scholarly journals The Role of the Integrated Stress Response and the Actin Cytoskeleton During Wound Healing

2020 ◽  
Vol 3 ◽  
Author(s):  
Erica Aukerman ◽  
Miguel Barriera Diaz ◽  
Dan Spandau
Keyword(s):  
Wound Healing ◽  
Stress Response ◽  
Actin Cytoskeleton ◽  
Wound Repair ◽  
Chronic Wounds ◽  
Leading Edge ◽  
Health Concern ◽  
Integrated Stress Response ◽  
Cutaneous Wound ◽  
Actin Depolymerization

Background and Hypothesis:  Chronic cutaneous wounds are a serious health concern afflicting millions of people. One of the primary factors preventing the closure of chronic wounds is the inability of keratinocytes to migrate across the wound bed. Epidermal keratinocytes migrate in a cohesive manner known as the keratinocyte collective cell migration (KCCM). Our lab has demonstrated that the integrated stress response (ISR) plays a key role in the KCCM. The ISR is initiated by stress-sensitive kinases, such as GCN2, and results in decreased global protein synthesis while preferentially increasing the translation of mRNAs encoding cytoprotective proteins. Wound repair also relies on the actin cytoskeleton, but the crosstalk between actin and the ISR is not well established. We hypothesize that the interaction between the ISR and the actin cytoskeleton is critical for KCCM during wound healing.     Methods:  Cutaneous wound healing was approximated in vitro using the KCCM-dependent scratch assay. Wild-type (WT) and GCN2-deleted (KO) keratinocytes were grown on coverslips, differentiated, scratched, and harvested at different times post-wounding. F-actin and vimentin (VIM) expression was monitored over time using fluorescent phalloidin-488 and immunofluorescence. In addition, WT keratinocytes were treated with actin-depolymerizing drugs and induction of ISR was measured using immunoblots.     Results:  Depolymerization of F-actin was observed along the leading edge of both wounded WT and GCN2-KO keratinocytes immediately following wounding. WT keratinocytes upregulated VIM expression at the leading edge whereas VIM expression remained unchanged in the wounded GCN2-KO keratinocytes. Treatment with latrunculin B and cytochalasin D, which both result in actin depolymerization, induced GCN2 phosphorylation in the differentiated WT keratinocytes.    Conclusion and Potential Impact:  F-actin depolymerization elicits a GCN2-mediated induction of the ISR. GCN2 and the ISR are critical components of the cutaneous wound repair process and their crosstalk with the actin cytoskeleton may serve as a novel therapeutic target in the treatment of chronic wounds.

scholarly journals Advances of Stem Cell Therapeutics in Cutaneous Wound Healing and Regeneration

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Suman Kanji ◽  
Hiranmoy Das
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Stem Cell ◽  
Wound Repair ◽  
Chronic Wounds ◽  
Healing Process ◽  
Treatment Modalities ◽  
Wound Healing Process ◽  
Cutaneous Wound Healing ◽  
Cutaneous Wound

Cutaneous wound healing is a complex multiple phase process, which overlaps each other, where several growth factors, cytokines, chemokines, and various cells interact in a well-orchestrated manner. However, an imbalance in any of these phases and factors may lead to disruption in harmony of normal wound healing process, resulting in transformation towards chronic nonhealing wounds and abnormal scar formation. Although various therapeutic interventions are available to treat chronic wounds, current wound-care has met with limited success. Progenitor stem cells possess potential therapeutic ability to overcome limitations of the present treatments as it offers accelerated wound repair with tissue regeneration. A substantial number of stem cell therapies for cutaneous wounds are currently under development as a result of encouraging preliminary findings in both preclinical and clinical studies. However, the mechanisms by which these stem cells contribute to the healing process have yet to be elucidated. In this review, we emphasize on the major treatment modalities currently available for the treatment of the wound, role of various interstitial stem cells and exogenous adult stem cells in cutaneous wound healing, and possible mechanisms involved in the healing process.

scholarly journals 962 Integrated stress response facilitates cutaneous wound healing

2019 ◽  
Vol 139 (5) ◽  
pp. S166
Author(s):  
R.R. Miles ◽  
P.C. Amin ◽  
J.C. Misra ◽  
D.F. Spandau ◽  
R.C. Wek
Keyword(s):  
Wound Healing ◽  
Stress Response ◽  
Integrated Stress Response ◽  
Cutaneous Wound Healing ◽  
Cutaneous Wound

scholarly journals Co-Transplantation of Skin-Derived Precursors and Collagen Sponge Facilitates Diabetic Wound Healing by Promoting Local Vascular Regeneration

