Electrical stimulation enhances epidermal proliferation in human cutaneous wounds by modulating p53-SIVA1 interaction

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.