Carnosic acid in topical rosemary extract promotes TRPA1-mediated scarless wound healing
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE298490 | GEO | 2025/10/15
REPOSITORIES: GEO
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Project description:Carnosic acid in topical rosemary extract promotes TRPA1-mediated scarless wound healing
| PRJNA1269542 | ENA
Project description:Wound healing is a multi-step process to rapidly restore barrier function. This process is often impaired in diabetic patients resulting in chronic wounds and amputation. We previously found that paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway via topical administration of the BRAF inhibitor vemurafenib accelerates wound healing by activating keratinocyte proliferation and reepithelialization pathways in healthy mice. Herein, we investigated whether this wound healing acceleration also occurs in impaired diabetic wounds and found that topical vemurafenib not only improves wound healing in a murine diabetic wound model, but unexpectedly promotes hair follicle regeneration. Neogenic hair follicles expressing Sox-9, CD34 and K15 were found in wounds of diabetic and non-diabetic mice, and their formation can be prevented by blocking downstream MEK signaling. Thus, topically applied BRAF inhibitors may accelerate wound healing, and promote the restoration of improved skin architecture in both normal and impaired wounds.
2021-05-22 | GSE148037 | GEO
Project description:BRAF inhibitors are highly effective therapies for patients with BRAF V600 mutated metastatic melanoma. Patients who receive BRAF inhibitors develop a variety of hyper-proliferative skin conditions, whose pathogenic basis is the paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyper-proliferative skin changes improve when a MEK inhibitor is co-administered, as a MEK inhibitor blocks paradoxical MAPK activation. We tested whether we could take advantage of the mechanistic understanding of the skin hyper-proliferative side effects of BRAF inhibitors to accelerate skin wound healing by inducing paradoxical MAPK activation. Here we show that the BRAF inhibitor vemurafenib accelerates human keratinocyte proliferation and migration by increasing ERK phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing models in mice accelerated cutaneous wound healing and improved the tensile strength of healing wounds through paradoxical MAPK activation; addition of a MEK inhibitor reversed the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor did not increase the incidence of cutaneous squamous cell carcinomas in mice even after the application of a carcinogen. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds. Full depth incisional wound mice tissues with/without Vemurafenib treatment were sent for RNAseq analysis on day 2, 6 and 14
2016-07-29 | E-GEOD-74558 | biostudies-arrayexpress
Project description:While considerable progress has been made towards understanding the complex processes and pathways that regulate human wound healing, regenerative medicine has been unable to develop therapies that coax the natural wound environment to heal scar-free. The inability to induce perfect skin regeneration stems partly from our limited understanding of how scar-free healing occurs in a natural setting. Here we have investigated the wound repair process in adult axolotls and demonstrate that they are capable of perfectly repairing full thickness excisional wounds made on the flank. In the context of mammalian wound repair, our findings reveal a substantial reduction in hemostasis, reduced neutrophil infiltration and a relatively long delay in production of new extracellular matrix (ECM) during scar-free healing. Additionally, we test the hypothesis that metamorphosis leads to scarring and instead show that terrestrial axolotls also heal scar-free, albeit at a slower rate. Analysis of newly forming dermal ECM suggests that low levels of fibronectin and high levels of tenascin-C promote regeneration in lieu of scarring. Lastly, a genetic analysis during wound healing comparing epidermis between aquatic and terrestrial axolotls suggests that matrix metalloproteinases may regulate the fibrotic response. Our findings outline a blueprint to understand the cellular and molecular mechanisms coordinating scar-free healing that will be useful towards elucidating new regenerative therapies targeting fibrosis and wound repair. We used microarray analysis to determine the gene expression changes that take place during scar free wound healing in aquatic and terrestrial axolotl salamanders. Epidermal tissue was harvested using a 4mm biopsy punch. Two wounds were made along the flank and posterior to the forelimbs. Harvested epidermis was pooled for each animal. Four biological replicates were collected from uninjured epidermis (D0) and at 1, 3, and 7 days post injury.
