The Polygenic Map of Keloid Fibroblasts Reveals Fibrosis-Associated Gene Alterations in Inflammation and Immune Responses

Due to many inconsistencies in differentially expressed genes (DEGs) related to genomic expression changes during keloid formation and a lack of satisfactory prevention and treatment methods for this disease, the critical biomarkers related to inflammation and the immune response affecting keloid formation should be systematically clarified. Normal skin/keloid scar tissue-derived fibroblast genome expression data sets were obtained from the Gene Expression Omnibus (GEO) and ArrayExpress databases. Hub genes have a high degree of connectivity and gene function aggregation in the integration network. The hub DEGs were screened by gene-related protein–protein interactions (PPIs), and their biological processes and signaling pathways were annotated to identify critical biomarkers. Finally, eighty-one hub DEGs were selected for further analysis, and some noteworthy signaling pathways and genes were found to be closely related to keloid fibrosis. For example, IL17RA is involved in IL-17 signal transduction, TIMP2 and MMP14 activate extracellular matrix metalloproteinases, and TNC, ITGB2, and ITGA4 interact with cell surface integrins. Furthermore, changes in local immune cell activity in keloid tissue were detected by DEG expression, immune cell infiltration, and mass CyTOF analyses. The results showed that CD4+ T cells, CD8+ T cells and NK cells were abnormal in keloid tissue compared with normal skin tissue. These findings not only support the key roles of fibrosis-related pathways, immune cells and critical genes in the pathogenesis of keloids but also expand our understanding of targets that may be useful for the treatment of fibrotic diseases.

TRANSDERMAL THERAPEUTIC SYSTEMS–AN INNOVATIVE METHOD TO PREVENT THE FORMATION OF KELOIDS

Modern medicine has achieved significant results in the development of techniques to avoid surgeries. However, surgical methods are still one of the main tools for treating pathologies in the human body. Plastic surgery and cosmetology are gaining popularity every year, and sports injuries require the use of combined treatment methods, but any such intervention leads to the risk of keloids. The younger the person, the higher the likelihood of developing a keloid, due to the high degree of elasticity of the skin at an earlier age, which is prone to scarring than in older people. Women are at higher risk of developing keloids than men because their skin is more elastic. Thus, children and young women are most at risk of keloid formation, both as a result of physiological processes of skin scarring and preference for plastic surgery, cosmetic procedures and other methods of correction. In world pharmaceutical practice, there are not enough existing ways to prevent the development of keloid. It is necessary to conduct research on the selection of a fundamentally new structural basis for a transdermal therapeutic system containing the most effective and safe compounds of the regenerating and antioxidant mechanisms of action (vitamins and other biologically active compounds) from the point of view of preventing the formation of keloids, which will help in solving the problem of not only preventing the formation of keloids in the dermis, but also its subsequent growth and exit to the surface layers of the skin.

Use of Adipose Stem Cells Against Hypertrophic Scarring or Keloid

Hypertrophic scars or keloid form as part of the wound healing reaction process, and its formation mechanism is complex and diverse, involving multi-stage synergistic action of multiple cells and factors. Adipose stem cells (ASCs) have become an emerging approach for the treatment of many diseases, including hypertrophic scarring or keloid, owing to their various advantages and potential. Herein, we analyzed the molecular mechanism of hypertrophic scar or keloid formation and explored the role and prospects of stem cell therapy, in the treatment of this condition.

Single-Cell Sequencing Analysis and Weighted Co-Expression Network Analysis Based on Public Databases Identified That TNC Is a Novel Biomarker for Keloid

BackgroundThe pathophysiology of keloid formation is not yet understood, so the identification of biomarkers for kelod can be one step towards designing new targeting therapies which will improve outcomes for patients with keloids or at risk of developing keloids.MethodsIn this study, we performed single-cell RNA sequencing analysis, weighted co-expression network analysis, and differential expression analysis of keloids based on public databases. And 3 RNA sequencing data from keloid patients in our center were used for validation. Besides, we performed QRT-PCR on keloid tissue and adjacent normal tissues from 16 patients for further verification.ResultsWe identified the sensitive biomarker of keloid: Tenascin-C (TNC). Then, Pseudotime analysis found that the expression level of TNC decreased first, then stabilized and finally increased with fibroblast differentiation, suggesting that TNC may play an potential role in fibroblast differentiation. In addition, there were differences in the infiltration level of macrophages M0 between the TNC-high group and the TNC-low group. Macrophages M0 had a higher infiltration level in low TNC- group (P<0.05).ConclusionOur results can provide a new idea for the diagnosis and treatment of keloid.

