment , re-epithelization , and wound contraction. (Am J Pathol 2010, 176:98 -107;

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“…The current strategies in tendon injury research using animal models are to either apply or suppress growth factors amplified during wound healing to tendon injury sites (Nakamura et al, 2000;Spindler et al, 2003;Kashiwagi et al, 2004;Anaguchi et al, 2005). This approach has been successful in skin, in which a scarless embryonic or scarforming adult healing response has been demonstrated to be a function of TGF-␤ isoform (Krummel et al, 1988;Shah et al, 1992Shah et al, , 1994Shah et al, , 1995. In tendon, altered healing response and induction of matrix molecules in response to abnormally high or low concentrations of growth factors, such as TGF-␤s, have been reported (Naka- Spindler et al, 2003;Kashiwagi et al, 2004;Anaguchi et al, 2005); however, rational therapy depends on knowledge of where and when these growth factors are present during embryonic tendon development and wound healing, which is critically lacking.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal protein distribution of TGF‐βs, their receptors, and extracellular matrix molecules during embryonic tendon development

Kuo

Petersen

Tuan

2008

Developmental Dynamics

109

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Tendon is one of the least understood tissues of the musculoskeletal system in terms of development and morphogenesis. Collagen fibrillogenesis has been the most studied aspect of tendon development, focusing largely on the role of matrix molecules such as collagen type III and decorin. While involvement of matrix molecules in collagen fibrillogenesis during chick tendon development is well understood, the role of growth factors has yet to be elucidated. This work examines the expression patterns of transforming growth factor (TGF) -␤1, -␤2, and -␤3, and their receptors with respect to expression patterns of collagen type III, decorin, and fibronectin. We focus on the intermediate stages of tendon development in the chick embryo, a period during which the tendon micro-and macro-architecture are being established. Our findings demonstrate for the first time that TGF-␤1, -␤2, and -␤3 have distinct spatiotemporal developmental protein localization patterns in the developing tendon and strongly suggest that these isoforms have independent roles in tendon development.

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Transforming growth factor beta (TGF-β) induces fibrosis in a fetal wound model

Cited by 214 publications

References 24 publications

Regulation of scar formation by vascular endothelial growth factor

Regulation of scar formation by vascular endothelial growth factor

Dermal Transforming Growth Factor-β Responsiveness Mediates Wound Contraction and Epithelial Closure

Spatiotemporal protein distribution of TGF‐βs, their receptors, and extracellular matrix molecules during embryonic tendon development

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