The Keloid Disorder: Heterogeneity, Histopathology, Mechanisms and Models

Limandjaja, Grace C.; Niessen, Frank B.; Scheper, Rik J.; Gibbs, Susan

doi:10.3389/fcell.2020.00360

Cited by 196 publications

(284 citation statements)

References 322 publications

(575 reference statements)

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“…14 Together with clinical observations, these data suggest that it would be pertinent to recognize keloids and hypertrophic scars as separate entities. [16][17][18] The principal genetically distinct collagens in keloids are types I, III and V, but type VI is also abundantly present particularly in the early stages of development. 19,20 Consequently, it has been suggested that upregulation of type VI collagen gene expression may serve as an early biomarker of the fibrotic process.…”

Section: Clini C Al and G Ene Tic Fe Ature S Of Keloidsmentioning

confidence: 99%

“…Hydrogel-based fabrication of matrices from silk and collagen has also been used to generate a matrix in which to grow fibroblasts; however, despite many attempts to use such unique polymers, collagen-based polymers still appear to be the most physiologic and widely used despite their limitations. In a recent review of the keloid disorder, Limandjaja et al suggest that direct co-culture systems that use full-thickness keloid equivalents are the most promising models of keloid disorder but that, ultimately, there is no single universal keloid model able to be applicable to all experimental objectives 18. Keloid scarring is not found in any other animal species including non-human primates.…”

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confidence: 99%

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Keloid disorder: Fibroblast differentiation and gene expression profile in fibrotic skin diseases

Macarak

Wermuth

Rosenbloom

et al. 2020

Experimental Dermatology

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Keloid disorder, a group of fibroproliferative skin diseases, is characterized by unremitting accumulation of the extracellular matrix (ECM) of connective tissue, primarily collagen, to develop cutaneous tumors on the predilection sites of skin. There is a strong genetic predisposition for keloid formation, and individuals of African and Asian ancestry are particularly prone. The principal cell type responsible for ECM accumulation is the myofibroblast derived from quiescent resident skin fibroblasts either through trans-differentiation or from keloid progenitor stem cells with capacity for multi-lineage differentiation and self-renewal. The biosynthetic pathways leading to ECM accumulation are activated by several cytokines, but particularly by TGF-β signalling. The mechanical properties of the cellular microenvironment also play a critical role in the cell's response to TGF-β, as demonstrated by culturing of fibroblasts derived from keloids and control skin on substrata with different degrees of stiffness. These studies also demonstrated that culturing of fibroblasts on tissue culture plastic in vitro does not reflect their biosynthetic capacity in vivo. Collectively, our current understanding of the pathogenesis of keloids suggests a complex network of interacting cellular, molecular and mechanical factors, with distinct pathways leading to myofibroblast differentiation and activation. Keloids can serve as a model system of fibrotic diseases, a group of currently intractable disorders, and deciphering of the critical pathogenetic steps leading to ECM accumulation is expected to identify targets for pharmacologic intervention, not only for keloids but also for a number of other, both genetic and acquired, fibrotic diseases.

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Section: Clini C Al and G Ene Tic Fe Ature S Of Keloidsmentioning

confidence: 99%

mentioning

confidence: 99%

Keloid disorder: Fibroblast differentiation and gene expression profile in fibrotic skin diseases

Macarak

Wermuth

Rosenbloom

et al. 2020

Experimental Dermatology

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“…Keloids are common in African, Spanish, and Asian populations, with an incidence ranging from 4.5 to 16%, and cause itching, pain, and a burning sensation (Niessen et al, 1999). Keloids can occur within years, and more likely after an inciting stimulus such as dermal injury or an inflammatory process (Limandjaja et al, 2020); however, they are most often found on the chest, shoulders, upper back, and back of the neck, where skin tension is higher than in other areas of the body (Ogawa et al, 2012;Liu et al, 2020). In addition, keloids tend to occur on the earlobes as a result of ear piercing, burns, or surgical procedures.…”

Section: Fibrosis Keloids and Hypertrophic Scarsmentioning

confidence: 99%

Primary Ciliary Signaling in the Skin—Contribution to Wound Healing and Scarring

Hosio

Jaks

Lagus

et al. 2020

Front. Cell Dev. Biol.

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“…Keloids may recur, are associated with pain and pruritus, and are disfiguring (1). Numerous pathophysiologic processes have been investigated (1)(2)(3), including hypoxic (4,5), mechanical tension (6,7), and inflammatory etiologies (8)(9)(10)(11)(12). In addition, genetic studies have identified certain susceptibility loci, including inflammationrelated genes, to be significantly associated with keloids (13)(14)(15)(16)(17)(18)).…”

Section: Introductionmentioning

confidence: 99%

RNA Sequencing Keloid Transcriptome Associates Keloids With Th2, Th1, Th17/Th22, and JAK3-Skewing

Duca

Espino

et al. 2020

Front. Immunol.

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Keloids are disfiguring, fibroproliferative growths and their pathogenesis remains unclear, inhibiting therapeutic development. Available treatment options have limited efficacy and harbor safety concerns. Thus, there is a great need to clarify keloid pathomechanisms that may lead to novel treatments. In this study, we aimed to elucidate the profile of lesional and non-lesional keloid skin compared to normal skin. We performed gene (RNAseq, qRT-PCR) and protein (immunohistochemistry) expression analyses on biopsy specimens obtained from lesional and non-lesional skin of African American (AA) keloid patients compared to healthy skin from AA controls. Fold-change≥2 and false-discovery rate (FDR)<0.05 was used to define significance. We found that lesional versus normal skin showed significant up-regulation of markers of T-cell activation/migration (ICOS, CCR7), Th2- (IL-4R, CCL11, TNFSF4/OX40L), Th1- (CXCL9/CXCL10/CXCL11), Th17/Th22- (CCL20, S100As) pathways, and JAK/STAT-signaling (JAK3) (false-discovery rate [FDR]<0.05). Non-lesional skin also exhibited similar trends. We observed increased cellular infiltrates in keloid tissues, including T-cells, dendritic cells, mast cells, as well as greater IL-4rα+, CCR9+, and periostin+ immunostaining. In sum, comprehensive molecular profiling demonstrated that both lesional and non-lesional skin show significant immune alternations, and particularly Th2 and JAK3 expression. This advocates for the investigation of novel treatments targeting the Th2 axis and/or JAK/STAT-signaling in keloid patients.

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The Keloid Disorder: Heterogeneity, Histopathology, Mechanisms and Models

Cited by 196 publications

References 322 publications

Keloid disorder: Fibroblast differentiation and gene expression profile in fibrotic skin diseases

Keloid disorder: Fibroblast differentiation and gene expression profile in fibrotic skin diseases

Primary Ciliary Signaling in the Skin—Contribution to Wound Healing and Scarring

RNA Sequencing Keloid Transcriptome Associates Keloids With Th2, Th1, Th17/Th22, and JAK3-Skewing

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