2015 ◽  
Vol 37 (5) ◽  
pp. 1725-1737 ◽  
Author(s):  
Tingyu Ke ◽  
Mei Yang ◽  
Duo Mao ◽  
Meifeng Zhu ◽  
Yongzhe Che ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Repair ◽  
Expression Patterns ◽  
Collagen Sponge ◽  
Health Concern ◽  
Diabetic Wound ◽  
Paracrine Signalling ◽  
Vascular Regeneration ◽  
Diabetic Wound Healing

Background/Aims: Impaired diabetes wound healing can often lead to serious complications and remains a major health concern due to the lack of effective therapeutic approaches. Compromised angiogenesis, disrupted growth factor and cytokine activity are all attributable to diabetic wound healing impairment. The skin-derived precursors (SKPs) have been shown to differentiate into vascular and nerve cells, both of which are crucial components for wound repair. Given their easy accessibility and multipotency, the SKPs were proposed as an ideal therapeutic candidate for diabetic wound healing. Since the efficacy of cell therapy is limited by poor cell survival, collagen sponge was employed for better SKPs delivery. Methods: SKPs were isolated and transplanted directly to the wound areas of diabetic mice in the absence and presence of collagen sponge. The effects of SKPs and/or collagen sponge on diabetic wound healing were examined histologically as well as immunostaining of isolectin and α-SMA. Mechanisms via which the SKPs facilitate wound healing were then investigated by transplanting SKPs that have been pre-labelled with a fluorescence dye, Dil. Expression patterns of Dil and an SKP marker, nestin, was also examined. Results and Conclusion: Accelerated wound healing and enhanced local capillary regeneration could be observed 14 days after skin ablation from both SKPs and collagen sponge co-transplanted and collagen sponge only groups. Subsequent analyses further revealed superior pro-angiogenic effects from the SKP and collagen sponge co-delivered group, which are mainly attributable to in vivo transdifferentation and paracrine signalling of the SKPs.

scholarly journals Microfluidic and Lab-on-a-Chip Systems for Cutaneous Wound Healing Studies

2021 ◽  
Author(s):  
Ghazal Shabestani Monfared ◽  
Peter Ertl ◽  
Mario Rothbauer
Keyword(s):  
Wound Healing ◽  
Molecular Mechanisms ◽  
Chronic Wounds ◽  
Cell Communication ◽  
Lab On A Chip ◽  
Tissue Level ◽  
Cutaneous Wound Healing ◽  
Cutaneous Wound

Cutaneous wound healing is a complex multi-stage process involving direct and indirect cell communication events with the aim of efficiently restoring the barrier function of the skin. One key aspect in cutaneous wound healing is associated with cell movement and migration into the physically, chemically and biologically injured area resulting in wound closure. Understanding the conditions under which cell migration is impaired and elucidating the cellular and molecular mechanisms that improve healing dynamics is therefore crucial in devising novel therapeutic strategies to elevate patient suffering, reduce scaring and eliminate chronic wounds. Following the global trend towards automation, miniaturization and integration of cell-based assays into microphysiological systems, conventional wound healing assays such as the scratch assay or cell exclusion assay have recently been translated and improved using microfluidics and lab-on-a-chip technologies. These miniaturized cell analysis systems allow precise spatial and temporal control over a range of dynamic microenvironmental factors including shear stress, biochemical and oxygen gradients to create more reliable in vitro models that resemble the in vivo microenvironment of a wound more closely on a molecular, cellular, and tissue level. The current review provides (a) an overview on the main molecular and cellular processes that take place during wound healing, (b) a brief introduction into conventional in vitro wound healing assays, and (c) a perspective on future cutaneous and vascular wound healing research using microfluidic technology.

scholarly journals Platelet-rich plasma accelerates skin wound healing by promoting re-epithelialization

2020 ◽  
Vol 8 ◽  
Author(s):  
Pengcheng Xu ◽  
Yaguang Wu ◽  
Lina Zhou ◽  
Zengjun Yang ◽  
Xiaorong Zhang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Wound Repair ◽  
Chronic Wounds ◽  
Platelet Rich Plasma ◽  
Skin Wound ◽  
Local Inflammation ◽  
Skin Wound Healing

