Keloid Lesions Research Articles

Myofibroblasts Are Not Characteristic Features of Keloid Lesions.

Myofibroblasts in tissue sections from keloids, hypertrophic scars (HTSs), and normal skin were localized by α-SMA immunostaining. Expression of α-SMA mRNA (ACTA2 gene) in normal skin and keloid tissue, and in fibroblasts from normal skin, keloid, and HTSs, was measured using quantitative polymerase chain reaction. Normal skin did not exhibit α-SMA-expressing myofibroblasts, but myofibroblasts were identified in 50% of keloids and 60% of HTSs. No significant differences in ACTA2 expression between keloid and normal skin tissue were observed. Mean ACTA2 expression was higher in HTS (2.54-fold, P = 0.005) and keloid fibroblasts (1.75-fold, P = 0.046) versus normal fibroblasts in vitro. However, α-SMA expression in keloids in vivo was not associated with elevated ACTA2 in keloid fibroblasts in vitro. Despite elevated ACTA2 in cultured keloid fibroblasts, myofibroblast presence is not a consistent feature of keloids. Therefore, therapies that target myofibroblasts may not be effective for all keloids. Further research is required to define the mechanisms driving keloid formation for development of more effective therapies.

Keloid Disorder: Genetic Basis, Gene Expression Profiles, and Immunological Modulation of the Fibrotic Processes in the Skin.

Keloid disorder, a group of fibroproliferative skin disorders, is clinically comprised of keloids, hypertrophic scars, keloidalis nuchae, and acne keloidalis. The prototype of these disorders is keloids, which manifest as cutaneous lesions with excessive deposition of collagen following an initiating trauma of varying degrees. The principal cell type responsible for collagen accumulation is the myofibroblast, and its gene expression is modulated by a network of regulatory factors, including cytokines, growth factors, and noncoding RNA species. In addition, keloids harbor a number of inflammatory cells, including macrophages and mast cells, that interact with fibroblastic cells by direct contact or by paracrine actions. Transforming growth factor-β1/Smad signaling regulates the expression of genes encoding extracellular matrix proteins and also controls cell proliferation and apoptosis. A key profibrotic molecule is the fibronectin splice variant cellular fibronectin extracellular domain A (cFN-EDA), which interacts with a number of cell-surface integrins and TLR4, contributing to the modulation of gene expression by lesional fibroblasts. Collectively, these complex cellular interactions result in accumulation of collagen with clinical development and growth of keloid lesions. Understanding of the precise pathomechanistic details of keloid formation will provide targets for pharmacological interference toward treatment of the keloid disorder, a group of currently difficult to treat skin diseases.

Lesion Site Is the Key Prognostic Factor for Keloid Patients Receiving Surgery With Adjuvant Radiotherapy.

Keloid is a benign tumor with high recurrence rate; accordingly, complete surgical excision with adjuvant radiotherapy is one of the most effective treatments. This study reviewed outcomes of keloid patients receiving surgery and adjuvant radiotherapy in Kaohsiung Medical University Hospital. All patients received radiation dose with 15 Gy, with their first radiotherapy within 24 hours after surgical excision. The end points were recurrence rate and local recurrence-free interval (LRFI), defined clinically as palpable gross tumor over the treatment site and duration from the last day of radiotherapy to disease recurrence. From May 2017 to July 2020, 32 patients with 40 keloid lesions were included. The mean age for these patients was 37.6 years, and the median follow-up time was 15.3 months. The overall recurrence rate was 52.5%, and the median LRFI was 9.7 months. Recurrence rates for males and females were 46.7% and 56% ( P = 0.567), respectively; for head and ear, chest, shoulder and upper extremities, and abdomen and back were 12.5%, 61.5%, 63.6%, and 62.5% ( P = 0.093); for lesions over 20 cm 2 and below 20 cm 2 were 62.5% and 50% ( P = 0.527); and for megavoltage electron beam and kilovoltage photon beam were 56.7% and 40% ( P = 0.361), respectively. Patients were further classified into 2 groups by lesion sites, which showed lower recurrence rate ( P = 0.011) and longer LRFI ( P = 0.028) with lesions over the head and ear than other sites. We found that lesion site might be a prognostic factor for keloid recurrence. Adjuvant radiation dose escalation for high-recurrence risk areas (other than the head and ear) might be required.

