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Background & Aims: Hypertrophic scar (HS) is a skin fibroproliferative disorder occurring after burns, surgeries or traumatic injuries, and it has caused a tremendous economic and medical burden. Its molecular mechanism is associated with the abnormal proliferation and transition of fibroblasts and excessive deposition of extracellular matrix. Cartilage intermediate layer protein 2 (CILP2), highly homologous to cartilage intermediate layer protein 1 (CILP1), is mainly secreted predominantly from chondrocytes in the middle/deeper layers of articular cartilage. Recent reports indicate that CILP2 is involved in the development of fibrotic diseases. We investigated the role of CILP2 in the progression of HS., Methods and Results: It was found in this study that CILP2 expression was significantly higher in HS than in normal skin, especially in myofibroblasts. In a clinical cohort, we discovered that CILP2 was more abundant in the serum of patients with HS, especially in the early stage of HS. In vitro studies indicated that knockdown of CILP2 suppressed proliferation, migration, myofibroblast activation and collagen synthesis of hypertrophic scar fibroblasts (HSFs). Further, we revealed that CILP2 interacts with ATP citrate lyase (ACLY), in which CILP2 stabilizes the expression of ACLY by reducing the ubiquitination of ACLY, therefore prompting Snail acetylation and avoiding reduced expression of Snail. In vivo studies indicated that knockdown of CILP2 or ACLY inhibitor, SB-204990, significantly alleviated HS formation., Conclusion: CILP2 exerts a vital role in hypertrophic scar formation and might be a detectable biomarker reflecting the progression of hypertrophic scar and a therapeutic target for hypertrophic scar., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hypertrophic scar (HS) is a chronic inflammatory skin disorder characterized by excessive deposition of extracellular matrix, and the mechanisms underlying their formation remain poorly understood. We analysed scRNA-seq data from samples of normal skin and HS. Using the hdWGCNA method, key gene modules of fibroblasts in HS were identified. Non-negative matrix factorization was employed to perform subtype analysis of HS patients using these gene modules. Multiple machine learning algorithms were applied to screen and validate accurate gene signatures for identifying and predicting HS, and a convolutional neural network (CNN) based on deep learning was established and validated. Quantitative reverse transcription-polymerase chain reaction and western blotting were performed to measure mRNA and protein expression. Immunofluorescence was used for gene localization analysis, and biological features were assessed through CCK8 and wound healing assay. Single-cell sequencing revealed distinct subpopulations of fibroblasts in HS. HdWGCNA identified key gene characteristics of this population, and pseudotime analysis was conducted to investigate gene variation during fibroblast differentiation. By employing various machine learning algorithms, the gene range was narrowed down to three key genes. A CNN was trained using the expression of these key genes and immune cell infiltration, enabling diagnosis and prediction of HS. Functional experiments demonstrated that THBS2 is associated with fibroblast proliferation and migration in HS and affects the formation and development of HS through the TGFβ1/P-Smad2/3 pathway. Our study identifies unique fibroblast subpopulations closely associated with HS and provides biomarkers for the diagnosis and treatment of HS., (© 2023 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Background: Hypertrophic scar (HS) is caused by the abnormal proliferation of fibroblasts and excessive deposition of extracellular matrix (ECM). Emerging evidence demonstrates that c-Maf positive M2 macrophages were mainly located in the hypertrophic scar tissues of proliferative phase. But whether c-Maf positive M2 macrophages can promote hypertrophic scar formation through modulating hypertrophic scar fibroblasts remains elusive., Aims: The aim of this study is to investigate the effects of c-Maf positive M2 macrophages on the biological behaviors and functions of hypertrophic scar fibroblasts and the potential mechanism., Methods: HE and Masson trichrome staining were used to examine the histological features of human hypertrophic scar. Immunofluorescence staining was employed to label and quantify the c-Maf + /CD68 + M2 macrophages. CCK8, wound healing, and transwell assays were utilized to test the effects of c-Maf overexpressed M2 macrophages or the cell culture supernatants on the proliferation and migration of hypertrophic scar derived fibroblasts (HFBs) and normal skin derived fibroblasts (NFBs). Western blot and qPCR were harnessed to test the expressions of COL1, COL3, and α-SMA in the co-cultivated fibroblasts and TGF-β1 in the c-Maf overexpressed M2 macrophages., Results: Increased number of c-Maf + /CD68 + M2 macrophages were found in HS in contrast to the normal skin (NS). Elevated proliferation and migration