Abstract Background Autologous platelet-rich plasma (PRP) has been suggested to be effective for wound healing. However, evidence for its use in patients with acute and chronic wounds remains insufficient. The aims of this study were to comprehensively examine the effectiveness, synergy and possible mechanism of PRP-mediated improvement of acute skin wound repair. Methods Full-thickness wounds were made on the back of C57/BL6 mice. PRP or saline solution as a control was administered to the wound area. Wound healing rate, local inflammation, angiogenesis, re-epithelialization and collagen deposition were measured at days 3, 5, 7 and 14 after skin injury. The biological character of epidermal stem cells (ESCs), which reflect the potential for re-epithelialization, was further evaluated in vitro and in vivo. Results PRP strongly improved skin wound healing, which was associated with regulation of local inflammation, enhancement of angiogenesis and re-epithelialization. PRP treatment significantly reduced the production of inflammatory cytokines interleukin-17A and interleukin-1β. An increase in the local vessel intensity and enhancement of re-epithelialization were also observed in animals with PRP administration and were associated with enhanced secretion of growth factors such as vascular endothelial growth factor and insulin-like growth factor-1. Moreover, PRP treatment ameliorated the survival and activated the migration and proliferation of primary cultured ESCs, and these effects were accompanied by the differentiation of ESCs into adult cells following the changes of CD49f and keratin 10 and keratin 14. Conclusion PRP improved skin wound healing by modulating inflammation and increasing angiogenesis and re-epithelialization. However, the underlying regulatory mechanism needs to be investigated in the future. Our data provide a preliminary theoretical foundation for the clinical administration of PRP in wound healing and skin regeneration.

scholarly journals Overweight induced by high-fat diet delays rat cutaneous wound healing

2006 ◽  
Vol 96 (6) ◽  
pp. 1069-1077 ◽  
Author(s):  
Adriana P. Nascimento ◽  
Andréa M. A. Costa
Keyword(s):  
Blood Pressure ◽  
Wound Healing ◽  
High Fat Diet ◽  
Inflammatory Infiltrate ◽  
Cellular Proliferation ◽  
Chronic Wounds ◽  
Wound Contraction ◽  
Cutaneous Wound Healing ◽  
High Fat ◽  
Cutaneous Wound

Prolonged wound healing is a complication that contributes to morbidity and mortality. Overweight people regularly undergo surgery and trauma, and often develop chronic wounds, but the effects of the adipose tissue excess on cutaneous wound healing are not well understood. This study tested the hypothesis that overweight induced by a high-fat diet impairs rat cutaneous wound healing. Male Wistar rats were fed with either a high-fat or a standard (control) diet. After 15 weeks, an excisional lesion was done and the animals were killed 21 d later. Wound contraction and re-epithelialization, blood pressure, glucose and retroperitoneal fat were evaluated. After killing, lesion and adjacent normal skin were formol-fixed and paraffin-embedded. Inflammatory infiltrate, myofibroblasts, collagen fibres and cellular proliferation were analysed and blood vessels were evaluated using stereological methods. There was no difference in blood pressure and glucose, but retroperitoneal fat increased in the high-fat diet group. Animals fed with the high-fat diet presented delayed wound contraction and re-epithelialization. It was found that 21 d after wounding, overweight induced by a high-fat diet increased the inflammatory infiltrate and delayed myofibroblastic differentiation, collagen deposition, epithelial and connective tissue cell proliferation, and angiogenesis. These findings support the hypothesis that a high-fat diet exerts negative effects on rat cutaneous wound healing, due mainly to the prolongation of the inflammatory phase.

scholarly journals A randomised controlled pilot trial of oral 11β-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus

2021 ◽  
Author(s):  
Ramzi Ajjan ◽  
Elizabeth MA Hensor ◽  
Kave Shams ◽  
Francesco Del Galdo ◽  
Afroze Abbas ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Wound Healing ◽  
Wound Repair ◽  
Chronic Wounds ◽  
Pilot Trial ◽  
Punch Biopsy ◽  
Preclinical Research ◽  
Double Blind ◽  
Randomised Controlled