Skin fibrosis associated with keloid, scleroderma and Jorge Lobo's disease (lacaziosis): An immuno-histochemical study.

Fibrosis is a common pathophysiological response of many tissues and organs subjected to chronic injury. Despite the diverse aetiology of keloid, lacaziosis and localized scleroderma, the process of fibrosis is present in the pathogenesis of all of these three entities beyond other individual clinical and histological distinct characteristics. Fibrosis was studied in 20 samples each of these three chronic cutaneous inflammatory diseases. An immunohistochemical study was carried out to explore the presence of α-smooth muscle actin (α-SMA) and vimentin cytoskeleton antigens, CD31, CD34, Ki67, p16; CD105, CD163, CD206 and FOXP3 antigens; and the central fibrotic cytokine TGF-β. Higher expression of vimentin in comparison to α-SMA in all three lesion types was found. CD31- and CD34-positive blood vessel endothelial cells were observed throughout the reticular dermis. Ki67 expression was low and almost absent in scleroderma. p16-positive levels were higher than ki67 and observed in reticular dermis of keloidal collagen in keloids, in collagen bundles in scleroderma and in the external layers of the granulomas in lacaziosis. The presence of α-actin positive cells and rarely CD34 positive cells, observed primarily in keloids, may be related to higher p16 antigen expression, a measure of cell senescence. Low FOXP3 expression was observed in all lesion types. CD105-positive cells were mainly found in perivascular tissue in close contact with the adventitia in keloids and scleroderma, while, in lacaziosis, these cells were chiefly observed in conjunction with collagen deposition in the external granuloma layer. We did not find high involvement of CD163 or CD206-positive cells in the fibrotic process. TGF-β was notable only in keloid and lacaziosis lesions. In conclusion, we have suggested vimentin to be the main myofibroblast general marker of the fibrotic process in all three studied diseases, while endothelial-to-mesenchymal transition (EndoMT) and mesenchymal stem cells (MSCs) and M2 macrophages may not play an important role.

Keloid Nodule Metabolic Activity for Continuous Expansion

Background:We previously reported that keloid nodules had such specific structures that higher expression of autophagy proteins and glycolytic markers was observed in the central zone fibroblasts than in marginal zone fibroblasts. The purpose of this study is to investigate how keloid nodules play a role in metabolic activity for continuous expansion.Methods:A total of 57 nodules were randomly chosen from seven keloid samples and divided into four groups of disease duration (2, 4, 6, and 17 years). Immunohistochemical and immunofluorescent analyses were performed.Results:Immunohistochemical analysis with anti-CD-31 confirmed that the nodules had a structure with a greater number of vessels in the marginal zone than in the central zone. The density of fibroblasts in nodules (190.29 ± 64.45) was significantly higher than that of surrounding connective tissue (140.18 ± 63.94) (P < 0.05).The area of each nodule increased for 2 to 4 years, then decreased, graphically represented by an approximately horizontal line, to 17 years. The ratio of total nodule area/dermis area increased as disease duration lengthened. The maximum ratio was the 17-year group at 48.01%. The nodule number/dermis area ratio rose approximately with advancing disease duration.Conclusions:Instead of increasing the size of the nodules, their number and total area increased within the keloid lesions. We believe that the keloid nodules must play an important role in energy metabolic activity for continuous growth by increasing in number and total area.

A Signature of Genes Featuring FGF11 Revealed Aberrant Fibroblast Activation and Immune Infiltration Properties in Keloid Tissue.

Keloid is a fibroproliferative disorder in the skin, which manifested with extensive deposition of collagen and extracellular matrix. Its etiology remains a mystery and its recurrence rate remains high despite combinative treatment regimens. Current hypotheses of its pathogenesis centered on the role of inflammatory processes as well as immune infiltration in the microenvironment. However, there are a lot of discrepancies when it comes to the verification of certain well-recognized pathways involved in the dysfunctional fibroblast. Further exploration and characterization are required to reveal the driving force and even leading genes responsible for keloid formation. In this study, we provided supportive evidence of the immunologic nature of keloids distinct from normal fibroblasts and physiological scars by incorporating multiple available expressional profiles in the Gene Expression Omnibus (GEO). Through differential analyses and functional analyses, we identified a set of genes that successfully captures the dissimilarities between keloid lesions and nonlesions. They were differentially regulated in keloid samples and had opposite behavior in exposure to hydrocortisone. A key signature of six genes featuring FGF11 not only was highly correlated with significantly dysregulated fibroblast activation but also reflected various levels of immune cell infiltration. FGF11, in particular, revealed the heterogenous immunologic nature of keloid lesions. This study further supported that aberrant fibroblast was one of the main contributing factors and shed some light on investigating immune properties in future studies.