were observed in the HFBs or NFBs co-cultured with c-Maf overexpressed macrophages or the cell culture supernatants. A higher mRNA and protein expressions of COL1, COL3, and α-SMA were recorded in the HFBs co-cultured with c-Maf overexpressed macrophages or treated with its culture supernatants. In addition, augmented mRNA and protein expressions of TGF-β1 were also investigated in the c-Maf overexpressed macrophages., Conclusion: c-Maf positive macrophages promote hypertrophic scar formation through regulating HFBs proliferation, migration, and ECM deposition via the secreted TGF-β1., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Hypertrophic scar (HS) is a chronic inflammatory skin disease characterized by excessive deposition of extracellular matrix, but the exact mechanisms related to its formation remain unclear, making it difficult to treat. This study aimed to investigate the potential role of cuproptosis in the information of HS. To this end, we used single-cell sequencing and bulk transcriptome data, and screened for cuproptosis-related genes (CRGs) using differential gene analysis and machine learning algorithms (random forest and support vector machine). Through this process, we identified a group of genes, including ATP7A, ULK1, and MTF1, as novel therapeutic targets for HS. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to confirm the mRNA expression of ATP7A, ULK1, and MTF1 in both HS and normal skin (NS) tissues. We also constructed a diagnostic model for HS and analyzed the immune infiltration characteristics. Additionally, we used the expression profiles of CRGs to perform subgroup analysis of HS. We focused mainly on fibroblasts in the transcriptional profile at single-cell resolution. By calculating the cuproptosis activity of each fibroblast, we found that cuproptosis activity of normal skin fibroblasts increased, providing further insights into the pathogenesis of HS. We also analyzed the cell communication network and transcription factor regulatory network activity, and found the existence of a fibroblast-centered communication regulation network in HS, where cuproptosis activity in fibroblasts affects intercellular communication. Using transcription factor regulatory activity network analysis, we obtained highly active transcription factors, and correlation analysis with CRGs suggested that CRGs may serve as potential target genes for transcription factors. Overall, our study provides new insights into the pathophysiological mechanisms of HS, which may inspire new ideas for the diagnosis and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Song, Liu, Zhu, Peng, Cui, Gao, Chen, Yu and Song.)

Objective: Hypertrophic scarring is a common skin fibro-proliferative disease, but currently there has no satisfactory drugs for anti-scar treatments. Previous study showed that epigallocatechin gallate (EGCG), the main catechin in green tea, improved wound healing and tissue fibrosis in both rats and mice. In the present study, the therapeutic effects of EGCG on hypertrophic scar were analyzed using a rabbit ear hypertrophic scar model., Materials: A rabbit ear model of hypertrophic scarring was used. DMSO, 0.5 mg EGCG/wound, 1.0 mg EGCG/wound or triamcinolone were injected subcutaneously once a week for 4 weeks. The scar elevation index (SEI) was measured using HE staining images, the collagen fibers were examined by Masson' trichrome staining images, and the number of capillaries in hypertrophic scar were calculated by CD31 staining images. The mRNA levels in the scar tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR)., Results: Gross observation and histological evaluation showed the inhibitory effects of EGCG on hypertrophic scar formation at both doses, and decreased scar height and SEI were detected. EGCG also attenuated the mean collagen area fraction and decreased the number of capillaries in scar tissues. qRT-PCR revealed that EGCG significantly inhibited the mRNA expression of TGF-β1, Col I, Col III, α-SMA, and eNOS., Conclusion: EGCG may serve as a useful candidate therapeutic drug for hypertrophic scar via inhibiting fibrotic gene expression and suppressing angiogenesis., (© 2022 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Hypertrophic scar is a common skin fibrosis disease. Currently, surgical resection, drug injection and radiotherapy were often used for treating it; however, limitations or adverse reactions still exist in these treatment. With the deepening understanding of immune response and related cytokines in the process of hypertrophic scar formation, the immunotherapy for hypertrophic scar is also gradually improved. Interleukin 10 (IL-10) is an important member of the leukocyte family, which has different expression in different cells and exerts an immunosuppressive effect mainly through regulating the activity of immune cells infiltrated in hypertrophic scar. However, in some cases, IL-10 also exhibits an immunostimulatory effect. Therefore, its role in the formation of hypertrophic scar is critical for developing and improving the immunotherapy for hypertrophic scar.

