Healing of Burn Wounds in Transgenic Mice Overexpressing Transforming Growth Factor-β1 in the Epidermis

Yang, Lei; Chan, Teddy; Demare, Jack; Iwashina, Takashi; Ghahary, Aziz; Scott, Paul; Tredget, Edward E.

doi:10.1016/s0002-9440(10)63066-0

Cited by 100 publications

(120 citation statements)

References 35 publications

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“…This was supported by previous studies demonstrating that TGFb1 was ex pressed in the suprabasal epithelial cells of human skin equivalents (20). The expression of latent TGFb1 was shown to increase markedly in suprabasal keratinocytes after injury, although its localization was faint in normal mouse epidermis (11). These findings indicate that dividing keratinocytes are one of the major cellular sources of TGFb1 during wound healing.…”

Section: Discussionsupporting

confidence: 79%

Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

et al. 2014

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Abstract. Transforming growth factorb1 (TGFb1) reportedly causes the differentiation of fibroblasts to myofibroblasts during wound healing. We investigated the mechanism underlying the activation of latent TGFb1 released by keratinocytes in efforts to identify promising pharma cological approaches for the prevention of hypertrophic scar formation. A threedimensional col lagen gel matrix culture was prepared using rat keratinocytes and dermal fibroblasts. Stratified keratinocytes promoted the TGF receptor-dependent increase in asmooth muscle actin (aSMA) immunostaining and mRNA levels in fibroblasts. Latent TGFb1 was found to be localized suprabasally and secreted. aSMA expression was inhibited by an antia v integrin antibody and a matrix metalloproteinase (MMP) inhibitor, GM6001. In a twodimensional fibroblast culture, aSMA expression depended on the production of endogenous TGFb1 and required a v integrin or MMP for the response to recombinant latent TGFb1. In keratinocyteconditioned medium, MMPdependent latent TGFb1 secretion was detected. Applying this medium to the fibroblast culture enhanced aSMA production. This effect was decreased by GM6001, the antia v integrin antibody, or the preabsorption of latent TGFb1. These results indicate that keratinocytes secrete latent TGFb1, which is liberated to fibroblasts over distance and is activated to produce aSMA with the aid of a positivefeedback loop. MMP inhibition was effective for targeting both keratinocytes and fibroblasts in this model. [Supplementary Figure: available only at http://dx

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Section: Discussionsupporting

confidence: 79%

Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

et al. 2014

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“…Previous studies on the role of TGFβ1 during re-epithelialization show contradictory results (Grose and Werner, 2004;Werner and Grose, 2003). Our conclusion is consistent with some previous reports (Crowe et al, 2000;Gailit et al, 1994;Hebda, 1988), but is inconsistent with others (Hosokawa et al, 2005;Yang et al, 2001). This inconsistency might be due to the use of different animal models.…”

Section: Dpr2supporting

confidence: 59%

“…However, experiments to address the role of TGFβ1 during wound healing are inconclusive (Gailit et al, 1994;Grose and Werner, 2004;Werner and Grose, 2003;Yang et al, 2001). Genetic ablation of TGFβ1 or its receptors has been shown to both reduce and enhance the rate of wound repair (Amendt et al, 2002;Brown et al, 1995;Crowe et al, 2000;Shah et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Accelerated re-epithelialization inDpr2-deficient mice is associated with enhanced response to TGFβ signaling