TSP1 promotes fibroblast proliferation and extracellular matrix deposition via the IL6/JAK2/STAT3 signalling pathway in keloids.

Keloids are benign fibroproliferative diseases with abnormally proliferated bulges beyond the edge of the skin lesions, and they are characterized by uncontrolled fibroblast proliferation and excessive extracellular matrix deposition in the dermis. However, the definite mechanisms that increase fibroblast proliferation and collagen deposition in keloids remain unclear. Thrombospondin 1 (TSP1) has been suggested to play an important role in wound healing and fibrotic disorders, but its role in keloids is unknown. In this study, we aimed to clarify the specific role of TSP1 in keloids and explore the potential mechanism. Our results demonstrated that TSP1 was highly expressed in keloid lesions compared to normal skin. Knockdown of TSP1 in keloid fibroblasts decreased cell proliferation and collagen I deposition. Exogenous TSP1 treatment increased cell proliferation and collagen I deposition in normal fibroblasts. We further investigated the underlying mechanism and found that TSP1 promoted fibroblast proliferation and extracellular matrix deposition by upregulating the IL6/JAK2/STAT3 pathway. Moreover, we verified that TSP1 expression was positively correlated with IL6/STAT3 signalling activity in keloids. Taken together, our findings indicate that TSP1 promotes keloid development via the IL6/JAK2/STAT3 signalling pathway and blocking TSP1 may represent a potential strategy for keloid therapy.

Combined analyses of RNA-sequence and Hi-C along with GWAS loci-A novel approach to dissect keloid disorder genetic mechanism.

Keloid disorder is a tumour-like disease with invasive growth and a high recurrence rate. Genetic contribution is well expected due to the presence of autosomal dominant inheritance and various genetic mutations in keloid lesions. However, GWAS failed to reveal functional variants in exon regions but single nucleotide polymorphisms in the non-coding regions, suggesting the necessity of innovative genetic investigation. This study employed combined GWAS, RNA-sequence and Hi-C analyses to dissect keloid disorder genetic mechanisms using paired keloid tissues and normal skins. Differentially expressed genes, miRNAs and lncRNAs mined by RNA-sequence were identified to construct a network. From which, 8 significant pathways involved in keloid disorder pathogenesis were enriched and 6 of them were verified. Furthermore, topologically associated domains at susceptible loci were located via the Hi-C database and ten differentially expressed RNAs were identified. Among them, the functions of six molecules for cell proliferation, cell cycle and apoptosis were particularly examined and confirmed by overexpressing and knocking-down assays. This study firstly revealed unknown key biomarkers and pathways in keloid lesions using RNA-sequence and previously reported mutation loci, indicating a feasible approach to reveal the genetic contribution to keloid disorder and possibly to other diseases that are failed by GWAS analysis alone.

Keloid Biomarkers and Their Correlation With Immune Infiltration.

Objective: This work aimed to verify the candidate biomarkers for keloid disorder (KD), and analyze the role of immune cell infiltration (ICI) in the pathology of keloid disorder. Methods: The keloid-related datasets (GSE44270 and GSE145725) were retrieved from the Gene Expression Omnibus (GEO). Then, differential expressed genes (DEGs) were identified by using the “limma” R package. Support vector machine-recursive feature elimination (SVM-RFE) and LASSO logistic regression were utilized for screening candidate biomarkers of KD. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic power of candidate biomarkers. The candidate biomarkers were further verified through qRT-PCR of keloid lesions and the matched healthy skin tissue collected from eight cases. In addition, ICI in keloid lesions was estimated through single-sample gene-set enrichment analysis (ssGSEA). Finally, the potential drugs to the treatment of KD were predicted in the Connectivity Map Database (CMAP). Results: A total of 406 DEGs were identified between keloid lesion and healthy skin samples. Among them, STC2 (AUC = 0.919), SDC4 (AUC = 0.970), DAAM1 (AUC = 0.966), and NOX4 (AUC = 0.949) were identified as potential biomarkers through the SVM-RFE, LASSO analysis and ROC analysis. The differential expressions of SDC4, DAAM1, and NOX4 were further verified in collected eight samples by qRT-PCR experiment. ICI analysis result showed a positive correlation of DAAM1 expression with monocytes and mast cells, SDC4 with effector memory CD4+ T cells, STC2 with T follicular helper cells, and NOX4 with central memory CD8+ T cells. Finally, a total of 13 candidate small molecule drugs were predicted for keloids treatment in CMAP drug database. Conclusion: We identified four genes that may serve as potential biomarkers for KD development and revealed that ICI might play a critical role in the pathogenesis of KD.

