The role of Wnt signaling in skin fibrosis

Huber, Julika; Evan, Fahy J; Quarto, Natalina; Longaker, Michael T.

doi:10.1002/med.21853

Cited by 35 publications

(22 citation statements)

References 100 publications

(281 reference statements)

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“…Similar activation of the myofibroblast transition has been suggested in other signaling pathways. For example, scars can develop when the translocation of β -catenin in fibroblasts is enhanced by Wnt, thereby leading to proliferation, migration, and transition of fibroblasts into myofibroblasts, as well as deposition of type I collagen [ 62 ]. Reduced expression of collagen I and III was observed in a biomimetic nanodrug delivery system with increased efficacy on hypertrophic scars by regulating Wnt/ β -catenin and JAK2/STAT3 pathways [ 63 ].…”

Section: Regulation Of Fibroblasts In Wound Healing and Scar Formationmentioning

confidence: 99%

Fibroblasts in Scar Formation: Biology and Clinical Translation

Qian

Shan

Gong

et al. 2022

Oxidative Medicine and Cellular Longevity

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Scarring, which develops due to fibroblast activation and excessive extracellular matrix deposition, can cause physical, psychological, and cosmetic problems. Fibroblasts are the main type of connective tissue cells and play important roles in wound healing. However, the underlying mechanisms of fibroblast in reaching scarless wound healing require more exploration. Herein, we systematically reviewed how fibroblasts behave in response to skin injuries, as well as their functions in regeneration and scar formation. Several biocompatible materials, including hydrogels and nanoparticles, were also suggested. Moreover, factors that concern transformation from fibroblasts into cancer-associated fibroblasts are mentioned due to a tight association between scar formation and primary skin cancers. These findings will help us better understand skin fibrotic pathogenesis, as well as provide potential targets for scarless wound healing therapies.

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Section: Regulation Of Fibroblasts In Wound Healing and Scar Formationmentioning

confidence: 99%

Fibroblasts in Scar Formation: Biology and Clinical Translation

Qian

Shan

Gong

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…To further assess potential targets of S. thermophilus lysate within TGF-β1 signaling pathways, we investigated the effects of bacterial lysate on β-catenin, a key component involved in Wnt/β-catenin signaling whose aberrant activation occurs in the development of skin fibrosis [ 6 ]. A significant up-regulation of β-catenin levels was found in TGF-β1-activated NHDF, while no significant difference was registered between the control and S. thermophilus lysate-treated cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The peculiar fibrogenic actions of TGF-β1 require the co-activation of multiple molecular pathways often interconnected, including the classical (Smad-dependent) or non-classical signaling, among which, the Wnt/β-catenin pathway plays a central role in regulating the dermal fibrosis [ 6 ]. As expected, β-catenin levels were significantly increased in TGF-β1-activated NHDF while treatment with S. thermophilus was able to reduce them.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, TGF-β1, upregulated in skin fibrosis, requires de novo synthesis by many cell types [2], and also through the autocrine induction of its gene expression in a positive feedback loop [3][4][5]. Another critical pathway in skin fibrosis is the Wnt/β-catenin signaling pathway [6]. β-catenin accumulation and its subsequent nuclear translocation may increase proliferation, migration, collagen I gene expression [7,8], and the excessive deposition of ECM proteins [9], contributing to dermal fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of probiotic Streptococcus thermophilus in counteracting TGF-β1-induced fibrotic response in normal human dermal fibroblasts

et al. 2022

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Background Abnormal and deregulated skin wound healing associated with prolonged inflammation may result in dermal fibrosis. Since the current therapeutic strategies revealed unsatisfactory, the investigation of alternative approaches such as those based on the use of specific probiotic strains could provide promising therapeutic options. In this study, we aimed to evaluate whether the lysate from S. thermophilus could antagonize the fibrogenic effects of TGF-β1 in normal human dermal fibroblasts (NHDF). Methods NHDF were exposed to TGF-β1 to establish a fibrotic phenotype. Proliferation rate and cell number were measured using the IncuCyte® Live Cell Imager system and the trypan blue dye exclusion test. Phenoconversion markers (α-SMA and fibronectin) and collagen I levels were assessed by western blot and immunofluorescence. The mRNA levels of TGF-β1 were evaluated by RT-PCR. The Smad2/3 phosphorylation level as well as β-catenin and PPARγ expression, were assessed by western blot. The cell contractility function and migration of NHDF were studied using collagen gel retraction assay, and scratch wound healing assay, respectively. The effects of S. thermophilus lysate, alone or combined with TGF-β1, were evaluated on all of the above-listed parameters and markers associated with TGF-β1-induced fibrotic phenotype. Results Exposure to the S. thermophilus lysate significantly reduced the key mediators and events involved in the abnormal activation of myofibroblasts by TGF-β1 within the fibrotic profile. The S. thermophilus treatment significantly reduced cell proliferation, migration, and myo-differentiation. In addition, the treatment with probiotic lysate reduced the α-SMA, fibronectin, collagen-I expression levels, and affected the collagen contraction ability of activated dermal fibroblasts. Moreover, the probiotic targeted the TGF-β1 signaling, reducing Smad2/3 activation, TGF-β1 mRNA level, and β-catenin expression through the upregulation of PPARγ. Conclusion This is the first report showing that S. thermophilus lysate had a remarkable anti-fibrotic effect in TGF-β1-activated NHDF by inhibiting Smad signaling. Notably, the probiotic was able to reduce β-catenin and increase PPARγ levels. The findings support our point that S. thermophilus may help prevent or treat hypertrophic scarring and keloids.

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“…Like other organ fibrosis, skin fibrosis is the excessive ECM deposition in the dermis and occurs following tissue injury such as burns, trauma, infection, surgery, and radiation, leading to scars that limit movement and cause significant psychological distress for patients [ 13 , 358 ]. Many molecular pathways have been implicated in the development of skin fibrosis, including TGF- β , Wnt, and epidermal growth factor receptor (EGFR) signaling pathways [ 359 ].…”

Section: Roles Of C/ebps In the Fibrotic Processmentioning

confidence: 99%

CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding

et al. 2022

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CCAAT/enhancer-binding proteins (C/EBPs) are a family of at least six identified transcription factors that contain a highly conserved basic leucine zipper domain and interact selectively with duplex DNA to regulate target gene expression. C/EBPs play important roles in various physiological processes, and their abnormal function can lead to various diseases. Recently, accumulating evidence has demonstrated that aberrant C/EBP expression or activity is closely associated with the onset and progression of fibrosis in several organs and tissues. During fibrosis, various C/EBPs can exert distinct functions in the same organ, while the same C/EBP can exert distinct functions in different organs. Modulating C/EBP expression or activity could regulate various molecular processes to alleviate fibrosis in multiple organs; therefore, novel C/EBPs-based therapeutic methods for treating fibrosis have attracted considerable attention. In this review, we will explore the features of C/EBPs and their critical functions in fibrosis in order to highlight new avenues for the development of novel therapies targeting C/EBPs.

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The role of Wnt signaling in skin fibrosis

Cited by 35 publications

References 100 publications

Fibroblasts in Scar Formation: Biology and Clinical Translation

Fibroblasts in Scar Formation: Biology and Clinical Translation

Efficacy of probiotic Streptococcus thermophilus in counteracting TGF-β1-induced fibrotic response in normal human dermal fibroblasts

CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding

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