title: Electrical stimulation enhances epidermal proliferation in human cutaneous wounds by modulating p53-SIVA1 interaction.
abstract: Cutaneous wounds establish endogenous "wound current" upon injury until re-epithelialization is complete. Keratinocyte proliferation, regulated partly by p53, is required for epidermal closure. SIVA1 promotes human double minute 2 homolog (HDM2)-mediated p53 regulation. However, the role of SIVA1 in wound healing is obscure. Here, we report that electrical stimulation (ES) accelerates wound healing by upregulating SIVA1 and its subsequent ability to modulate p53 activities. Cultured donut-shaped human skin explants, subjected to ES, exhibited better epidermal stratification, increased proliferation, and upregulation of gene and protein expression of HDM2/SIVA1, compared with non-ES-treated explants. ES significantly increased in vitro keratinocyte proliferation and phospho-p53-SIVA1 interaction; however, this showed stable expression of phospho-p53, which increased significantly in the absence of SIVA1. Here, HDM2 alone was unable to downregulate nuclear-accumulated phospho-p53, which was evident from decreased proliferation and increased sub-G1 population seen by flow cytometry. Further examination of the epidermis of human cutaneous wounds showed higher p53-SIVA1 coexpression and proliferation 7 days after injury in ES-treated wounds compared with control wounds. In summary, ES-inducible SIVA1 modulates p53 activities in proliferating keratinocytes, and exogenous ES affects p53/HDM2/SIVA1 axis leading to increased proliferation during re-epithelialization. This highlights ES as a potential strategy for enhancing cutaneous repair.
authors.affiliation: Plastic and Reconstructive Surgery Research, Institute of Inflammation and Repair, Manchester Institute of Biotechnology, School of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Anil
authors.initials: A
authors.lastname: Sebastian
authors.affiliation: Plastic and Reconstructive Surgery Research, Institute of Inflammation and Repair, Manchester Institute of Biotechnology, School of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Iqbal
authors.affiliation: Fenzian Ltd, Hungerford, Berkshire, UK.
authors.forename: James
authors.initials: J
authors.lastname: Colthurst
authors.affiliation: Section of Surgery, Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Susan W
authors.initials: SW
authors.lastname: Volk
authors.affiliation: Plastic and Reconstructive Surgery Research, Institute of Inflammation and Repair, Manchester Institute of Biotechnology, School of Medical and Human Sciences, University of Manchester, Manchester, UK; Centre for Dermatology, Institute of Inflammation and Repair, University of Manchester, Manchester, UK; Manchester Academic Health Science Centre, South Manchester University Hospital Foundation Trust, Wythenshawe Hospital, Manchester, UK. Electronic address: ardeshir.bayat@manchester.ac.uk.
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Bayat
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002453:Cell Cycle; D002455:Cell Division; D049109:Cell Proliferation; D004558:Electric Stimulation; D004817:Epidermis / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology; D009924:Organ Culture Techniques; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012871:Skin Diseases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D014945:Wound Healing / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D018809:Proliferating Cell Nuclear Antigen; C106549:SIVA1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2