Enhanced Neurogenic Biomarker Expression and Reinnervation in Human Acute Skin Wounds Treated by Electrical Stimulation

Anil, Sukumaran; Volk, Susan W.; Halai, Poonam; Colthurst, James; Paus, Ralf

doi:10.1016/j.jid.2016.09.038

Cited by 29 publications

(25 citation statements)

References 51 publications

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“…Its increased amounts were noted to be released from nerve terminals in psoriasis [ 34 , 35 ]. Opposite results were obtained by Sebastian et al, who demonstrated that, in electrically induced wound injury model, expression of UCHL1 gene and PGP 9.5 was significantly increased at nerve terminals, but also in MCs together with other commonly applied neuronal markers [ 36 ]. Keratinocytes in psoriatic lesions are neuroinflammatory cells and induced expression of other neurorelated proteins may reflect their injured conditions [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

UCHL1/PGP 9.5 Dynamic in Neuro-Immune-Cutaneous Milieu: Focusing on Axonal Nerve Terminals and Epidermal Keratinocytes in Psoriatic Itch

Kupczyk

Reich

Gajda

et al. 2018

BioMed Research International

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Psoriasis is an immunogenetic skin disease manifesting as plaque lesions on the skin. Patients with psoriasis frequently suffer from itch, an unpleasant sensation causing a desire to scratch. Psoriatic itch is mainly transmitted by unmyelinated C-fibers; however, the exact molecular mechanism of psoriatic itch is still unexplained. Protein gene product 9.5 (PGP 9.5) is a panneurological marker commonly used for analysis of peripheral peptidergic and nonpeptidergic nerves and identification of cutaneous neuro-immune-endocrine cells. However, some studies suggested that nonneuronal cells, like keratinocytes, may also express PGP 9.5. This phenomenon might be linked with impaired axonal transport, keratinocyte injury, or dysfunctions of neuro-immune-cutaneous connections. The aim of this study was to analyze the expression of PGP 9.5 in psoriatic skin. We observed significantly altered density of PGP 9.5-positive axonal nerve terminals in pruritic lesional (p=0.04) and nonlesional psoriatic skin (p>0.001) compared with controls. In contrast, no significant differences were observed between psoriatic skin without itch and controls. Furthermore, PGP 9.5 expression by suprabasal keratinocytes (SBKs) was significantly increased in itchy skin lesions (p=0.007) compared to skin without itch, and a positive correlation was observed between PGP 9.5 expression and itch intensity (r=0.64; p=0.02). Our findings indicate changes in peripheral innervations and psoriatic keratinocytes, which may influence neuro-immune-cutaneous homeostasis and modulate itch transmission.

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Section: Discussionmentioning

confidence: 99%

UCHL1/PGP 9.5 Dynamic in Neuro-Immune-Cutaneous Milieu: Focusing on Axonal Nerve Terminals and Epidermal Keratinocytes in Psoriatic Itch

Kupczyk

Reich

Gajda

et al. 2018

BioMed Research International

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“…24,59 Furthermore, both Merkel cells and keratinocytes express neural differentiation biomarkers associated with reinnervation during human cutaneous repair. 60 Consequently, the term "free nerve ending" is no longer relevant, because nerves are not "free" but connected to keratinocytes. FNE portions can even progress in keratinocyte cytoplasmic tunnels.…”

