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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218922 | GEO | 2023/12/13

REPOSITORIES: GEO

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

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 | 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

Keloid-specific gene expression profiling for accurate diagnostic and therapeutic applications.

Project description:Scars are a heterogeneous disease including normotrophic scars, hypertrophic scars, and keloids. Of these lesions, keloids are a distinct subtype from any other type of scar because clinically, it causes pain, itching, or tenderness, causing life discomfort and characteristically irreversible. Therefore, for accurate diagnosis and treatment of keloids, it is essential to identify keloid-specific genes. However, in previous studies, keloids were compared with controls such as scar-free normal skin. In these studies, general scar-related genes were likely to be chosen rather than keloid-specific genes. In this study, we acquired transcriptomic profiles of normotrophic scars, hypertrophic scars, and keloids from formalin-fixed paraffin-embedded human skin samples using high-throughput RNA-sequencing techniques. We compared the transcriptome profile of keloids with those of other scar lesions to select for highly accurate keloid-specific genes and pathways. The results revealed that genes related with several biological processes such as sensory/visual perception are upregulated strongly in keloids, whereas genes related with activation of immune response were downregulated remarkably in keloids. Furthermore, the biological process of extracellular matrix organization was highlighted in both hypertrophic scars and keloids. In conclusion, our study provides insight into the pathogenesis of keloids distinct from other scar lesions as well as potential keloid-specific biomarkers.

2021-11-23 | GSE188952 | GEO

Keratinocyte and fibroblast gene expression in skin and keloid scar tissue

Project description:Keloids are scars that extend beyond original wounds and are resistant to treatment. In order to improve understanding of the molecular basis of keloid scarring, we have assessed the genomic profiles of keloid fibroblasts and keratinocytes. Skin and scar tissues were obtained for isolation of primary keratinocytes and fibroblasts. Keloid scars were excised from patients undergoing scar excision surgery, normal skin samples were isolated from patients undergoing elective plastic surgery. Primary culters were prepared for keratinocytes and fibroblasts, and were harvested for analysis up to passage three. Nine keloid scars, for adjacent non-lesional keloid skin samples, and three normal skin samples were obtained and cultured. RNA was isolated using RNeasy, and quality verified using an Agilent 2100 Bioanalyzer. Labeling and hybridization to Affymetrix Human Gene 1.0 ST microarray chips was performed by the Vanderbilt Genome Sciences Resource at Vanderbilt University Medical Center.

2013-05-28 | E-GEOD-44270 | 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

Transcriptome network analysis of inflammation and fibrosis in keloids [scRNA-seq]

Project description:Background:Keloid (KL) is a common benign skin tumor. KL is typically characterized by significant fibrosis and an intensive inflammatory response. Therefore, a comprehensive understanding of the interactions between cellular inflammation and fibrotic cells is essential to elucidate the mechanisms driving the progression of KL and to develop therapeutics. Objective: Investigate the transcriptome landscape of inflammation and fibrosis in keloid scars. Methods: In this paper, we performed transcriptome sequencing and microRNA (miRNA) sequencing on unselected live cells from six human keloid tissues and normal skin tissues to elucidate a comprehensive transcriptome landscape. In addition, we used single-cell RNA sequencing (scRNA-seq) analysis to analyze intercellular communication networks and enrich fibroblast populations in two additional keloid and normal skin samples to study fibroblast diversity. Results: By RNA sequencing and a miRNA-mRNA-PPI network analysis, we identified miR-615-5p and miR-122b-3p as possible miRNAs associated with keloids, as they differed most significantly in keloids. Similarly, COL3A1, COL1A2, THBS2, TNC, IGTA, THBS4, TGFB3 as genes with significant differences in keloid may be associated with keloid development. Using single-cell RNA sequencing data from 24086 cells collected from normal or keloid, we report reconstructed intercellular signaling network analysis and aggregation to modules associated with specific cell subpopulations at the cellular level for keloid alterations. Conclusions: Our multitranscriptomic dataset delineates inflammatory and fibro heterogeneity of human keloids, underlining the importance of intercellular crosstalk between inflammatory cells and fibro cells and revealing potential therapeutic targets.

2024-09-30 | GSE237754 | GEO

Transcriptome network analysis of inflammation and fibrosis in keloids [miRNA-seq]

2024-09-30 | GSE237753 | GEO

Transcriptome network analysis of inflammation and fibrosis in keloids [mRNA-seq]

2024-09-30 | GSE237752 | GEO

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

Phosphoproteomics of induced and inhibited early Hh signaling in human medulloblastoma cells

Project description:Aberrant sonic hedeghog signaling is implicated in the development of various cancer entities such as medulloblastoma. The canonical signaling cascade has been studied for years. Activation of GLI transcription factors was revealed as the driving force upon pathway activation. Phosphorylation by Proteinkinase A, Casein Kinase 1 and Glycogen Synthase Kinase 3 β has been found to influence the degradation of the GLI transcription factors. However, the deeper role of phosphorylation in the signal transduction remains unclear. We, therefore, applied comprehensive HPLC-MS/MS based phosphoproteomics to reveal phosphorylation dynamics underlying the chemical activation and inhibition of sonic hedgehog signaling in human medulloblastoma cells. Human medulloblastoma cells were treated with SAG (Hh pathway induction) and Vismodegib (Hh pathway inhibition) for 5 and 15 minutes. Our phosphoproteomic profiling revealed a central role of phosphorylation in the regulation of ciliary assembly, trafficking and signal transduction after 5 minutes treatment. ERK/MAPK signaling besides protein kinase A signaling and mTOR signaling were differentially regulated. Activation of Polo-like kinase 1 and inhibtion of Caseinkinase 2A1 was characteristic for Vismodegib treatment while SAG treatment induced Aurora kinase A activity. Distinctive phosphorylation of central players of sonic Hh signaling such as Smoothened, SUFU, Gli2 and Gli3 was obtained after 15 minutes treatment.

2021-09-08 | PXD013408 | Pride

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