Meng

Chen²,

Yang³

et al. 2008

Journal of Cell Science

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Members of the Dapper (Dpr)/Dact protein family are involved in the regulation of distinct signaling pathways, including TGFβ/Nodal, canonical and noncanonical Wnt pathways. Three Dpr genes, Dpr1, Dpr2 and Dpr3, are expressed in mouse embryos and in many adult tissues; however, their in vivo functions have not been reported. In this study, we generated Dpr2-deficient mice using a gene-knockout approach. Homozygous Dpr2 knockout (Dpr2–/–) embryos developed normally and postnatal Dpr2–/– mice grew to adulthood without obvious morphological or behavioral defects. We found that Dpr2 was expressed highly in epidermal keratinocytes and in hair follicles of adult mice, and that Dpr2 deficiency resulted in accelerated re-epithelialization during cutaneous wound healing. Furthermore, we demonstrated that loss of Dpr2 function enhanced the responses of keratinocytes to TGFβ stimulation, and that TGFβ signals promoted adhesion to fibronectin and migration of keratinocytes, by regulating the expression of specific integrin genes. Thus, Dpr2 plays an inhibitory role in the re-epithelialization of adult skin wounds by attenuating TGFβ signaling.

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“…26 Briefly, protein was precipitated from the conditioned media using acetonitrile. Sample was centrifuged at 41C for 15 min.…”

Section: Hydroxyproline Determinationmentioning

confidence: 99%

Deep dermal fibroblasts contribute to hypertrophic scarring

Wang

Dodd

Shankowsky

et al. 2008

Laboratory Investigation

186

140

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Hypertrophic scar (HTS) following thermal injury is a dermal fibroproliferative disorder that leads to considerable morbidity. The development of HTS involves numerous cell types and cytokines with dermal fibroblasts being a key cell. We have previously reported that the phenotype of fibroblasts isolated from HTS was altered compared to fibroblasts from normal skin. In this study, normal skin was horizontally sectioned into five layers using a dermatome from which fibroblasts were isolated and cultured. Cells from the deeper layers were observed to proliferate at a slow rate, but were morphologically larger. In ELISA and FACS assays, cells from the deeper layers produced more TGF-b1 and TGF-b1 producing cells were higher. In quantitative RT-PCR, the cells from the deeper layers had higher CTGF and HSP47 mRNA levels compared to those from superficial layers. In western blot, FACS and collagen gel assays, fibroblasts from the deeper layers produced more a-smooth muscle actin (a-SMA), had higher a-SMA positive cells and contracted collagen gels more. Fibroblasts from the deeper layers were also found to produce more collagen, but less collagenase by mass spectrometry and collagenase assay. Interestingly, cells from the deeper layers also produced more of the proteoglycan, versican, but less decorin. Taken together, these data strongly demonstrate that fibroblasts from the deeper layers of the dermis resemble HTS fibroblasts, suggesting that the deeper layer fibroblasts may be critical in the formation of HTS. Hypertrophic scarring is a common fibroproliferative disorder of the human dermis characterized by erythematous, raised, pruritic lesions of the healing skin, which is usually following thermal and other injuries that involve the deep dermis. 1 These lesions lead to scarring that compromises the appearance of healing skin and are commonly associated with contractures that limit movement and function of involved joints and facial features. As such, HTS is the principal factor that contributes to the prolonged and often uncomfortable rehabilitation period for thermally injured patients, particularly those who have survived large lifethreatening injuries, children, and individuals of dark-skinned races, in whom such scarring occurs more commonly. 2 The undesirable physical properties of HTS tissue can be attributed to the presence of a large amount of extracellular matrix that is of altered composition and organization, compared to normal dermis or mature scar. This matrix is the product of a dense population of fibroblasts, maintained in a hyperactive state by inflammatory cytokines such as TGF-b and other factors, some of which may be physical in origin. 3 Although the molecular and cellular events that lead to HTS have been extensively studied, the pathogenesis of this condition is still not well understood, making treatment difficult.Key cells involved in HTS are the dermal fibroblasts. Dermal fibroblasts are a dynamic and diverse population of cells whose function in skin and HTS in many respects remain unkn...

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Healing of Burn Wounds in Transgenic Mice Overexpressing Transforming Growth Factor-β1 in the Epidermis

Cited by 100 publications

References 35 publications

Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

Accelerated re-epithelialization inDpr2-deficient mice is associated with enhanced response to TGFβ signaling

Deep dermal fibroblasts contribute to hypertrophic scarring

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