Background: Hypertrophic scar (HS) is the most common complication after skin injury with unknown etiopathogenesis. There is increasing evidence to suggest that aberrant Notch signaling contributes directly to skin pathogenesis and altered expression of the Notch intracellular domain (NICD) identified in HS. Therefore, the aim of this study was to investigate the effects of Notch signaling pathway in HS pathogenesis., Methods: Hypertrophic scar and normal skin samples were collected. Notch intracellular domain expression was detected by immunohistochemistry staining and fibroblasts were separated from the samples. We compared fibrotic factors production, cell viability, migration and apoptosis of HS fibroblasts (HFB) versus normal skin fibroblasts (NFB) by real time quantitative polymerase chain reaction, MTS, cell scratch assay and flow cytometry respectively under the impact of inhibition of Notch signaling by NICD-small-interfering RNA (SiRNA)., Results: The results showed that NICD was overexpressed in the dermis of HS tissues. Inhibition of Notch signaling by NICD-SiRNA suppressed the production of the fibrotic factors including collagen 1, collagen 3, α-SMA, and TGF-β1 by HFB and NFB. Cell viability and migration were reduced in NICD-SiRNA-treated NFB and HFB, whereas cell apoptosis was enhanced by NICD-SiRNA., Conclusions: Conclusively, the study demonstrates a potential role for Notch signaling in HS progression, and targeting this pathway may provide a novel strategy for treatment of HS., Competing Interests: Conflicts of interest and sources of funding: The authors declare no conflicts of interest. This work was supported by the National Natural Science Foundation of China (81571906) and the Foundation of Xijing Hospital (XJZT18MJ72)., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The pathogenesis of hypertrophic scar (HS) is still poorly understood. Macrophages, especially the polarisation of that to M1 or M2, play a pivotal role in control of the degree of scar formation. Profiling of macrophage phenotypes in human specimens during long-term period of wound healing and HS formation may provide valuable clinical evidence for understanding the pathology of human scars. Human wound and HS specimens were collected, the macrophage phenotype was identified by immunofluorescence, and biomarkers and cytokines associated with M1 and M2 macrophages were detected by RT-PCR. The correlation between the macrophage phenotype and HS characteristics was analysed by linear regression analyses. We found excessive and persistent infiltration by M1 macrophages around the blood vessels in the superficial layer of the dermis at early wound tissues, whereas M2 macrophages predominated in later wound tissues and the proliferative phase of HS and were scattered throughout the dermis. The density of M1 macrophages was positively correlated with mRNA expression levels of tumour necrosis factor-alpha (TNF-α) and IL-6. The density of M2 macrophages was positively correlated with ARG1 and negatively correlated with the duration of HS. The sequential infiltration by M1 macrophage and M2 macrophages in human wound and HS tissues was confirmed., (© 2018 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Hypertrophic scarring remains a major problem for patients who have suffered from surgeries or burns. Vascularization plays an important role in the early phase of hypertrophic scarring. Therefore, the inhibition of angiogenesis might be used as a preventive strategy. In this study, we assessed the effect of anti-angiogenesis resulting from adenovirus-mediated METH1 (metalloprotease and thrombospondin1) gene expression on the hypertrophic scar formation in a rabbit ear model of hypertrophic scarring. We first investigated the number of microvessel and microcirculatory perfusion in untreated scars on days 10, 30, 60, and 90 after epithelialization. Then, we examined the effect of anti-angiogenesis by adenovirus-mediated METH1 expression on hypertrophic scar formation by calculating the scar elevation index, counting the microvessel and argyrophilic nucleolar organizer region particle, and detecting the amount of collagen on days 30 and 60 after treatment. We found that untreated scar tissues at the proliferative phase (days 10-60 after epithelialization) had a significantly higher density of microvessel and microcirculatory perfusion than those at the mature phase (day 90 after epithelization) (both p<0.05). On days 30 and 60 after treatment, the hypertrophic scar formation was significantly inhibited in the treatment group. There was significantly reduced scar elevation index, microvessel count, number of argyrophilic nucleolar organizer region, and total collagen content for treated scars. Our results demonstrate that METH1 has a markedly inhibitive effect on the formation of hypertrophic scar, and may thus have a promising application in the prevention of human hyperthropic scars.