Rehabilitation methods using carboxytherapy in patients with keloid scar pathology

The article presents the materials of examination and treatment of women aged 20–55 years with keloid scar pathology before and after the use of carboxytherapy injection methods. Research methods: The data from 291 outpatient records of patients with scar pathology detected in the long-term period (4.2±1.4 years) were studied. In 92 patients with scar pathology, a dermatologist performed a clinical and functional assessment of the dermis using a digital video camera (Aramo SG, USA), which allows performing dermatoscopy and assessing both the superficial and deeper layers, microrelief and morphofunctional features of scar tissue with a score of the area of the affected skin surface: 0 — there is no lesion; 1 —&lt; 10%; 2 — 10–25%; 3 — 26–50%; 4 — 51–75%; 5 — 76–90%; 6 — 91–100%. PCR diagnostics of immune parameters (IgM, IgA, IgG, cytokines) was performed before and after the injection carboxytherapy. Results: It has been established that the severity of keloid dermal pathology is interrelated with immune indicators, which confirms our assumption about the pathogenetic role of injectable carboxytherapy, which provides immune correction and improvement of the structure of scarring in the skin, since an indirect mechanism of action on a protein in skin tissues involved in the formation of ROS — NF-kB has been clarified. Conclusion: thus, injectable carboxytherapy with the drug «Fermencol» provides significantly more effective anti-inflammatory and antimicrobial correction, stimulation of microcirculation and metabolic processes in scar tissue, which is more reliably expressed in comparison with other methods of treatment presented in this study. Injectable carboxytherapy with the drug «Fermencol» allows to form high immunocorrecting effects, providing a significant increase in the levels of T-helper cells (Th1) by 14%, which is accompanied by correction of the immune status and improvement of the structure in the zone of keloid lesion.

Evaluating the efficacy of photodynamic therapy with indocyanine green in the treatment of keloid

BackgroundThis study aimed to evaluate the efficacy of photodynamic therapy (PDT) with topical indocyanine green (ICG) in the treatment of keloid lesions. MethodsIn this pilot study, fifteen keloids (6 lesions on the sternal area, 3 on the shoulders, 2 on the abdomen, 2 on the legs, and 2 on the forearms) were selected. To enhance drug penetration, pretreatment with CO2 laser was performed. Then Lesions were covered with 0.2% transfersomal ICG gel with 1 mm thickness and occluded with light-proof plastic nylon for 2 h. Afterward, it was wiped off and underwent photodynamic therapy with source LumaCare with 730 nm probe and fluence of 23 J/cm2 every week for 6 sessions. Patients were also assessed 6 and 12 weeks after the treatment for any recurrences. The Patient and Observer Scar Assessment Scale (POSAS) was used to evaluate the scars. ResultsThe mean POSAS score significantly reduced by 23.69% from 46.86 at baseline to 35.76 at the 6th treatment session (P< 0.001). The mean scores of patient and observer overall opinion significantly decreased by 16.35% (P< 0.001) and 12.31% (P = 0.001) respectively. No side effects were observed during treatment and after 3 months of follow-ups. After discontinuation of therapy, the mean score of POSAS significantly increased by 13.77% to 40.80. (P = 0.001) ConclusionAccording to our study, ICG-PDT is an effective and safe treatment for keloid. However, due to the recurrence following discontinuation of treatment, further studies are needed.