Chronic wounds (e.g. diabetic foot ulcers) have a major impact on quality of life, yet treatments remain limited. Glucocorticoids impair wound healing; preclinical research suggests that blocking glucocorticoid activation by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves wound repair. This investigator-initiated double-blind, randomised, placebo-controlled parallel-group phase 2b pilot trial investigated efficacy, safety and feasibility of 11β-HSD1 inhibition for 35 days by oral AZD4017 (AZD) treatment in adults with type 2 diabetes (n=14) compared to placebo (PCB, n=14) in a single-centre secondary care setting. Computer-generated 1:1 randomisation was pharmacy-administered. From 300 screening invitations, 36 attended, 28 were randomised. There was no proof-of-concept that AZD inhibited 24 hour skin 11β-HSD1 activity at day 28 (primary outcome: adjusted difference AZD-PCB 90% CI (diffCI)=-3.4,5.5) but systemic 11β-HSD1 activity (median urinary [THF+alloTHF]/THE ratio) was 87% lower with AZD at day 35 (PCB 1.00, AZD 0.13, diffCI=-1.04,-0.69). Mean wound gap diameter (mm) following baseline 2mm punch biopsy was 34% smaller at day 2 (PCB 1.51, AZD 0.98, diffCI=-0.95,-0.10) and 48% smaller after repeat wounding at day 30 (PCB 1.35, AZD 0.70, diffCI=-1.15,-0.16); results also suggested greater epidermal integrity but modestly impaired barrier function with AZD. AZD was well-tolerated with minimal side effects and comparable adverse events between treatments. Staff availability restricted recruitment (2.9/month); retention (27/28) and data completeness (95.3%) were excellent. These preliminary findings suggest that AZD may improve wound healing in patients with type 2 diabetes and warrant a fully-powered trial in patients with active ulcers. [Trial Registry: www.isrctn.com/ISRCTN74621291. Funding: MRC Confidence in Concept and NIHR Senior Investigator Award.]

scholarly journals Wound Healing Activities and Potential of Selected African Medicinal Plants and Their Synthesized Biogenic Nanoparticles

Plants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 2635
Author(s):  
Caroline Tyavambiza ◽  
Phumuzile Dube ◽  
Mediline Goboza ◽  
Samantha Meyer ◽  
Abram Madimabe Madiehe ◽  
...  
Keyword(s):  
Wound Healing ◽  
Medicinal Plants ◽  
Wound Repair ◽  
Chronic Wounds ◽  
In Vivo Models ◽  
Repair Mechanisms ◽  
Treatment Of Wounds ◽  
Biogenic Nanoparticles

In Africa, medicinal plants have been traditionally used as a source of medicine for centuries. To date, African medicinal plants continue to play a significant role in the treatment of wounds. Chronic wounds are associated with severe healthcare and socio-economic burdens despite the use of conventional therapies. Emergence of novel wound healing strategies using medicinal plants in conjunction with nanotechnology has the potential to develop efficacious wound healing therapeutics with enhanced wound repair mechanisms. This review identified African medicinal plants and biogenic nanoparticles used to promote wound healing through various mechanisms including improved wound contraction and epithelialization as well as antibacterial, antioxidant and anti-inflammatory activities. To achieve this, electronic databases such as PubMed, Scifinder® and Google Scholar were used to search for medicinal plants used by the African populace that were scientifically evaluated for their wound healing activities in both in vitro and in vivo models from 2004 to 2021. Additionally, data on the wound healing mechanisms of biogenic nanoparticles synthesized using African medicinal plants is included herein. The continued scientific evaluation of wound healing African medicinal plants and the development of novel nanomaterials using these plants is imperative in a bid to alleviate the detrimental effects of chronic wounds.

scholarly journals Improved Wound Closure Rates and Mechanical Properties Resembling Native Skin in Murine Diabetic Wounds Treated with a Tropoelastin and Collagen Wound Healing Device

2020 ◽  
Author(s):  
Robert S. Kellar ◽  
Robert B. Diller ◽  
Aaron J. Tabor ◽  
Dominic D. Dominguez ◽  
Robert G. Audet ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Wound Healing ◽  
Wound Closure ◽  
Chronic Wounds ◽  
Critical Role ◽  
Recovery Process ◽  
Health Concern ◽  
Full Thickness ◽  
Healthy Human ◽  
Wound Matrix

AbstractChronic wounds in patients suffering from type II diabetes mellitus (DMII) where wounds remain open with a complicated pathophysiology, healing, and recovery process is a public health concern. Normal wound healing plays a critical role in wound closure, restoration of mechanical properties, and the biochemical characteristics of the remodeled tissue. Biological scaffolds provide a tissue substitute to help facilitate wound healing by mimicking the extracellular matrix (ECM) of the dermis. In the current study an electrospun biomimetic scaffold, wound healing device (WHD), containing tropoelastin (TE) and collagen was synthesized to mimic the biochemical and mechanical characteristics of healthy human skin. The WHD was compared to a commercially available porcine small intestinal submucosa (SIS) matrix that has been used in both partial and full-thickness wounds, Oasis® Wound Matrix. Wound closure rates, histochemistry, qPCR, and mechanical testing of treated wound sites were evaluated. The WHD in a splinted, full-thickness, diabetic murine wound healing model demonstrated an enhanced rate of wound closure, decreased tissue inflammation, skin organ regeneration, and a stronger and more durable remodeled tissue that more closely mimics native unwounded skin compared to the control device.

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