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Gene profiling of keloid fibroblasts shows altered expression in multiple fibrosis-associated pathways

ABSTRACT: Keloids are benign tumors of the dermis that form during a protracted wound healing process. Susceptibility to keloid formation occurs predominantly in people of African and Asian descent. The key alteration(s) responsible for keloid formation has not been identified and there is no satisfactory treatment for this disorder. The altered regulatory mechanism is limited to dermal wound healing, although several diseases characterized by an exaggerated response to injury are prevalent in individuals of African ancestry. We have observed a complex pattern of phenotypic differences in keloid fibroblasts grown in standard culture medium or induced by hydrocortisone. In this study Affymetrix-based microarray was performed on RNA obtained from fibroblasts cultured from normal scars and keloids grown in the absence and presence of hydrocortisone. We observed differential regulation of approximately 500 genes of the 38,000 represented on the Affymetrix chip. Of particular interest was increased expression of several IGF-binding and IGF-binding related proteins and decreased expression of a subset of Wnt pathway inhibitors and multiple IL-1-inducible genes. Increased expression of CTGF and IGFBP-3 was observed in keloid fibroblasts only in the presence of hydrocortisone. These findings support a role for multiple fibrosis-related pathways in the pathogenesis of keloids Keywords: cell-type comparison, drug treatment comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE7890 | GEO | 2007/11/26

SECONDARY ACCESSION(S): PRJNA99931

REPOSITORIES: GEO

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Gene profiling of keloid fibroblasts shows altered expression in multiple fibrosis-associated pathways

Project description:Keloids are benign tumors of the dermis that form during a protracted wound healing process. Susceptibility to keloid formation occurs predominantly in people of African and Asian descent. The key alteration(s) responsible for keloid formation has not been identified and there is no satisfactory treatment for this disorder. The altered regulatory mechanism is limited to dermal wound healing, although several diseases characterized by an exaggerated response to injury are prevalent in individuals of African ancestry. We have observed a complex pattern of phenotypic differences in keloid fibroblasts grown in standard culture medium or induced by hydrocortisone. In this study Affymetrix-based microarray was performed on RNA obtained from fibroblasts cultured from normal scars and keloids grown in the absence and presence of hydrocortisone. We observed differential regulation of approximately 500 genes of the 38,000 represented on the Affymetrix chip. Of particular interest was increased expression of several IGF-binding and IGF-binding related proteins and decreased expression of a subset of Wnt pathway inhibitors and multiple IL-1-inducible genes. Increased expression of CTGF and IGFBP-3 was observed in keloid fibroblasts only in the presence of hydrocortisone. These findings support a role for multiple fibrosis-related pathways in the pathogenesis of keloids Keywords: cell-type comparison, drug treatment comparison Cell cultures were initiated from human biopsy material from normal dermal scars and keloids of adult males and females. Experimental cultures were derived from the first passage of cells thawed from liquid nitrogen. Cultures of fibroblasts from samples were grown with or without 1.5 micromolar hydrocortisone. RNA from each cell strain was isolated from three independent cell cultures and pooled, then run on an Affymetrix Human Genome U133 Plus 2.0 GeneChip.

2007-11-26 | E-GEOD-7890 | biostudies-arrayexpress

The Role of the Mammalian Target of Rapamycin in Keloid and Hypertrophic Scars

Project description:We hypothesize that, the mTOR pathway is a dominant pathway in cultured keloid and hypertrophy scar fibriblasts compared to normal skin cells. Certain pathway changes can be detected after medication treatment. Global gene expression in RNA samples from rapamycin and tacrolimus treated fibroblasts (from normal skin and hypertrophic scars, keloid scars) is assayed to study the possibility to use mTOR inhibitors as potential drug to treat abnormal scarring. We investigated the difference between normal wound healing and hypertrophic scars and keloids as well.

