Atypical Diabetic Foot Ulcer Keratinocyte Protein Signaling Correlates with Impaired Wound Healing

Hoke, Glenn D.; Ramos, Corrine; Hoke, Nicholas N; Crossland, Mary C.; Shawler, Lisa G.; Boykin, Joseph V.

doi:10.1155/2016/1586927

Cited by 21 publications

(10 citation statements)

References 53 publications

(51 reference statements)

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“…As shown in Figure 4 , the presence of EVs in the culture medium was associated with a more rapid decrease in the area affected by the initial wound, indicating increased migration after 24 h of exposure to MSC EVs in cells of both types. Cell migration in the wound bed is essential for skin wound healing, and it is known to be affected in some chronic conditions, for example, in diabetic chronic wounds [ 25 ]. It has been suggested that one of the reasons of skin cell migration impairment in chronic wounds is the depletion of stem cells in those areas, which creates imbalance in the microenvironment and decelerates wound healing process.…”

Section: Resultsmentioning

confidence: 99%

Extracellular Vesicles from Adipose-Derived Mesenchymal Stem/Stromal Cells Accelerate Migration and Activate AKT Pathway in Human Keratinocytes and Fibroblasts Independently of miR-205 Activity

Ferreira

Cunha

Carregal

et al. 2017

Stem Cells International

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Mesenchymal stem/stromal cells (MSCs) are promising tools in cell therapy. They secrete extracellular vesicles (EVs) that carry different classes of molecules that can promote skin repair, but the mechanisms are poorly understood. Skin wound healing is a complex process that requires the activity of several signaling pathways and cell types, including keratinocytes and fibroblasts. In this study, we explored whether adipose tissue MSC-derived EVs could accelerate migration and proliferation of keratinocytes and fibroblasts, activate the AKT pathway, and promote wound healing in vivo. Furthermore, we evaluated if EV effects are miR-205 dependent. We found that MSC EVs had an average diameter of 135 nm. Keratinocytes and fibroblasts exposed to EVs exhibited higher levels of proliferation, migration, and AKT activation. Topical administration of EVs accelerated skin wound closure. Knockdown of miR-205 decreased AKT phosphorylation in fibroblasts and keratinocytes, whereas migration was decreased only in keratinocytes. Moreover, knockdown of miR-205 failed to inhibit AKT phosphorylation in fibroblasts and keratinocytes exposed to EVs. About the mechanism of EV effects, we found that incubation with EVs prevented inhibition of AKT activation by miR-205 knockdown, suggesting that EVs activate AKT independently of miR-205. In conclusion, we demonstrated that EVs are a promising tool for wound healing.

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Section: Resultsmentioning

confidence: 99%

Extracellular Vesicles from Adipose-Derived Mesenchymal Stem/Stromal Cells Accelerate Migration and Activate AKT Pathway in Human Keratinocytes and Fibroblasts Independently of miR-205 Activity

Ferreira

Cunha

Carregal

et al. 2017

Stem Cells International

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show abstract

“…The chronic wound environment also detrimentally affects keratinocytes. Comparisons of keratinocytes obtained from healthy skin and DFUs have indicated that there are significant changes in many of the signalling pathways associated with apoptosis, migration and proliferation . Keratinocytes analysed along the margins of DFUs have been found to be hyper‐proliferative and lacking in their ability to migrate and completely differentiate .…”

Section: Introductionmentioning

confidence: 99%

In vitro assessment of a novel, hypothermically stored amniotic membrane for use in a chronic wound environment

McQuilling¹,

Vines²,

Mowry³

2017

International Wound Journal

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Chronic wounds require extensive healing time and place patients at risk of infection and amputation. Recently, a fresh hypothermically stored amniotic membrane (HSAM) was developed and has subsequently shown promise in its ability to effectively heal chronic wounds. The purpose of this study is to investigate the mechanisms of action that contribute to wound-healing responses observed with HSAM. A proteomic analysis was conducted on HSAM, measuring 25 growth factors specific to wound healing within the grafts. The rate of release of these cytokines from HSAMs was also measured. To model the effect of these cytokines and their role in wound healing, proliferation and migration assays with human fibroblasts and keratinocytes were conducted, along with tube formation assays measuring angiogenesis using media conditioned from HSAM. Additionally, the cell-matrix interactions between fibroblasts and HSAM were investigated. Conditioned media from HSAM significantly increased both fibroblast and keratinocyte proliferation and migration and induced more robust tube formation in angiogenesis assays. Fibroblasts cultured on HSAMs were found to migrate into and deposit matrix molecules within the HSAM graft. These collective results suggest that HSAM positively affects various critical pathways in chronic wound healing, lending further support to promising qualitative results seen clinically and providing further validation for ongoing clinical trials.

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“…PI3K encompasses a family of lipid kinases that are classified based on their capability to activate inositol phospholipids. PI 3 K-dependent activation of AKT was strongly confirmed to affect the activity of numerous downstream biological pathways involved in apoptosis, cell proliferation, cellular survival, senescence, and angiogenesis [49,50]. Additionally, it is associated with cancer progression.…”

Section: Discussionmentioning

confidence: 96%

Gastroprotection against Rat Ulcers by Nephthea Sterol Derivative

et al. 2021

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Different species belonging to the genus Nephthea (Acyonaceae) are a rich resource for bioactive secondary metabolites. The literature reveals that the gastroprotective effects of marine secondary metabolites have not been comprehensively studied in vivo. Hence, the present investigation aimed to examine and determine the anti-ulcer activity of 4α,24-dimethyl-5α-cholest-8β,18-dihydroxy,22E-en-3β-ol (ST-1) isolated from samples of a Nephthea species. This in vivo study was supported by in silico molecular docking and protein–protein interaction techniques. Oral administration of ST-1 reduced rat stomach ulcers with a concurrent increase in gastric mucosa. Molecular docking calculations against the H+/K+-ATPase transporter showed a higher binding affinity of ST-1, with a docking score value of −9.9 kcal/mol and a pKi value of 59.7 nM, compared to ranitidine (a commercial proton pump inhibitor, which gave values of −6.2 kcal/mol and 27.9 µM, respectively). The combined PEA-reactome analysis results revealed promising evidence of ST-1 potency as an anti-ulcer compound through significant modulation of the gene set controlling the PI3K signaling pathway, which subsequently plays a crucial role in signaling regarding epithelialization and tissue regeneration, tissue repairing and tissue remodeling. These results indicate a probable protective role for ST-1 against ethanol-induced gastric ulcers.

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Atypical Diabetic Foot Ulcer Keratinocyte Protein Signaling Correlates with Impaired Wound Healing

Cited by 21 publications

References 53 publications

Extracellular Vesicles from Adipose-Derived Mesenchymal Stem/Stromal Cells Accelerate Migration and Activate AKT Pathway in Human Keratinocytes and Fibroblasts Independently of miR-205 Activity

Extracellular Vesicles from Adipose-Derived Mesenchymal Stem/Stromal Cells Accelerate Migration and Activate AKT Pathway in Human Keratinocytes and Fibroblasts Independently of miR-205 Activity

In vitro assessment of a novel, hypothermically stored amniotic membrane for use in a chronic wound environment

Gastroprotection against Rat Ulcers by Nephthea Sterol Derivative

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