2012-01-31 | E-GEOD-35255 | biostudies-arrayexpress
Project description:Effectively managing skin wounds to achieve quick and scarless healing is a significant clinical challenge. Several cell types participate in wound healing, including keratinocytes, fibroblasts, and many others. Human adipose-derived mesenchymal stem cell-derived exosomes (hADSC-Exos) are regarded as promising therapeutic choice. However, a comprehensive understanding of what mechanisms promote regenerative healing respond to hADSC-Exos treatment is still limited. Here, we utilize a high-resolution single-cell RNA sequencing analysis (scRNA-seq) from adult wild-type mice, postoperative day (POD) 14 mice and hADSC-Exos-treated postoperative day (POD) 14 mice. hADSC-Exos influences epithelial cells and fibroblasts, leading to scar-free wound healing. Among epithelial cell subtypes, Lef1high proliferating keratinocytes (prolif KC) are particularly remodeled by hADSC-Exos. Prolif KC exhibit epithelial-mesenchymal plasticity (EMP). The cell-cell communication between keratinocytes and fibroblasts in anti-scar healing is modulated by TGF-β1, which promote EMP transition cascade. hADSC-Exos may inhibit wound fibrosis through the 14-3-3Zeta-YES-associated protein (YAP)-hippo signaling pathway. This study enhances our understanding of epithelial cell diversity and interactions in wound healing, highlighting hADSC-Exos-induced prolif KC as potential reprogramming targets. These epithelial cells present promising therapeutic targets for improving wound healing strategies.
2025-06-03 | GSE298086 | GEO
Project description:When compared to skin, oral mucosal wounds heal rapidly and with reduced scar formation. This study used an Affymetrix microarray platform to compare the transcriptomes of oral mucosa and skin wounds in order to identify critical differences in the healing response at these two sites. Using microarrays, we explored the differences in gene expression in skin and oral mucosal wound healing in a murine model of paired equivalent-sized wounds. Samples were examined from day 0 to day 10 and spanned all stages of the wound healing process. Unwounded matched tissue was used as a control. Tissue samples collected at each post-wounding time point, as well as control samples, were represented by 3 biological replicates.
2010-07-20 | E-GEOD-23006 | biostudies-arrayexpress
Project description:Bacterial infections of wounds are associated with poor healing and worse scarring. We sought to identify transcriptomic patterns associated with impaired healing of wounds infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) using a rabbit ear wound model. Wounds created on post-operative day (POD) 0 were infected on POD3, within the inflammatory phase of healing. On POD4 the infected wounds were harvested for microarray/transcriptome analysis. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12. On POD4 before antibiotic treatment, both wounds contained elevated transcripts that enriched predominantly into inflammation/infection-response pathways and functions characteristic of infiltrating leukocytes. But there were 5-fold more elevated transcripts in P.a.- than K.p.-infected wounds. Additionally, unique to P.a.-infected wounds, was a minor network of inflammation/infection-response molecules with predicted upstream regulation predominated by type I interferons. Also on POD4, Dnr-transcripts of both wounds were enriched into stress-response pathways such as EIF2 signaling. But there were 8-fold more Dnr-transcripts in P.a.- than K.p.-infected wounds, and many more of them enriched in the function, cell death, suggesting that resident dermal cells of P.a.-infected wounds failed to survive a more destructive P.a. infection. On POD6, following two days of antibiotic treatment, the biofilm-colonized wounds expressed magnitudes fewer inflammation and stress-response transcripts. However, a single regulatory network of P.a.-infected wounds was found to consist of Upr-transcripts enriching immune/infection-response functions predicted to be regulated by type I interferons, which was similar to the network unique to P.a.-infected wounds on POD4. On POD12, genes expressed by K.p.-infected wounds suggesting healing, while for P.a.-infected wounds they suggested stalled healing. The similarities and differences between the wound responses to these infections further define the molecular foundations of healing impaired by infections. Rabbit ear Wounds created on post-operative day (POD) 0 were infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) on POD3 and harvested on POD4 for RNA extraction. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12.
