title: Enhanced Neurogenic Biomarker Expression and Reinnervation in Human Acute Skin Wounds Treated by Electrical Stimulation.
abstract: Electrical stimulation (ES) is known to promote cutaneous healing; however, its ability to regulate reinnervation remains unclear. First, we show that ES treatment of human acute cutaneous wounds (n = 40) increased reinnervation. Next, to define neurophysiologic mechanisms through which ES affects repair, microarray analysis of wound biopsy samples was performed on days 3, 7, 10, and 14 after wounding. This identified neural differentiation biomarkers TUBB3 (melanocyte development and neuronal marker) and its upstream molecule FIG4 (phosphatidylinositol (3,5)-bisphosphate 5-phosphatase) as significantly up-regulated after ES treatment. To demonstrate a functional ES-TUBB3 axis in cutaneous healing, we showed increased TUBB3+melanocytes and melanogenesis plus FIG4 and nerve growth factor expression, suggesting higher cellular differentiation. In support of this role of ES to regulate neural crest-derived cell fate and differentiation in vivo, knockdown of FIG4 in neuroblastoma cells resulted in vacuologenesis and cell degeneration, whereas ES treatment after FIG4-small interfering RNA transfection enhanced neural differentiation, survival, and integrity. Further characterization showed increased TUBB3+and protein gene product 9.5+Merkel cells during in vivo repair, after ES. We demonstrate that ES contributes to increased expression of neural differentiation biomarkers, reinnervation, and expansion of melanocyte and Merkel cell pool during repair. Targeted ES-assisted acceleration of healing has significant clinical implications.
authors.affiliation: Plastic Surgery Research Group, Dermatology Research Centre, Institute of Inflammation & Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Anil
authors.initials: A
authors.lastname: Sebastian
authors.affiliation: Section of Surgery, Department of Clinical Studies-Philadelphia, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Susan W
authors.initials: SW
authors.lastname: Volk
authors.affiliation: Plastic Surgery Research Group, Dermatology Research Centre, Institute of Inflammation & Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Poonam
authors.initials: P
authors.lastname: Halai
authors.affiliation: Oxford Bioelectronics, Abingdon, UK.
authors.forename: James
authors.initials: J
authors.lastname: Colthurst
authors.affiliation: Hair Follicle Biology Research Group, Dermatology Research Centre, Institute of Inflammation & Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Department of Dermatology, University of Muenster, Muenster, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Paus
authors.affiliation: Plastic Surgery Research Group, Dermatology Research Centre, Institute of Inflammation & Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK. Electronic address: ardeshir.bayat@manchester.ac.uk.
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Bayat
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D001706:Biopsy; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D004558:Electric Stimulation; D005420:Flavoproteins / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D018862:Merkel Cells / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D009432:Neural Crest / Q000378:metabolism; D009482:Neurophysiology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D012867:Skin / Q000294:innervation* / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
chemical_list: D015415:Biomarkers; D005420:Flavoproteins; C502240:NGF protein, human; C498585:TUBB3 protein, human; D014404:Tubulin; D020932:Nerve Growth Factor; C522215:FIG4 protein, human; D010744:Phosphoric Monoester Hydrolases