Abstract Traditionally, peripheral sensory neurons hold the monopole of transducing external stimuli. Current research moves epidermal keratinocytes into focus as sensors and transmitters of nociceptive and non-nociceptive sensations, tightly interacting with intraepidermal nerve fibers at the neuro-cutaneous unit. In animal models, epidermal cells establish close contacts and ensheath sensory neurites. However, ultrastructural morphological and mechanistic data examining the human keratinocyte-nociceptor interface are sparse. We investigated this exact interface in human skin applying super-resolution array tomography, expansion microscopy, and structured illumination microscopy. We show keratinocyte ensheathment of nociceptors and connexin 43 plaques at keratinocyte-nociceptor contact sites in healthy native skin. We further derived a fully human co-culture system, modeling ensheathment and connexin 43 plaques in vitro . Unraveling human intraepidermal nerve fiber ensheathment and interaction sites marks a milestone in research at the neuro-cutaneous unit. These findings are mind-changers on the way to decipher the mechanisms of cutaneous nociception.

Interaction of human keratinocytes and nerve fiber terminals at the neuro-cutaneous unit