scholarly journals The initiation of the wound healing program is regulated by the convergence of mechanical and epigenetic cues

2021 ◽  
Author(s):  
Tanay Bhatt ◽  
Akshay Hegde ◽  
Rakesh Dey ◽  
Alhad Ketkar ◽  
Ajai Pulianmackal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Tissue Repair ◽  
Dna Methyltransferase ◽  
Nuclear Translocation ◽  
Repair Process ◽  
Cellular Reprogramming ◽  
Cellular Behavior ◽  
A Cell ◽  
Signaling Modules

Wound healing in the skin is a complex physiological process that is a product of a cell state transition from homeostasis to repair. Mechanical cues are increasingly being recognized as important regulators of cellular reprogramming, but the mechanism by which it is translated to changes in gene expression and ultimately cellular behavior remains largely a mystery. To probe the molecular underpinnings of this phenomenon further, we used the downregulation of caspase-8 as a biomarker of a cell entering the wound-healing program. We found that the wound-induced release of tension within the epidermis leads to the alteration of gene expression via the nuclear translocation of the DNA methyltransferase 3A (DNMT3a). This enzyme then methylates promoters of genes that are known to be downregulated in response to wound stimuli as well as potentially novel players in the repair program. Overall, these findings illuminate the convergence of mechanical and epigenetic signaling modules that are important regulators of the transcriptome landscape required to initiate the tissue repair process in the differentiated layers of the epidermis.

Abstract 16637: Antioxidant-1, a Novel Cu-Dependent Transcription Factor for NADPH Oxidase p47phox, Promotes Wound Healing by Regulating Inflammation and Angiogenesis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Archita Das ◽  
Gin-Fu Chen ◽  
Ha Won Kim ◽  
Seock-Won Youn ◽  
Sudhahar Varadarajan ◽  
...  
Keyword(s):  
Wound Healing ◽  
Transcription Factor ◽  
Nadph Oxidase ◽  
Wound Repair ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Mouse Skin ◽  
Underlying Mechanism ◽  
Repair Process ◽  
Impaired Wound Healing

Background: Wound healing is important repair process after injury associated with inflammation and angiogenesis. Copper (Cu) plays an important role in wound healing and angiogenesis; however, underlying mechanism is unknown. Bioavailability of Cu is tightly controlled by transport proteins (Cu importer CTR1 and Cu exporter ATP7A) and chaperone (antioxidant-1, Atox1) which transfers Cu to ATP7A. We reported that Atox1 also functions as a Cu-dependent transcription factor; however, its role in wound healing is unclear. Results: Using mouse skin puncture model, here we show that, Atox 1 protein (8 fold) and Cu level (by X-ray Fluorescence Microscope; 2.5 fold) increased in skin after wounding in WT mice at day 7 when Atox1 was localised in the nucleus of dermis endothelial cell (ECs) and ATP7A was markedly decreased. ATP7A transgenic mice showed impaired wound healing. Atox1 knockout (KO) mice exhibited decrease in wound repair (40% inhibition vs. WT, day 7) which was rescued by Atox1 gene transfer by lentivirus. Macrophage which secrets angiogenic cytokines/chemokines was significantly reduced which resulted in decreased VEGF and SDF-1α protein and angiogenesis at day 7. In cultured human ECs, inflammatory cytokine TNF-stimulation significantly decreased ATP7A protein (80%) and increased intracellular Cu and Atox1 in nucleus. ATP7A knockdown with siRNA in ECs increased intracellular Cu and promoted nuclear Atox1, which were rescued by Cu importer CTR1 siRNA or Cu chelator BCS, indicating ATP7A downregulation-induced Cu accumulation is required for Atox1 nuclear translocation. By screening Atox1 target genes, we found that NADPH oxidase p47phox promoter contains Atox1 binding responsible element. p47phox protein expression was significantly increased by wounding or overexpression of nuclear-targeted Atox1, which was markedly decreased in Atox1 KO mice with its downstream VCAM1/ICAM1. Conclusions: Cu chaperone Atox1 functions as a transcription factor by sensing ATP7A downregulation-induced intracellular Cu to upregulate NADPH oxidase p47phox and its downstream redox-sensitive VCAM1/ICAM1 expression in response to injury. This in turn promotes inflammatory cell recruitment and angiogenesis, and thus stimulating wound repair.