2014-01-01 | E-GEOD-51167 | biostudies-arrayexpress
Project description:Foetal skin is known to heal without scar. This ability is lost in the third trimester of gestation. In mouse, scarless wound healing was reported until the day 15-16 of gestation. A range of factors that could explain the mechanisms of scarless skin wound healing have been identified, to mention reduced immune response, a greater proportion of collagen type III, hyaluronic acid and transforming growth factor beta isoform 3. The involvement of epigenetic changes, which are known to determine developmental processes, has not been examined in the context of scarless foetal skin healing so far. We performed the microarray analysis methylome and transcriptome of murine foetal dorsal skin at embryonic day 15 contrasted with those in later phases at embryonic days 18-19 as well as the in the adult mouse. The group of genes which show decreased methylation status in the foetal skin before the loss of ability to scarless healing between embryonic day 15 and 18 are enriched with transcriptional factors involved in embryonic morphogenesis, epithelium development, neuron differentiation, and synapse functions. The genes with increased methylation after the transition are associated with cell death and epithelial cell differentiation, inflammatory and wounding response and the degradation of hyaluronic acid. A substantial part of DNA methylation differences observed between embryonic day 15 and 18 were retained later at embryonic day 19 and in adults and remarkably correlated with gene expression changes. A major part of genes encoding the key factors responsible for cutaneous wound healing show significant changes in gene expression following the transition from scar free to normal healing. The results show that skin methylome and transcriptome undergoe extensive alterations following the loss of ability to scarless healing, while the functions associated with the changes imply their central role in skin wound repair.
2016-12-31 | GSE67876 | GEO
Project description:Foetal skin is known to heal without scar. This ability is lost in the third trimester of gestation. In mouse, scarless wound healing was reported until the day 15-16 of gestation. A range of factors that could explain the mechanisms of scarless skin wound healing have been identified, to mention reduced immune response, a greater proportion of collagen type III, hyaluronic acid and transforming growth factor beta isoform 3. The involvement of epigenetic changes, which are known to determine developmental processes, has not been examined in the context of scarless foetal skin healing so far. We performed the microarray analysis methylome and transcriptome of murine foetal dorsal skin at embryonic day 15 contrasted with those in later phases at embryonic days 18-19 as well as the in the adult mouse. The group of genes which show decreased methylation status in the foetal skin before the loss of ability to scarless healing between embryonic day 15 and 18 are enriched with transcriptional factors involved in embryonic morphogenesis, epithelium development, neuron differentiation, and synapse functions. The genes with increased methylation after the transition are associated with cell death and epithelial cell differentiation, inflammatory and wounding response and the degradation of hyaluronic acid. A substantial part of DNA methylation differences observed between embryonic day 15 and 18 were retained later at embryonic day 19 and in adults and remarkably correlated with gene expression changes. A major part of genes encoding the key factors responsible for cutaneous wound healing show significant changes in gene expression following the transition from scar free to normal healing. The results show that skin methylome and transcriptome undergoe extensive alterations following the loss of ability to scarless healing, while the functions associated with the changes imply their central role in skin wound repair.
2016-12-31 | GSE67877 | GEO
Project description:Impaired healing of diabetic wounds causes significant morbidity and mortality. This study aimed to identify novel mechanisms of diabetic wound healing defects and test a therapeutic intervention using diabetic mouse and pig models. We found Smad7 transgene expression in mouse epidermis promoting wound healing in diabetic db/db mice, with reductions in obesity and blood glucose. To isolate effects of Smad7 on wounds, we created a Smad7-based biologic (Tat-PYC-Smad7) that penetrates wound cells. Topical application of Tat-PYC-Smad7 to diabetic pig and mouse wounds accelerated healing compared to controls. RNAseq analysis of mouse wound samples showed reduced TGFβ/NFκB signaling, leading to faster re-epithelialization and better extracellular matrix remodeling. Tat-PYC-Smad7 also attenuated neutrophil degranulation and NETosis by blocking histone 3 citrullination and inhibiting myeloperoxidase activities. Our study reveals that Tat-PYC-Smad7 promotes diabetic wound healing by targeting keratinocytes and neutrophils, providing insight into cellular mechanisms of diabetic wound healing defects targetable by Smad7-based therapy.
2024-08-13 | GSE274513 | GEO