2014-05-20 | E-MTAB-2509 | biostudies-arrayexpress

Gene expression profile at single cell level of primary keloid fibroblasts treated with various radiotherapy modalities

Project description:Keloids are benign dermal tumors that arise from abnormal wound healing processes following skin lesions. Postoperative radiotherapy (PORT) is a clinically effective measure to reduce recurrence rates of keloid. We used single cell RNA sequencing (scRNA-seg) to analyze the different of primary keloid fibroblasts treated with various radiation modalities.

2024-04-07 | GSE261116 | GEO

Exclusive expression of KANK4 promotes myofibroblast mobility in keloid tissues

Project description:Keloids are characterized by abnormal wound healing with excessive accumulation of extracellular matrix. Myofibroblasts are the primary contributor to extracellular matrix secretion, playing an essential role in the wound healing process. However, the differences between myofibroblasts involved in keloid formation and normal wound healing remain unclear. To identify the specific characteristics of keloid myofibroblasts, we initially assessed the expression levels of well-established myofibroblast markers, α-smooth muscle actin (α-SMA) and transgelin (TAGLN), in scar and keloid tissues (n = 63 and 51, respectively). The objective was to evaluate the enrichment of myofibroblasts in these tissues. Although myofibroblasts were present in significant quantities in keloids and immature scars, they were absent in mature scars. Next, we conducted RNA sequencing using myofibroblast-rich areas from keloids and immature scars to investigate the difference in RNA expression profiles among myofibroblasts. Comparison of the results with publicly available RNA-sequencing datasets revealed that 112 genes were significantly upregulated and 108 genes were downregulated in keloid samples compared with immature scar samples. Among them, KN motif and ankyrin repeat domains 4 (KANK4) was identified as a specifically upregulated gene in keloids. Immunohistochemical analysis showed that KANK4 protein was expressed in myofibroblasts in keloid tissues; however, it was not expressed in any myofibroblasts in immature scar tissues. There are two main isoforms of KANK4 transcripts, with short isoforms being dominantly expressed in keloid tissue. Overexpression of the short isoform of KANK4 enhanced cell mobility in keloid myofibroblasts. Our results suggest that the KANK4-mediated increase in myofibroblast mobility contributes to keloid pathogenesis.

2024-03-19 | GSE245660 | GEO

Time series integrative analysis of RNA-Seq and miRNA expression data reveals key biologic pathways during keloid formation [miRNA]

Project description:Keloids represent a common form of exaggerated wound scarring that cause considerable morbidity. Moreover, there are limited data on molecular mechanisms underlying keloids and effective therapies are lacking. To gain new insight in the transcriptomic alterations of wound healing in keloid-prone individuals, we followed an integrative approach of RNA-Seq and miRNA expression data analysis in serial skin biopsies of the same site (baseline and six weeks after wounding) in keloid-prone (n=8) and healthy matched control individuals (n=6). Bioinformatic analysis identified 37 miRNAs and 1449 genes that are differentially expressed specifically in keloid-prone individuals during wound healing. Pathway enrichment analysis was undertaken in the RNA-Seq data and identified NOTCH signaling, MAPK signaling, and Toll-like receptor pathways to be altered in keloid-prone individuals after wounding. In addition, dysregulation of DNA repair, p53 signalling and metabolic pathways (RNA, protein, fructose, mannose and glycerophospholipid metabolism) was highlighted during keloid formation. Gene association network analysis demonstrated divergent average expression profiles of cytokine signaling genes, as well as lipid metabolism genes between keloid-prone and healthy individuals during wound healing. In summary, our study provides a comprehensive and integrative analysis of the keloid transcriptome and miRNAome and highlights biological pathways that feature during keloid formation.

