The Role of the Mammalian Target of Rapamycin in Keloid and Hypertrophic Scars
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Amiee Potter
PROVIDER: E-MTAB-2509 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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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
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
Project description:Fibrosis is vaguely described as connective tissue deposition that can be excessive in pathological conditions. This suggests a quantitative spectrum of fibrosis wherein there can be more or less extracellular matrix (ECM), which in the context of a repairing skin wound could reflect the range from normal scar to keloid. This depiction, however, does not encompass the potential qualitative differences between normal and pathological scars. In keloids, the markedly different physical (hard and dense) and histological (hyalinization) characteristics compared to normal scars indicate an altered and inappropriate matrix, rather than simply too much. With this quantitative discovery-based proteomics we provide a thorough molecular description of keloid lesions relative to normal scars, which is an essential step towards our understanding of this problem.
2019-12-03 | PXD015057 | Pride
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
Project description:Keloids are wounding-induced fibroproliferative human tumor–like skin scars of complex genetic makeup and poorly defined pathogenesis. Fibroblasts are the principal mediator of fibroproliferative disorders. To reveal dynamic epigenetic and transcriptome changes of keloid fibroblasts, a vertical study from RNA-seq and ATAC-seq analyses followed by in vivo confirmation of candidate molecule expression and subsequent functional testing was carried out using an early passage, freshly isolated keloid fibroblast cell strain and its paired normal control. These keloid fibroblasts produce keloid-like scars in a plasma clot-based skin equivalent humanized keloid animal model. RNA-seq analysis reveals that Hepatic fibrosis is the most significant pathway followed by Wnt–b-catenin signaling, TGF-b signaling, regulation of the EMT pathway, the STAT3 pathway, and adherens junction signaling. ATAC-seq analysis shows that STAT3 signaling is the most active pathway in keloid fibroblasts, followed by Wnt signaling (Wnt5) and regulation of the EMT pathway. Immunohistochemistry confirms that activated STAT3, (Tyr705 phospho-STAT3) and/or b-catenin are upregulated in dermal fibroblasts of keloid clinical specimens and mature keloid skin equivalent implants from the humanized mouse model compared to the normal control. The effect of STAT3 signaling on keloid fibroblast collagen expression was further tested in plasma clot-based skin equivalents using Cucurbitacin I, a selective JAK2/STAT3 inhibitor. A non-linear dose response of Cucurbitacin I was observed in collagen type I expression indicating a likely role of STAT3 signaling pathway in keloid pathogenesis. This work also demonstrates the utility of the recently established humanized keloid mouse model in exploring the mechanism of keloid formation.
2020-01-11 | GSE125022 | GEO
Project description:Background Hypertrophic scars and keloids are both pathological scars with similar appearance and pathological features. Currently, the differential diagnosis of the two mainly depends on the subjective judgment of physicians, and there is a lack of objective diagnostic indicators and treatment methods. Objectives To provide single-cell level evidence and new approaches for the differential diagnosis and clinical treatment of hypertrophic scars and keloids. Methods Single-cell RNA sequencing (scRNA-seq) was performed on a hypertrophic scar and a keloid tissue from the same patient to compare the differences in the cellular and tissue microenvironments of the two conditions. Results ScRNA-seq results depicted the distribution of cell subpopulations and different microenvironments between hypertrophic scars and keloids. Conclusions The results of the analysis showed significant differences in cell subcluster distribution and cell communication between hypertrophic scars and keloids. This study demonstrated the potential of scRNA-seq to differentiate the two conditions and provide a new approach to refine differential diagnosis and a possible target for therapeutic research.
2024-11-15 | GSE243716 | GEO
Project description:Purpose: We aimed to identify the molecular drivers that initiate or sustain keloid pathogenesis. Method: Bulk tissue RNA sequencing of Asian keloid and normal tissues was performed to identify genes that contribute to keloid pathogenesis. We also established a preclinical model of inflammatory skin fibrosis by injecting C57BL/6 mice with bleomycin intradermally for 3 weeks to provide an alternative animal model of keloid scar. Result: Gene set enrichment analysis revealed upregulation of WNT5A gene expression, along with significant enrichment of genes related to EMT in keloid tissues. These results correlate with those of histological analysis in which human keloid tissues and the bleomycin-induced fibrosis animal model showed increased WNT5A expression along with EMT markers. Our in vitro data showed increased expression of the IL-6/JAK/STAT pathway and subsequent elevation in EMT markers on keratinocytes when co-cultured with WNT5A-activated fibroblasts or keloid fibroblasts. Silencing of WNT5A reversed the hyperactivation of the STAT pathway and EMT. Conclusion: IL-6 secreted from WNT5A-activated fibroblasts or keloid fibroblasts may induce adjacent keratinocytes to express EMT markers by activating the JAK/STAT signalling pathway. A better understanding of keloid pathogenesis and the role of WNT5A in EMT will promote the development of next-generation targeted treatments for keloid scars.
2021-05-06 | GSE173900 | GEO
Project description:This study investigated the effects of extracellular matrix (ECM) rigidty on gene expression patterns in normal dermal fibroblasts (NDFs) and keloid dermal fibroblasts (KDFs). Cells were cultured on collagen coated polyacrylamide hydrogels with elastic moduli mimicking normal skin (8 kPa) or keloid scar tissue (214 kPa), and changes in gene expression were profiled using next-generation RNA-sequencing. Differential gene expression analysis identified overall significant differences in gene expression between the NDF and KDF populations. Despite high levels of inter-patient heterogeneity in the KDF samples, further principal components analysis revealed a subset of genes (PC5) that were specifically regulated by ECM rigidity. Gene set enrichment analysis of the PC5 genes identified classic pathways associated with mechanotransduction, including Hippo Signalling and Regulation of the Actin Cytoskeleton, as well as genes associated with the Autophagy pathway. Additional in vitro studies and human tissue staining confirmed the biomechanical regulation of autophagic flux in NDFs and KDFs and differential remodelling of the lysosome in KDFs and keloid scars. Together, these findings implicate autophagy and lysosomal remodelling as biomechanically dysregulated pathways in keloid fibroblasts, and these mechanisms may contribute to scar pathogenesis.
2023-11-02 | GSE246562 | GEO
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
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