4‐Aminopyridine promotes cutaneous reinnervation and accelerates wound healing

Skin wound healing is a tightly orchestrated process between epithelial, dermal, neuronal and vascular cells, all working in concert to restore tissue integrity and skin barrier function. Here, we report the therapeutic regenerative effects of FDA-approved 4-aminopyridine (4-AP) to promote skin wound healing by accelerating re-epithelialization, wound induced hair neogenesis (WIHN), dermal collagen deposition, angiogenesis, and reinnervation. We demonstrate that 4-AP enhanced wound closure by promoting keratinocyte proliferation and migration as well as collagen deposition through myofibroblast differentiation. 4-AP treatment increased both epidermal thickness, as well as the number of hair follicles and blood vessels in healed wounds, suggesting better restoration of skin function and architecture compared to simple wound scar formation. Moreover, 4-AP enhanced reinnervation of healed wounds by promoting Schwann cell (SC) de-differentiation and secretion of neuromediators (NGF, SP) associated with regeneration. In-vitro studies using human cells demonstrated that 4-AP enhanced proliferation and migration of keratinocytes, and SCs and that 4-AP enhances cellular interactions between neuronal and non-neuronal cells to further accelerate wound healing. 4-AP induced secretion of NGF from both SCs and keratinocytes. 4-AP enhances many of the key attributes of successful wound healing and is a promising therapeutic adjuvant for skin wound healing and tissue regeneration.