Keloids: The paradigm of skin fibrosis — Pathomechanisms and treatment

Andrews, Jonathan; Marttala, Jaana; Macarak, Edward J.; Rosenbloom, Joel; Uitto, Jouni

doi:10.1016/j.matbio.2016.01.013

Cited by 293 publications

(325 citation statements)

References 93 publications

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“…Interestingly, in line with observations about AM treatment inducing re‐epithelialization of chronic wounds (Alcaraz et al, ; Insausti, Alcaraz, et al, ), previous work in our laboratory has demonstrated that AM is able of attenuating the expression profile of relevant genes involved in cell cycle regulation under TGF‐ß control (Alcaraz et al, ), which resembles how attenuation of TGF‐ß signalling has also been demonstrated to be critical for some tumour cells to escape from cell cycle arrest (Nicolas & Hill, ). In that sense, exacerbated canonical TGF‐ß signalling has been linked to the promotion of skin fibrosis in an intricate process that involves fibroblast, keratinocyte and leucocyte interaction (Andrews, Marttala, Macarak, Rosenbloom, & Uitto, ; Ashcroft & Roberts, ). Coherently, interfering with TGF‐ß signalling by means of AM treatment may emerge as a good strategy for addressing skin fibrosis in humans.…”

Section: Discussionmentioning

confidence: 99%

Amniotic membrane stimulates cell migration by modulating transforming growth factor‐β signalling

Ruiz‐Cañada

Bernabé‐García

Liarte

et al. 2017

J Tissue Eng Regen Med

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Keratinocyte migration is a mandatory aspect of wound healing. We have previously shown that amniotic membrane (AM) applied to chronic wounds assists healing through a process resulting in the overexpression of c-Jun at the wound's leading edge. We have also demonstrated that AM modifies the genetic programme induced by transforming growth factor-ß (TGF-ß) in chronic wounds. Here we used a scratch assay of mink lung epithelial cells (Mv1Lu) and a spontaneously immortalized human keratinocyte cell line (HaCaT) cells to examine the influence of AM application on the underlying signalling during scratch closure. AM application induced c-Jun phosphorylation at the leading edge of scratch wounds in a process dependent on MAPK and JNK signalling. Strikingly, when the TGF-ß-dependent Smad-activation inhibitor SB431542 was used together with AM, migration improvement was partially restrained, whereas the addition of TGF-ß had a synergistic effect on the AM-induced cell migration. Moreover, antagonizing TGF-ß with specific antibodies in both cell lines or knocking out TGF-ß receptors in Mv1Lu cells had similar effects on cell migration as using SB431542. Furthermore, we found that AM was able to attenuate TGF-ß-Smad signalling specifically at the migrating edge; AM treatment abated Smad2 and Smad3 nuclear localization in response to TGF-ß in a process dependent on mitogen-activated protein kinase kinase 1 (MEK1) activation but independent of EGF receptor or JNK activation. The involvement of Smad signalling on AM effects on HaCaT keratinocytes was further corroborated by overexpression of either Smad2 or Smad3 and the use of Smad phosphorylation-specific inhibitors, revealing a differential influence on AM-induced migration for each Smad. Thus, AM TGF-ß-Smad signalling abating is essential for optimal cell migration and wound closure.

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Section: Discussionmentioning

confidence: 99%

Amniotic membrane stimulates cell migration by modulating transforming growth factor‐β signalling

Ruiz‐Cañada

Bernabé‐García

Liarte

et al. 2017

J Tissue Eng Regen Med

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“…Current skin fibrosis treatments typically require expensive pharmacologic, surgical, or invasive treatments associated with a significant risk of side effects. Even with combination therapy and a good treatment outcome, skin fibrosis frequently recurs .…”

Section: Introductionmentioning

confidence: 99%

High fluence light emitting diode‐generated red light modulates characteristics associated with skin fibrosis

Mamalis

Koo

Garcha

et al. 2016

Journal of Biophotonics

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Skin fibrosis, often referred to as skin scarring, is a significant international health problem with limited treatment options. The hallmarks of skin fibrosis are increased fibroblast proliferation, collagen production, and migration speed. Recently published clinical observations indicate that visible red light may improve skin fibrosis. In this study we hypothesize that high-fluence light-emitting diode-generated red light (HF-LED-RL) modulates the key cellular features of skin fibrosis by decreasing cellular proliferation, collagen production, and migration speed of human skin fibroblasts. Herein, we demonstrate that HF-LED-RL increases reactive oxygen species (ROS) generation for up to 4 hours, inhibits fibroblast proliferation without increasing apoptosis, inhibits collagen production, and inhibits migration speed through modulation of the phosphoinositide 3-kinase (PI3K)/Akt pathway. We demonstrate that HF-LED-RL is capable of inhibiting the unifying cellular processes involved in skin fibrosis including fibroblast proliferation, collagen production, and migration speed. These findings suggest that HF-LED-RL may represent a new approach to treat skin fibrosis. LED advantages include low cost, portability, and ease of use. Further characterizing the photobiomodulatory effects of HF-LED-RL on fibroblasts and investigating the anti-fibrotic effects of HF-LED-RL in human subjects may provide new insight into the utility of this therapeutic approach for skin fibrosis.

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“…Keloid is a fibrotic dermal tumor with overproduction of extracellular matrix components such as collagen, due to excessive expression of growth factors and cytokines . Significant upregulation of galectin‐1 in keloid tissue extract was reported by comparative proteomic analysis .…”

Section: Fibrotic Disordersmentioning

confidence: 99%

The expression and function of galectins in skin physiology and pathology

Liu

2018

Experimental Dermatology

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The galectin family comprises β-galactoside-binding proteins widely expressed in many organisms. There are at least 16 family members, which can be classified into three groups based on their carbohydrate-recognition domains. Pleiotropic functions of different galectins in physiological and pathological processes through extracellular or intracellular actions have been revealed. In the skin, galectins are expressed in a variety of cells, including keratinocytes, melanocytes, fibroblasts, dendritic cells, lymphocytes, macrophages and endothelial cells. Expression of specific galectins is reported to affect cell status, such as activation or death, and regulate the interaction between different cell types or between cells and the extracellular matrix. In vitro cellular studies, in vivo animal studies and studies of human clinical material have revealed the pathophysiologic roles of galectins in the skin. The pathogenesis of diverse non-malignant skin disorders, such as atopic dermatitis, psoriasis, contact dermatitis and wound healing, as well as skin cancers, such as melanoma, squamous cell carcinoma, basal cell carcinoma and cutaneous haematologic malignancy can be regulated by different galectins. Revelation of biological roles of galectins in skin may pave the way to future development of galectin-based therapeutic strategies for skin diseases.

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Keloids: The paradigm of skin fibrosis — Pathomechanisms and treatment

Cited by 293 publications

References 93 publications

Amniotic membrane stimulates cell migration by modulating transforming growth factor‐β signalling

Amniotic membrane stimulates cell migration by modulating transforming growth factor‐β signalling

High fluence light emitting diode‐generated red light modulates characteristics associated with skin fibrosis

The expression and function of galectins in skin physiology and pathology

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