610 Myofibroblasts Are Not Characteristic Features of Keloid Lesions

IntroductionKeloids are disfiguring, fibroproliferative lesions that can result from an abnormal wound healing process. Keloids are characterized by excessive and abnormal deposition of extracellular matrix and unrestrained expansion beyond the original wound boundary. Keloids are challenging to treat, with low response rates to current interventions and high recurrence rates. Development of more effective, targeted therapies will require a deeper understanding of the mechanisms driving keloid pathology. It has been widely reported that keloids are characterized by the presence of myofibroblasts, which are specialized, contractile fibroblasts that express alpha-smooth muscle actin (αSMA) and play important roles during wound healing and tissue remodeling. However, the evidence supporting a role for myofibroblasts in keloid development is inconclusive, with conflicting reports in the literature. This complicates development of more effective therapies, as the benefit of interventions targeting myofibroblasts is unclear. The current study evaluated the presence of αSMA+ myofibroblasts in keloids, and analyzed αSMA expression in keloid-derived fibroblasts, to determine whether myofibroblast presence can be considered diagnostic of keloid lesions.MethodsKeloid, hypertrophic scar (HTS), and normal human skin samples were collected with Institutional Review Board approval and primary fibroblast cultures were established. Myofibroblasts in tissue sections were localized by αSMA immunostaining, and αSMA expression in pericytes of blood vessels was distinguished from αSMA+ myofibroblasts by collagen IV immunostaining of vessels. Expression of αSMA mRNA (ACTA2 gene) was measured using quantitative real-time PCR. Statistical analysis via t test was performed using SigmaPlot.ResultsNormal human skin samples did not exhibit αSMA+ myofibroblasts (0/8), but myofibroblasts were identified in 53% of keloids (8/15) and 60% of HTS (3/5) tissue samples. When present in keloids or HTS, the αSMA+ cells were not uniformly distributed, but were often observed in clusters in the deeper regions of the lesions. Comparison of ACTA2 mRNA expression did not reveal any significant differences between normal skin and keloid tissues (N=3/group), or between normal fibroblasts (N=7 donors) and keloid fibroblasts (N=9 donors).ConclusionsThe results suggest that although many keloids contain αSMA+ myofibroblasts, these cells do not appear to be diagnostic for keloids. Therefore, therapies that target myofibroblasts may not be effective for all keloid lesions. However, a limitation of this study is that only excised keloid and HTS tissues, which tend to be larger, more mature lesions, were examined; thus we cannot rule out a potential role for myofibroblasts in early development of abnormal scars.

LARP6 Regulates Keloid Fibroblast Proliferation, Invasion, and Ability to Synthesize Collagen

Keloid is a skin fibroproliferative disease currently having no uniformly successful treatment. The lesion is composed of actively proliferating and collagen-overproducing fibroblasts. LARP6 is an RNA-binding protein able to regulate collagen synthesis in fibroblasts and to promote proliferation and invasion of tumor cells. To explore LARP6's likely functions in keloid pathogenesis, we performed immunohistochemistry staining on human keloid tissues and discovered markedly upregulated LARP6 expression in lesion fibroblasts compared with that of normal skin and hypertrophic scar tissues. In addition, the keloid tissue‒derived fibroblasts showed constitutive upregulation of LARP6 expression as well as significantly upregulated mRNA and protein expressions of type I collagen and enhanced cell proliferation and invasive behavior in cell culture system. Intriguingly, LARP6 knockdown by targeting with small interfering RNAs significantly inhibited type I collagen expression, proliferation, and invasion capability of keloid tissue‒derived fibroblasts relative to that of normal skin‒ and hypertrophic scar‒derived fibroblasts and control keloid tissue‒derived fibroblasts that were transfected with a scrambled small interfering RNA. In conclusion, the abnormally upregulated expression of LARP6 in fibroblasts may play an important role in the growth and invasive behavior of keloid lesions.

Downregulated cytotoxic CD8+ T-cell identifies with the NKG2A-soluble HLA-E axis as a predictive biomarker and potential therapeutic target in keloids.