scholarly journals Expression of Pentraxin 3 and Thrombospondin 1 in Gingival Crevicular Fluid during Wound Healing after Gingivectomy in Postorthodontic Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Anne Marie Rauten ◽  
Isabela Silosi ◽  
Stefan Ioan Stratul ◽  
Liliana Foia ◽  
Adrian Camen ◽  
...  
Keyword(s):  
Wound Healing ◽  
Tissue Repair ◽  
Orthodontic Treatment ◽  
Gingival Crevicular Fluid ◽  
Repair Process ◽  
Pentraxin 3 ◽  
Gingival Overgrowth ◽  
Thrombospondin 1 ◽  
Main Components ◽  
Crevicular Fluid

Background. Wound healing is a tissue repair process after an injury, and two of its main components are inflammation and angiogenesis, in which course a cascade of mediators is involved. The aim of this research was to evaluate the involvement of Pentraxin 3 and Thrombospondin 1 in wound healing after periodontal surgery (gingivectomy) for gingival overgrowth during orthodontic treatment with or without magnification devices, by assessing their levels in GCF.Methods. From 19 patients with gingival overgrowth as a result of fixed orthodontic treatment, the overgrown gingiva was removed by gingivectomy, from one half of the mandibular arch without magnification and from the other under magnification. Pentraxin 3 and Thrombospondin 1 were determined from gingival crevicular fluid by ELISA tests.Results. Statistically significant differences (p<0.05) and correlations between levels of the two biomarkers were analyzed. Statistically significant differences were established between levels of the two biomarkers at different time points, with significant positive correlation at the point of 24 hours.Conclusions. Within the limitations of this study, the results seem to sustain the involvement of Pentraxin 3 and Thrombospondin 1 in the processes of inflammation and angiogenesis in wound healing of patients with postorthodontic gingivectomy. The dynamics of Pentraxin 3 and Thrombospondin 1 levels could suggest a reduced inflammation and a faster angiogenesis using microsurgery.

scholarly journals Wound healing-related functions of the p160 steroid receptor co-activator family

Endocrinology ◽  
2020 ◽  
Author(s):  
Lisa K Mullany ◽  
David M Lonard ◽  
Bert W O’Malley
Keyword(s):  
Wound Healing ◽  
Cell Signaling ◽  
Tissue Repair ◽  
Steroid Receptor ◽  
Cellular Reprogramming ◽  
Model Organisms ◽  
Special Focus ◽  
Transcriptomic Response ◽  
Organ Systems ◽  
Cell Cell

Abstract Multicellular organisms have evolved sophisticated mechanisms to recover and maintain original tissue functions following injury. Injury responses require a robust transcriptomic response associated with cellular reprogramming involving complex gene expression programs critical for effective tissue repair following injury. Steroid receptor coactivators (SRCs) are master transcriptional regulators of cell-cell signaling that is integral for embryogenesis, reproduction, normal physiological function and tissue repair following injury. Effective therapeutic approaches for facilitating improved tissue regeneration and repair will likely involve temporal and combinatorial manipulation of cell-intrinsic and cell-extrinsic factors. Pleotropic actions of SRCs that are critical for wound healing range from immune regulation and angiogenesis to maintenance of metabolic regulation in diverse organ systems. Recent evidence derived from studies of model organisms during different developmental stages indicates the importance of the interplay of immune cells and stromal cells to wound healing. With SRCs being the master regulators of cell-cell signaling integral to physiologic changes necessary for wound repair, it is becoming clear that therapeutic targeting SRCs provides a unique opportunity for drug development in wound healing. This review will provide an overview of wound healing-related functions of SRCs with a special focus on cellular and molecular interactions important for limiting tissue damage after injury. Finally, we review recent findings showing stimulation of SRCs following cardiac injury with the SRC small molecule stimulator MCB-613 can promote cardiac protection and inhibit pathologic remodeling after myocardial infarction.

scholarly journals Principles of Cell Circuits for Tissue Repair and Fibrosis

2019 ◽  
Author(s):  
Miri Adler ◽  
Avi Mayo ◽  
Xu Zhou ◽  
Ruth Franklin ◽  
Matthew Meizlish ◽  
...  
Keyword(s):  
Wound Healing ◽  
Tissue Repair ◽  
Time Window ◽  
Pathological State ◽  
Protective Response ◽  
Dynamic Mechanisms ◽  
Normal Wound Healing ◽  
A Cell ◽  
Cell Circuit ◽  
Scar Maturation

