Onur Egriboz, Markus Fehrholz, Moe Tsutsumi, Marta Sousa, Jeremy Cheret, Wolfgang Funk, Maximilian Kückelhaus, Ralf Paus, Kentaro Kajiya, Ilaria Piccini, Marta Bertolini
January 2025

Epidermal melanocytes form synaptic-like contacts with cutaneous nerve fibers, but the functional outcome of these connections remains elusive. In this pilot study we used our fully humanized re-innervated skin organ culture model to investigate melanocyte-nerve fiber interactions in UV-B-induced melanogenesis. UV-B-irradiation significantly enhanced melanin content and tyrosinase activity in re-innervated skin compared to non-innervated controls, indicating that neuronal presence is essential for exacerbating pigmentation upon UV-B irradiation in long-term culture.

Comparative transcriptomic analysis between laser-capture-microdissected melanocytes from freshly embedded human skin and published microarray data on in vitro primary melanocytes identified Semaphorin-4A (SEMA4A) as possible mediator of melanocyte-nerve fibers interactions. SEMA4A protein levels in Gp100⁺-epidermal melanocytes were significantly higher in re-innervated skin, and reduced by UV-B treatment. Analysis of melanocytes in vitro showed reduced SEMA4A protein expression 24 h after UV-B-irradiation while SEMA4A secretion into the medium was increased.

Beta-tubulin expression and axon growth in sensory neurons were stimulated by conditioned media (CM) from UV-B irradiated melanocytes. When this neuronal-conditioned medium was transferred to fresh melanocytes, melanin content increased, but only if neurons had been treated with CM from UV-B irradiated melanocytes. These findings highlight the importance of melanocyte-neuron interactions for UV-B-induced melanogenesis and suggest that secreted proteins (e.g., SEMA4A) can function as a novel target to treat hypo- and hyperpigmentation disorders.

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