Keloids are an abnormal fibroproliferative wound-healing disease with a poorly understood pathogenesis, making it difficult to predict and prevent this disease in clinical settings. Identifying disease-specific signatures at the molecular and cellular levels in both the blood circulation and primary lesions is urgently needed to develop novel biomarkers for risk assessment and therapeutic targets for recurrence-free treatment. There is mounting evidence of immune cell dysregulation in keloid scarring. In this study, we aimed to profile keloid scar tissues and blood cells and found that downregulation of cytotoxic CD8+ T cells is a keloid signature in the peripheral blood and keloid lesions. Single-cell RNA sequencing revealed that the NKG2A/CD94 complex was specifically upregulated, which might contribute to the significant reduction in CTLs within the scar tissue boundary. In addition, the NKG2A/CD94 complex was associated with high serum levels of soluble human leukocyte antigen-E (sHLA-E). We subsequently measured sHLA-E in our hospital-based study cohort, consisting of 104 keloid patients, 512 healthy donors, and 100 patients with an interfering disease. The sensitivity and specificity of sHLA-E were 83.69% (87/104) and 92.16% (564/612), respectively, and hypertrophic scars and other unrelated diseases exhibited minimal interference with the test results. Furthermore, intralesional therapy with triamcinolone combined with 5-fluorouracil drastically decreased the sHLA-E levels in keloid patients with better prognostic outcomes, while an incomplete reduction in the sHLA-E levels in patient serum was associated with higher recurrence. sHLA-E may effectively serve as a diagnostic marker for assessing the risk of keloid formation and a prognostic marker for the clinical outcomes of intralesional treatment.

Fully Digital Workflow for Fabrication of A 3D Printed Ear Stent for Auricular Keloids: A Technique Article.

Keloids are skin lesions which result from an aberration in the physiological healing process marked with overgrowth of collagen fibers. Keloid of the ear is cosmetically challenging and has an increased chance of re-growth. To minimize recurrence, pressure therapy in combination with other treatment forms has been used. Various techniques have been used to fabricate a passive or active stent. This report presents a fully digital workflow to fabricate an ear stent after intralesional excision and skin autografting of an extensive recurrence of a keloid lesion of the left ear involving the helix, antihelix, scapha, and conchal bowl.

Perioperative interstitial high-dose-rate brachytherapy for keloids scar.

PurposeTo evaluate the results of keloids treated with perioperative interstitial high-dose-rate brachytherapy (HDR-BT).Material and methodsA retrospective review of 61 keloids in 51 patients treated with perioperative interstitial HDR-BT was performed. Keloid lesions were treated with 12 Gy in 4 fractions within 48 hours. Time between surgery and brachytherapy was less than 90 minutes. Local failure was defined as recurrence of apparent keloid or symptoms in the same place. Median age of patients was 46 years (range, 20-89 years). Keloid scars were located on the chest (41%), ear lobe (21%), back (1.6%), extremities (11.5%), and mean keloid size was 6.3 cm.ResultsWith a median follow-up of 47.95 months (range, 1-96 months), the recurrence rate was 4.9%, all located on the chest. The multivariate analysis showed no statistically significant relationship between location, scar size, and previously treated lesions with the recurrence rate.ConclusionsThe treatment of keloid scars with perioperative interstitial high-dose-rate brachytherapy achieved excellent results, with a recurrence rate of only 4.9% and excellent cosmetic outcomes, suggesting that this technique might be one of the best options for treating keloids.

Downregulation of hsa_circ_0002198 inhibits keloid fibroblast activities in vitro by reducing NLRP3 inflammasome activity

The levels of hsa circular RNA_0002198 (hsa_circ_0002198) have been found to be significantly upregulated in keloid dermal fibroblasts. However, the functional role of hsa_circ_0002198 in keloid fibroblasts and the underlying molecular mechanism for its effects have not been reported. In this study, the levels of hsa_circ_0002198 and nucleotide-binding and oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) expression in keloid scar tissues and adjacent normal skin tissues were determined by quantitative real-time PCR and western blotting, respectively. In vitro models of keloid tissue were created by culturing primary keloid fibroblasts obtained from patients. A series of functional experiments, including CCK-8 assays, Transwell assays, and ELISA assays were performed to analyze the functional role of hsa_circ_0002198/NLRP3. Our data showed that hsa_circ_0002198 and NLRP3 were upregulated in keloid scar tissues when compared with adjacent normal tissues. Knockdown of hsa_circ_0002198 expression significantly suppressed cell proliferation, migration, and invasion, and those effects could be partially reversed by forced NLRP3 overexpression in keloid fibroblasts. At the molecular level, knockdown of hsa_circ_0002198 downregulated the levels of Col I, α-SMA, and NLRP3 proteins, as well as the levels of TGF-β, IL-1ß, and IL-33, but upregulated caspase 3 expression in keloid fibroblasts. All those effects were partially reversed after NLRP3 overexpression. In conclusion, our results suggest hsa_circ_0002198 as a potential target for treating keloid lesions.