Section: Discussionmentioning

confidence: 99%

Keratinocytes Communicate with Sensory Neurons via Synaptic‐like Contacts

Talagas

Lebonvallet

Leschiera

et al. 2020

Annals of Neurology

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Objective: Pain, temperature, and itch are conventionally thought to be exclusively transduced by the intraepidermal nerve endings. Although recent studies have shown that epidermal keratinocytes also participate in sensory transduction, the mechanism underlying keratinocyte communication with intraepidermal nerve endings remains poorly understood. We sought to demonstrate the synaptic character of the contacts between keratinocytes and sensory neurons and their involvement in sensory communication between keratinocytes and sensory neurons. Methods: Contacts were explored by morphological, molecular, and functional approaches in cocultures of epidermal keratinocytes and sensory neurons. To interrogate whether structures observed in vitro were also present in the human epidermis, in situ correlative light electron microscopy was performed on human skin biopsies. Results: Epidermal keratinocytes dialogue with sensory neurons through en passant synaptic-like contacts. These contacts have the ultrastructural features and molecular hallmarks of chemical synaptic-like contacts: narrow intercellular cleft, keratinocyte synaptic vesicles expressing synaptophysin and synaptotagmin 1, and sensory information transmitted from keratinocytes to sensory neurons through SNARE-mediated (syntaxin1) vesicle release. Interpretation: By providing selective communication between keratinocytes and sensory neurons, synaptic-like contacts are the hubs of a 2-site receptor. The permanent epidermal turnover, implying a specific en passant structure and high plasticity, may have delayed their identification, thereby contributing to the long-held concept of nerve endings passing freely between keratinocytes. The discovery of keratinocyte-sensory neuron synaptic-like contacts may call for a reassessment of basic assumptions in cutaneous sensory perception and sheds new light on the pathophysiology of pain and itch as well as the physiology of touch.

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“…Sebastian et al have shown that ES contributes to increased expression of PGP9.5 and TUBB3, neural differentiation biomarkers, and SP neuropeptide within the wound. They also describe an expansion of melanocytes and TUBB3+ Merkel cells (specialized epidermal mechanoreceptors) during healing . Considering the role of innervation in wound healing and the beneficial impact of ES treatment, it can be suggested that ES could directly stimulate local nerve fibre endings to promote repair and/or encourage the reinnervation process within the wound.…”

Section: Therapeutic Strategies To Improve Wound Healing and Reinnervmentioning

confidence: 99%

New insights into the roles of myofibroblasts and innervation during skin healing and innovative therapies to improve scar innervation

Lebonvallet

Laverdet

Miséry

et al. 2018

Experimental Dermatology

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During the resolution phase of normal skin wound healing, there is a considerable loss of various cell types, including myofibroblasts by apoptosis. Inappropriate delay of apoptosis, and thus increased survival of myofibroblasts, may be a factor leading to pathologies and excessive scarring. Considerable data now clearly suggest that innervation plays a major role in wound healing, including the modulation of fibroblast cellular activity. An abnormal level of neuromediators is implicated not only in the development of chronic wounds but also in excessive scar formation.Understanding interactions between neuromediators and myofibroblasts, allowing normal reinnervation and having adequate levels of neuromediators during the healing process are clearly important to avoid the appearance of pathological healing or fibrosis/scarring. The aim of this review was first to discuss the mechanisms leading to normal or excessive scarring and then to present the roles of innervation during wound healing. Finally, the latest therapeutic strategies to help wound repair and reinnervation after skin damage will be introduced. Advantages and limitations in the use of neuropeptides, growth factors and biomaterials will be discussed as well as the most recent studies on electrostimulation and the potential of targeting resident skin mesenchymal stem cells. K E Y W O R D Sinnervation, myofibroblast, pathological scarring, skin repair, skin-derived precursor | 951LEBONVALLET ET AL.

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Enhanced Neurogenic Biomarker Expression and Reinnervation in Human Acute Skin Wounds Treated by Electrical Stimulation

Cited by 29 publications

References 51 publications

UCHL1/PGP 9.5 Dynamic in Neuro-Immune-Cutaneous Milieu: Focusing on Axonal Nerve Terminals and Epidermal Keratinocytes in Psoriatic Itch

UCHL1/PGP 9.5 Dynamic in Neuro-Immune-Cutaneous Milieu: Focusing on Axonal Nerve Terminals and Epidermal Keratinocytes in Psoriatic Itch

Keratinocytes Communicate with Sensory Neurons via Synaptic‐like Contacts

New insights into the roles of myofibroblasts and innervation during skin healing and innovative therapies to improve scar innervation

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