AbstractTissue-repair is a protective response after injury, but repetitive or prolonged injury can lead to fibrosis, a pathological state of excessive scarring. To pinpoint the dynamic mechanisms underlying fibrosis, it is important to understand the principles of the cell circuits that carry out tissue-repair. In this study, we establish a cell-circuit framework for the myofibroblast-macrophage circuit in wound-healing, including the accumulation of scar-forming extracellular matrix. We find that fibrosis results from multistability between three outcomes, which we term ‘hot fibrosis’ characterized by many macrophages, ‘cold fibrosis’ lacking macrophages, and normal wound-healing. The cell-circuit framework clarifies several unexplained phenomena including the paradoxical effect of macrophage depletion, the limited time-window in which removing inflammation leads to healing, the effects of cellular senescence, and why scar maturation takes months. We define key parameters that control the transition from healing to fibrosis, which may serve as potential targets for therapeutic reduction of fibrosis.

scholarly journals Breastfeeding by Human Milk Significantly Increases the Expression of TLR4, TNF-α, CCL2, and CCL3 in the Prepuce Tissue of Neonates

2021 ◽  
Author(s):  
Shadi Behfar ◽  
Alireza Nazari ◽  
Aliakbar Yousefi-Ahmadipour ◽  
Soheila Pourmasoumi ◽  
Ahmadreza Sayadi ◽  
...  
Keyword(s):  
Wound Healing ◽  
Innate Immunity ◽  
Immune Responses ◽  
Tissue Repair ◽  
Significant Negative Correlation ◽  
Repair Process ◽  
Mrna Levels ◽  
Protein Levels ◽  
Tnf Α ◽  
Duration Of Pregnancy

Abstract Introduction: Innate immunity significantly participates in the tissue repair process. It has been documented that breastfeeding may alter immune responses. Thus, this project was designed to evaluate the effects of breastfeeding on the levels of TLR1-4, TNF-α, TGF-β, CCL2, and CCL3 in the prepuce tissue of neonates.Material and methods: This project was performed on the 90 samples (45 cases with breastfeeding and 45 cases without breastfeeding) of prepuce tissue of neonates. The tissues were homogenized and mRNA levels of TLR1-4 and protein levels of TNF-α, TGF-β, CCL2, and CCL3 were evaluated by Real-Time PCR and ELISA techniques, respectively.Results: Protein levels of TNF-α, CCL2, and CCL3 and mRNA levels of TLR4 were significantly decreased in the cases without breastfeeding when compared to the neonates with breastfeeding. There was a significant negative correlation between duration of pregnancy and mRNA levels of TLR1 in the neonates without breastfeeding.Conclusion: Due to the results, breastfeeding can modulate the expression of TLR4 and its related cytokines/chemokines to improve its wound healing and fight against pathogens.

Abstract 19493: Sirt7 Contributes to Myocardial Tissue Repair by Maintaining TGF-β Signaling Pathway

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Satoshi Araki ◽  
Yasuhiro Izumiya ◽  
Yuichi Kimura ◽  
Shinsuke Hanatani ◽  
Yoshiro Onoue ◽  
...  
Keyword(s):  
Wound Healing ◽  
Tissue Repair ◽  
Cardiac Fibroblasts ◽  
Repair Process ◽  
Border Zone ◽  
Hindlimb Ischemia ◽  
Protein Loss ◽  
Impaired Wound Healing ◽  
Cardiovascular Tissue

Background: Sirt7, one of the seven members of the mammalian sirtuin family, promotes oncogenic transformation. Tumor growth and metastasis require fibrotic and angiogenic responses. Here, we investigated the role of Sirt7 in cardiovascular tissue repair process. Methods and Results: In wild type (WT) mice, Sirt7 expression increased in response to acute cardiovascular injury, including myocardial infarction (MI) and hindlimb ischemia, particularly at the active wound healing site. Homozygous Sirt7 deficient (Sirt7-/-) mice showed susceptibility to cardiac rupture after MI, delayed blood flow recovery following hindlimb ischemia and impaired wound healing after skin injury, compared to WT mice. Histological analysis showed reduced fibrosis, fibroblast differentiation and inflammatory cell infiltration in the border zone of infarction in Sirt7-/- mice. In vitro, Sirt7-/- mice-derived or Sirt7 siRNA-treated cardiac fibroblasts showed reduced TGF-β signal activation and low expression levels of fibrosis-related genes compared with WT mice-derived or control siRNA-treated cells. These changes were accompanied by reduction in TGF-β receptor I (TβRI) protein. Loss of Sirt7 activated autophagy in cardiac fibroblasts. TβRI downregulation induced by loss of Sirt7 was blocked by autophagy inhibitor, and interaction of Sirt7 with protein interacting with protein kinase C, alpha (PICK1) was involved in this process. Conclusions: Sirt7 maintains TβRI by modulating autophagy and contributes to tissue repair processes.