Multi-Antigen Imaging Reveals Inflammatory DC, ADAM17 and Neprilysin as Effectors in Keloid Formation.

Keloid is an aberrant scarring process of the skin, characterized by excessive extracellular matrix synthesis and deposition. The pathogenesis of this prevalent cutaneous disorder is not fully understood; however, a persistent inflammatory process is observed. To obtain more insight into this process, we analyzed lesional, perilesional and healthy tissue using multi-antigen-analysis (MAA) in conjunction with a data mining approach. Here, we demonstrate that monocyte-derived inflammatory dendritic cells (CD1a+, CD11c+, CD14+) and activated CD4+ T lymphocytes (CD45 RO+) dominated the immune infiltration in keloids while associating with fibroblasts. In perilesional tissue, precursor immune cells were dominant in the perivascular area, suggesting that they were attracted by an immune process, potentially in the lesional area. Supporting this hypothesis, only in keloid lesions, high levels of ADAM10/17 and Neprilysin (CD10) were observed in both fibroblasts and leukocytes. The spatial proximity of these two cell types, which could be confirmed by image analysis only in lesional tissue, could be a potential factor leading to the activation of fibroblasts. Our findings provide new insight into the pathogenesis of keloid formation and reveal metalloproteinases as a target for therapeutical intervention.

Timing of Adjuvant Radiotherapy After Keloid Excision: A Systematic Review and Meta-Analysis.

No consensus exists regarding the appropriate timing of adjuvant radiotherapy administration after surgical excision of keloids. This study investigated the appropriate timing of adjuvant radiotherapy. A systematic review and meta-analysis of randomized controlled trials and observational cohort studies was performed. A pooled estimate of the incidence rate was performed using a random-effects model. Subgroup analyses based on different anatomic region, biologically effective dose, keloid length, and radiotherapy regimen were also conducted. Sixteen observational cohort studies (1,908 keloid lesions) met the inclusion criteria. The incidence rate was significantly lower in the group treated with electron beam therapy more than 24 hours after surgery (3.80%; 95% confidence interval [CI], 1.78%-8.13%) than that in the group treated with the same therapy within 24 hours of surgery (37.16%; 95% CI, 20.80%-66.37%; p < .0001), but no significant difference was observed between the groups regarding brachytherapy and x-ray treatments. Immediate adjuvant radiotherapy did not significantly reduce the incidence rate of recurrent keloids.

Multifaceted array-based keloidal gene expression profiling reveals specific MDFI upregulation in keloid lesions.

Keloid lesions are characterized by mesenchymal cell proliferation and excessive extracellular matrix deposition. Previous microarray analyses have been performed to investigate the mechanism of keloid development. However, the molecular pathology that contributes to keloid development remains obscure. To explore the underlying essential molecules of keloids using microarrays. We performed microarray analyses of keloid and nonlesional skin tissues both invivo and invitro. Gene expression levels were compared between tissues and cells. Quantitative reverse transcription (qRT)-PCR and immunohistochemical staining were used to determine the expression levels of molecules of interest in keloid tissues. Several common molecules were upregulated in both keloid tissues and keloid-lesional fibroblasts. PTPRD and NTM were upregulated both invivo and invitro. The genes MDFI and ITGA4 were located at the centre of the gene coexpression network analysis using keloid tissues. qRT-PCR revealed significant expression levels of PTPRD and MDFI in keloid tissues. Immunopathological staining revealed that MDFI-positive cells, which have fibroblast characteristics, were located in the keloid-associated lymphoid tissue (KALT) portion of the keloid tissue. Our gene expression profiles of keloids could distinguish the difference between lesional tissue and cultured lesional fibroblasts, and MDFI was found to be commonly expressed in both tissues and cells. Thus, MDFI-positive cells, which were located in the KALT, may play an important role in keloid pathogenesis and thus might be useful for invitro keloid studies.