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

• Published in: eLife Vol. 13
• Main Authors: Erbacher, Christoph, Britz, Sebastian, Dinkel, Philine, Klein, Thomas, Sauer, Markus, Stigloher, Christian, Üçeyler, Nurcan
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 16.01.2024; eLife Sciences Publications, Ltd
• Subjects: Animal models; Animals; Axons; Cell culture; Connexin 43; Epidermis; External stimuli; Humans; keratinocyte; Keratinocytes; Keratinocytes - physiology; Labeling; Microscopy; Nerve Fibers; neuro-cutaneous unit; neuropathic pain; Neuropathy; Neuroscience; Pain perception; Pathology; Peripheral neuropathy; Proteins; Scanning electron microscopy; Sensory neurons; Signal transduction; Skin; Skin - innervation; super-resolution microscopy; Tomography; neuropathic pain; keratinocyte; neuroscience; sensory neurons; neuro-cutaneous unit; human; super-resolution microscopy
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.77761

Traditionally, peripheral sensory neurons are assumed as the exclusive transducers of 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-nerve fiber 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 afferents and adjacent connexin 43 contacts in native skin and have applied a pipeline based on expansion microscopy to quantify these parameter in skin sections of healthy participants versus patients with small fiber neuropathy. We further derived a fully human co-culture system, visualizing ensheathment and connexin 43 plaques in vitro. Unraveling human intraepidermal nerve fiber ensheathment and potential interaction sites advances research at the neuro-cutaneous unit. These findings are crucial on the way to decipher the mechanisms of cutaneous nociception.