Nutrient-regulated gene expression in eukaryotes

2006 ◽  
Vol 73 ◽  
pp. 85-96 ◽  
Author(s):  
Richard J. Reece ◽  
Laila Beynon ◽  
Stacey Holden ◽  
Amanda D. Hughes ◽  
Karine Rébora ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Transcriptional Control ◽  
Direct Interaction ◽  
Signalling Pathways ◽  
A Cell ◽  
One Step ◽  
Higher Eukaryotes ◽  
Regulated Gene Expression

The recognition of changes in environmental conditions, and the ability to adapt to these changes, is essential for the viability of cells. There are numerous well characterized systems by which the presence or absence of an individual metabolite may be recognized by a cell. However, the recognition of a metabolite is just one step in a process that often results in changes in the expression of whole sets of genes required to respond to that metabolite. In higher eukaryotes, the signalling pathway between metabolite recognition and transcriptional control can be complex. Recent evidence from the relatively simple eukaryote yeast suggests that complex signalling pathways may be circumvented through the direct interaction between individual metabolites and regulators of RNA polymerase II-mediated transcription. Biochemical and structural analyses are beginning to unravel these elegant genetic control elements.

scholarly journals Surgical Strategies to Promote Cutaneous Healing

2021 ◽  
Vol 9 (2) ◽  
pp. 45
Author(s):  
Ines Maria Niederstätter ◽  
Jennifer Lynn Schiefer ◽  
Paul Christian Fuchs
Keyword(s):  
Wound Healing ◽  
Wound Closure ◽  
Chronic Wounds ◽  
Treatment Algorithm ◽  
Surgical Site Infections ◽  
Repair Process ◽  
Suture Technique ◽  
The Body ◽  
Wound Debridement ◽  
Reconstructive Ladder

Usually, cutaneous wound healing does not get impeded and processes uneventfully, reaching wound closure easily. The goal of this repair process is to restore the integrity of the body surface by creating a resilient and stable scar. Surgical practice and strategies have an impact on the course of wound healing and the later appearance of the scar. By considering elementary surgical principles, such as the appropriate suture material, suture technique, and timing, optimal conditions for wound healing can be created. Wounds can be differentiated into clean wounds, clean–contaminated wounds, contaminated, and infected/dirty wounds, based on the degree of colonization or infection. Furthermore, a distinction is made between acute and chronic wounds. The latter are wounds that persist for longer than 4–6 weeks. Care should be taken to avoid surgical site infections in the management of wounds by maintaining sterile working conditions, using antimicrobial working techniques, and implementing the principles of preoperative antibiotics. Successful wound closure is influenced by wound debridement. Wound debridement removes necrotic tissue, senescent and non-migratory cells, bacteria, and foreign bodies that impede wound healing. Additionally, the reconstructive ladder is a viable and partially overlapping treatment algorithm in plastic surgery to achieve successful wound closure.

scholarly journals Wound Healing Promotion by Hyaluronic Acid: Effect of Molecular Weight on Gene Expression and In Vivo Wound Closure

2021 ◽  
Vol 14 (4) ◽  
pp. 301
Author(s):  
Yayoi Kawano ◽  
Viorica Patrulea ◽  
Emmanuelle Sublet ◽  
Gerrit Borchard ◽  
Takuya Iyoda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Weight ◽  
Wound Healing ◽  
Hyaluronic Acid ◽  
Healing Process ◽  
Dermal Fibroblasts ◽  
Water Soluble ◽  
Wound Healing Process ◽  
And Migration ◽  
Proliferation And Migration

Hyaluronic acid (HA) has been known to play an important role in wound healing process. However, the effect of molecular weight (MW) of exogenously administered HA on the wound healing process has not been fully understood. In this study, we investigated HA with different MWs on wound healing process using human epidermal keratinocytes and dermal fibroblasts. Cell proliferation and migration ability were assessed by water soluble tetrazolium (WST) assay and wound scratch assay. We examined the effect of HA addition in a full-thickness wound model in mice and the gene expression related to wound healing. Proliferation and migration of HaCaT cells increased with the increase of MW and concentration of HA. Interleukin (IL-1β), IL-8 and vascular endothelial growth factor (VEGF) as well as matrix metalloproteinase (MMP)-9 and MMP-13 were significantly upregulated by high molecular weight (HMW) HA in keratinocytes. Together with VEGF upregulation and the observed promotion of HaCaT migration, HA with the MW of 2290 kDa may hold potential to improve re-epithelialization, a critical obstacle to heal chronic wounds.

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