Skin innervation and its in vitro modeling

Skin innervation consists of myelinated Aβ fibers connected to sensory corpuscles and responsible for the sense of touch, and of free nerve endings including myelinated Aδ fibers and unmyelinated C fibers, that detect temperature and transmit pain signals, in addition to induce neurogenic inflammation through the release of neuropeptides. Moreover, the ability of skin innervation to detect pathogens that trigger or modulate immune reactions, such as TH1, TH2, or TH17 responses, has recently been identified, further growing interest in studying these neuroimmune interactions in the context of skin diseases. To this end, increasing efforts are being devoted to the development of in vitro models capable of reproducing the interactions between skin innervation and the various cutaneous cell types in both 2D and 3D culture systems. Combining sensory neurons and Schwann cells in a skin model that must be maintained at the air-liquid interface to promote epidermal differentiation is complex. Furthermore, guiding the migration of neurites through the dermis to make contact with keratinocytes remains a major challenge. The most advanced tissue-engineered 3D models can reproduce innervated skin containing vascular networks and immune cells, while also recapitulating disease phenotypes with cells obtained from patients. Moreover, these models enable real-time monitoring of neuronal electrical activity by connecting neurons with microelectrode arrays. In vitro modeling of skin innervation and reproducing the phenotype of skin diseases, should enable major advances in the development of new therapies targeting innervation, with the key advantage to induce far fewer side effects than conventional anti-inflammatory treatments.