2018-06-29 | GSE113620 | GEO

Time series integrative analysis of RNA-Seq and miRNA expression data reveals key biologic pathways during keloid formation [RNA-seq]

2018-06-29 | GSE113619 | GEO

Keloid fibroproliferative properties are dependent on stem cells modified by the HEDGEHOG-GLI1 pathway [EA1488]

Project description:Keloids are benign fibroproliferative skin tumors caused by aberrant wound healing, the etiology of which is unknown. Although keloids cause life inconveniences and cosmetic problems, the lack of animal models has yet to elucidate their pathogenesis or develop effective treatments. Here, we found that the characteristics of stem cells from keloid lesions and surrounding dermis differ from those of normal skin and that HEDGEHOG (HH) signal and its downstream transcription factor GLI1 were upregulated in keloid patient-derived stem cells. Inhibition of the HH-GLI1 pathway reduced the expression of genes involved in keloids and fibrosis-inducing cytokines, including osteopontin. Moreover, HH-signal inhibitor vismodegib reduced keloid reconstituted tumor size and the expression of keloid related genes in nude mouse, and the collagen bundle and the expression of cytokines characteristic for keloids in ex vivo culture of keloid tissues. These results implicate the HH-GLI1 pathway in keloid pathogenesis and suggest therapeutic target of keloids.

2023-12-13 | GSE218922 | GEO

Keloid fibroproliferative properties are dependent on stem cells modified by the HEDGEHOG-GLI1 pathway [EA1874]

2023-12-13 | GSE218894 | GEO

Quantitative proteomic analysis of keloid scars and normal skin tissues

Project description:Keloid scars is a pathologic fibro-proliferative disorders of the skin, which exhibit abnormal phenotypes including fibroblasts proliferation and collagen deposits. There have been several treatments of keloids including conventional surgical therapies and adjuvant therapies, but a high recurrence rate of keloids was also observed after treatment. Quantitative proteomics approach has been proved an efficient approach to investigate pathological mechanism and novel biomarkers. In this study, we present a label-free quantitative proteomics analysis to explore differential protein expression profiles in normal skin and keloid scar tissues based on nano-liquid chromatography and tandem mass spectrometry (Nano-LC–MS/MS). The study results displayed a more comprehensive keloid protein expression landscape and provided novel pathological insight of keloid.

2023-03-11 | PXD029631 | Pride

Transcriptomic analysis of keloid fibroblasts demonstrates reduced expression of vitamin D binding partner Retinoid-X receptor α: Implications for clinical treatment

Project description:Keloids are benign fibroproliferative tumours resulting from skin damage such as trauma, burns or surgery. Keloids are more prevalent in populations with darkly pigmented skin. Links between skin pigmentation and vitamin D production have been established and some studies indicate involvement of vitamin D signalling in keloid pathology. This study assessed the impact of paricalcitol (a selective vitamin D signalling activator) on fibroblasts derived from keloid and normal skin, to further investigate the role and potential clinical relevance of vitamin D signalling in keloid pathology. Analysis of keloid and normal skin tissue using immunohistochemistry demonstrated a significant reduction of nuclear vitamin D receptor (VDR) in keloid tissue. After treatment with paricalcitol, nuclear VDR was increased in both keloid and normal fibroblasts. RNA sequencing of normal fibroblasts treated with paricalcitol demonstrated significant changes in gene expression, with many upregulated genes identified to have anti-fibrotic effects. However, paricalcitol failed to alter gene expression in Keloid fibroblasts. To investigate this further, we performed RNA sequencing of normal and keloid fibroblasts and found that retinoid-X receptor α (RXRα), a key binding partner of VDR required for downstream transcriptional activation, is significantly downregulated in keloid fibroblasts. Our results indicate that paricalcitol can effectively activate VDR translocation to the nucleus but is unable to effect change at the transcriptional level in keloid fibroblasts, most likely due to the reduced expression of RXRα. This suggests Vitamin D signalling may be aberrant in keloids, and that supplementation with Vitamin D alone would likely be ineffective in restoring signalling. Keywords: Keloid, Vitamin D receptor, Paricalcitol, Retinoid-X receptor α

2024-12-03 | GSE282479 | GEO

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