Neurovascular interactions in skin wound healing

Kiya, Koichiro; Kubo, Tateki

doi:10.1016/j.neuint.2019.02.014

Cited by 32 publications

(25 citation statements)

References 100 publications

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“…Besides its role in angiogenesis (Calzà et al, 2001;Ahluwalia et al, 2017; and its action on skin cells (Gostynska et al, 2020), NGF may act by improving local reinnervation, fundamental to the wound healing process (Kiya and Kubo, 2019). Our transcriptomic study on the CHF6467 molecule also points to the modulation of Akt/mTOR signaling as the main driver of NGF action (Giuliani et al, 2020).…”

Section: Skinmentioning

confidence: 60%

Nerve Growth Factor Biodelivery: A Limiting Step in Moving Toward Extensive Clinical Application?

et al. 2021

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Nerve growth factor (NGF) was the first-discovered member of the neurotrophin family, a class of bioactive molecules which exerts powerful biological effects on the CNS and other peripheral tissues, not only during development, but also during adulthood. While these molecules have long been regarded as potential drugs to combat acute and chronic neurodegenerative processes, as evidenced by the extensive data on their neuroprotective properties, their clinical application has been hindered by their unexpected side effects, as well as by difficulties in defining appropriate dosing and administration strategies. This paper reviews aspects related to the endogenous production of NGF in healthy and pathological conditions, along with conventional and biomaterial-assisted delivery strategies, in an attempt to clarify the impediments to the clinical application of this powerful molecule.

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Section: Skinmentioning

confidence: 60%

Nerve Growth Factor Biodelivery: A Limiting Step in Moving Toward Extensive Clinical Application?

et al. 2021

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“…Various growth factors, including VEGF, TGF-β, and bFGF, have been reported to play important roles in skin wound-healing. These growth factors contribute to the progression of re-epithelialization, angiogenesis, and granulation tissue formation [ 3 , 4 ]. In fact, it is well known that platelet-rich plasma (PRP), an effective endogenous therapeutic strategy for chronic wounds, contains these growth factors, which accelerate this process [ 30 , 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…In the inflammatory phase, keratinocytes, fibroblasts, and leukocytes produce inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which are important for leukocyte recruitment and protection against infection [ 2 , 3 ]. In the proliferative phase, numerous growth factors, such as transforming growth factor (TGF)-β, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF), are essential for the formation of granulation tissue, angiogenesis, and epithelialization, which play critical roles in the healing process [ 3 , 4 ]. In contrast, skin wound-healing in immunocompromised hosts, such as those with diabetes mellitus, are frequently delayed due to a prolonged inflammatory phase, leading to chronic and intractable diseases [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Topical Administration of Heat-Killed Enterococcus faecalis Strain KH2 Promotes Re-Epithelialization and Granulation Tissue Formation during Skin Wound-Healing

et al. 2021

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Lactic acid bacteria (LAB) are known to have beneficial effects on immune responses when they are orally administered as bacterial products. Although the beneficial effects of LAB have been reported for the genera Lactobacillus and Lactococcus, little has been uncovered on the effects of the genus Enterococcus on skin wound-healing. In this study, we aimed to clarify the effect of heat-killed Enterococcus faecalis KH2 (heat-killed KH2) strain on the wound-healing process and to evaluate the therapeutic potential in chronic skin wounds. We analyzed percent wound closure, re-epithelialization, and granulation area, and cytokine and growth factor production. We found that heat-killed KH2 contributed to the acceleration of re-epithelialization and the formation of granulation tissue by inducing tumor necrosis factor-α, interleukin-6, basic fibroblast growth factor, transforming growth factor (TGF)-β1, and vascular endothelial growth factor production. In addition, heat-killed KH2 also improved wound closure, which was accompanied by the increased production of TGF-β1 in diabetic mice. Topical administration of heat-killed KH2 might have therapeutic potential for the treatment of chronic skin wounds in diabetes mellitus. In the present study, we concluded that heat-killed KH2 promoted skin wound-healing through the formation of granulation tissues and the production of inflammatory cytokines and growth factors.

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“…Appropriate skin innervation plays a preeminent role in wound healing (Kiya and Kubo 2019), and a reduction in neurotrophic support to peripheral neurons has been described in diabetic skin (Sima 2003). NGF is the neurotrophin responsible for establishing sensory innervation of the skin during development, and for its maintenance in adulthood (Indo 2010).…”

Section: Discussionmentioning

confidence: 99%

Effects of Topical Application of CHF6467, a Mutated Form of Human Nerve Growth Factor, on Skin Wound Healing in Diabetic Mice

Giuliani

Lorenzini

Baldassarro

et al. 2020

J Pharmacol Exp Ther

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Nerve growth factor (NGF) is the protein responsible for the development and maintenance of sensory skin innervation. Given the role of appropriate innervation in skin healing, NGF has been indicated as a possible prohealing treatment in pathological conditions characterized by nerve ending loss, such as chronic ulcers in diabetes, however its use as a therapeutic agent is limited by its hyperalgesic effect. We tested the effect of topical application of the non-algogenic NGF derivative hNGFP61S/R100E in two models of skin ulcer induced in dbdb diabetic mice, investigating healing time, skin histology, reinnervation and angiogenesis using morphological and molecular approaches. We showed that the topical administration of CHF6467, a recombinant human NGF in which an amino acid substitution (R100E) abolished the hyperalgesic effect usually associated with NGF, accelerates skin repair in experimental wounds (full-excision and pressure ulcer) induced in diabetic mice (dbdb). CHF6467-induced acceleration of wound healing was accompanied by increased reepithelization, re-innervation and re-vascularization, as assessed by histology, immunohistochemistry and image analysis. Bioinformatic analysis of differentially expressed genes and signaling pathways in the wound tissues showed that Akt-mTOR was the most regulated pathway. In spite of the transdermal absorption leading to measurable, dose-dependent increases in CHF6467 plasma levels, no systemic thermal or local mechanical hyperalgesia was observed in treated mice. When tested in vitro in human cell lines, CHF6467 stimulated keratinocyte and fibroblast proliferation and tube formation by endothelial cells. Collectively, these results support a possible use of CHF6467 as a pro-healing agent in skin lesions in diabetes. SIGNIFICANCE STATEMENT Topical application of CHF6467 accelerates re-innervation, neoangiogenesis and wound healing in diabetic mice in both full-thickness skin excision and pressure ulcer models through the Akt/mTOR pathway, and does not induce hyperalgesia.

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Neurovascular interactions in skin wound healing

Cited by 32 publications

References 100 publications

Nerve Growth Factor Biodelivery: A Limiting Step in Moving Toward Extensive Clinical Application?

Nerve Growth Factor Biodelivery: A Limiting Step in Moving Toward Extensive Clinical Application?

Topical Administration of Heat-Killed Enterococcus faecalis Strain KH2 Promotes Re-Epithelialization and Granulation Tissue Formation during Skin Wound-Healing

Effects of Topical Application of CHF6467, a Mutated Form of Human Nerve Growth Factor, on Skin Wound Healing in Diabetic Mice

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