A Prospective Randomized Pilot Study Evaluating the Scar Outcome after Gluteal Dermis Fat Graft with and without Kinesiotaping

Purpose: To compare gluteal wound healing after dermis fat graft (DFG) implantation in patients with and without local application of kinesiotapes.Methods: In this prospective, single-center analysis, 16 patients who underwent DFG implantation were randomized in two groups. Wound healing was compared 4-6 weeks after therapy and 3 months later (after application of 2 cycles of kinesiotaping for 2-3 weeks in the case and no specific therapy in the control group). Demographic data, patient content and wound healing were assessed. Scarring was graded (0-3) by evaluation of photodocumentation by 2 blinded, independent observers.Results: Mean scar grading by both observers decreased from 2.31±0.48 to 1.13±0.72 in the case and from 2.38±0.52 to 1.44±0.50 in the control group with interobserver-agreement on scar grading being substantial to almost perfect in both groups. Scar length decreased significantly in both groups (p=0.008). Scar prominence decreased in 2/3 of cases in the case and 1/3 in the control group. Scar coloring significantly improved in the case group alone (p=0.031).Conclusion: No functionally impairing or painful scar developed. No adverse effects occurred after kinesiotaping. Gluteal scars shortened significantly over time and were significantly paler in the case group. Kinesiotaping could prevent hypertrophic scarring or keloid formation.Trial registration number: DRKS00023111; trial register: Deutsches Register Klinischer Studien (www.drks.de), retrospectively registered

Tauroursodeoxycholic Acid Decreases Keloid Formation by Reducing Endoplasmic Reticulum Stress as Implicated in the Pathogenesis of Keloid

Keloids are a common form of pathologic wound healing and are characterized by an excessive production of extracellular matrix. This study examined the major contributing mechanism of human keloid pathogenesis using transcriptomic analysis. We identified the upregulation of mitochondrial oxidative stress response, protein processing in the endoplasmic reticulum, and TGF-β signaling in human keloid tissue samples compared to controls, based on ingenuity pathway and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Electron microscopic examinations revealed an increased number of dysmorphic mitochondria and expanded endoplasmic reticulum (ER) in human keloid tissue samples than that in controls. Western blot analysis performed using human tissues suggested noticeably higher ER stress signaling in keloids than in normal tissues. Treatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, significantly decreased scar formation in rabbit models, compared to normal saline and steroid injections. In summary, our findings demonstrate the contributions of mitochondrial dysfunction and dysregulated ER stress signaling in human keloid formation and the potential of TUDCA in the treatment of keloids.

Integrated bioinformatics analysis of core regulatory elements involved in keloid formation

Background Keloid is a benign fibro-proliferative dermal tumor formed by an abnormal scarring response to injury and characterized by excessive collagen accumulation and invasive growth. The mechanism of keloid formation has not been fully elucidated, especially during abnormal scarring. Here, we investigated the regulatory genes, micro-RNAs (miRNAs) and transcription factors (TFs) that influence keloid development by comparing keloid and normal scar as well as keloid and normal skin. Methods Gene expression profiles (GSE7890, GSE92566, GSE44270 and GSE3189) of 5 normal scar samples, 10 normal skin samples and 18 keloid samples from the Gene Expression Omnibus (GEO) database were interrogated. Differentially expressed genes (DEGs) were identified between keloid and normal skin samples as well as keloid and normal scar samples with R Project for Statistical Computing. Gene Ontology (GO) functional enrichment analysis was also performed with R software. DEG-associated protein–protein interaction (PPI) network was constructed by STRING, followed by module selection from the PPI network based on the MCODE analysis. Regulatory relationships between TF/miRNA and target genes were predicted with miRnet and cytoscape. Core regulatory genes were verified by RT-qPCR. Results We identified 628 DEGs, of which 626 were up-regulated and 2 were down-regulated. Seven core genes [neuropeptide Y(NPY), 5-hydroxytryptamine receptor 1A(HTR1A), somatostatin (SST), adenylate cyclase 8 (ADCY8), neuromedin U receptor 1 (NMUR1), G protein subunit gamma 3 (GNG3), and G protein subunit gamma 13 (GNG13)] all belong to MCODE1 and were enriched in the “G protein coupled receptor signaling pathway” of the GO biological process category. Furthermore, nine core miRNAs (hsa-mir-124, hsa-let-7, hsa-mir-155, hsa-mir-26a, hsa-mir-941, hsa-mir-10b, hsa-mir-20, hsa-mir-31 and hsa-mir-372), and two core TFs (SP1 and TERT) were identified to play important roles in keloid formation. In the TF/miRNA-target gene network, both hsa-mir-372 and hsa-mir-20 had a regulatory effect on GNG13, ADCY8 was predicted to be target by hsa-mir-10b, and HTR1A and NPY were potentially by SP1. Furthermore, the expression of core regulatory genes (GNG13, ADCY8, HTR1A and NPY) was validated in clinical samples. Conclusions GNG13, ADCY8, NPY and HTR1A may act as core genes in keloid formation and these core genes establish relationship with SP1 and miRNA (hsa-mir-372, hsa-mir-20, hsa-mir-10b), which may influence multiple signaling pathways in the pathogenesis of keloid.

LncRNA HOXA11-AS Aggravates The Keloid Formation By Targeting miR-148b-3p/IGFBP5 Axis

The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.