Objective: To investigate the angiogenesis in hypertropic scar tissue of rabbit ears at different periods and to explore a new method to prevent hyperplastic scar., Methods: Nineteen Japanese white rabbits (weigthing 2.0-2.5 kg) were made animal models of hypertropic scar of ear. At 10th, 30th, 60th and 90 days, after epithelization, the microvessel and microcirculation in hyperplastic scar of 8 rabbits were studied by microcirculation microscope and laser Doppler flowmetry. The other 11 rabbits' right or left ears were randomly chosen into experimental group and control group. At 10 days after epithelization, 40 microL of adenovirus extracellular protein with metalloprotease and thrombospondin 1 domains (Ad-METH1) was injected into tissue of scar along the perimeter of the scar in experimental group. The same volume of empty adenovirus was injected in control group. After 30 days of injection, the gross appearance of 10 rabbits' ears scar was recorded, the number of microvessel in scar was counted and HE stainning of scar tissue was performed in experimental and control groups. One additional rabbit was used to evaluate the mRNA and protein expression of METH1 by RT-PCR and Western blot after 3 days of injection., Results: The average number of microvessel at 10, 30, 60 and 90 days after epithelization was 42.37 +/- 3.89, 49.46 +/- 4.13, 33.12 +/- 4.34 and 13.24 +/- 2.31, respectively; the average value of microcirculatory perfusion at 10, 30, 60 and 90 days after epithetlization was (37.75 +/- 2.11), (59.87 +/- 6.46), (44.53 +/- 6.14) and (29.21 +/- 1.84) PU; the density of microvessels and perfusion of microcirculation in scar tissues during proliferative stage (from 10 to 60 days after epithelization) were markedly higher than that during mature period (90 days after epithelization, P < 0.05). At 10 to 30 days after epithelization, the histoligical features of scar showed early stage of proliferation and proliferative stage appearance; at 60 days after epithelization, it is still in proliferative stage, while some of scars were in mature phase; at 90 days after epithelization, the histoligical features of scar were mature period appearance. At 3 days after Ad-METH1 injection, METH1 gene was successfully expressed at both mRNA and protein levels in experimental group, but not in control group. At 30 days after injection, the gross appearance observation showed that scars in experimental group were flat and soft with the color close to normal, but scars in control group were obvious and hard. The number of microvessel of scar tissue was 12.38 +/- 2.56 in experimental group and 48.12 +/- 6.46 in control group, showing statistically significant difference between two groups (P < 0.01). In experimental group, HE staining shows that the density of microvessel and the number of fibroblasts were greatly decreased and collagen fibers arranged regularly. In control group, plenty of fibroblasts and abundant microvessels were observed. Thick and tight collagen fibers were seen in the outer layer of dermis with a irregular arrangement., Conclusion: The anti-angiogenesis by Ad-METH1 may have a promising application in the prevention of human hyperthropic scar.