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In this pilot study we used our fully humanized re\u2010innervated skin organ culture model to investigate melanocyte\u2010nerve fiber interactions in UV\u2010B\u2010induced melanogenesis. UV\u2010B\u2010irradiation significantly enhanced melanin content and tyrosinase activity in re\u2010innervated skin compared to non\u2010innervated controls, indicating that neuronal presence is essential for exacerbating pigmentation upon UV\u2010B irradiation in long\u2010term culture. Comparative transcriptomic analysis between laser\u2010capture\u2010microdissected melanocytes from freshly embedded human skin and published microarray data on in\u00a0vitro primary melanocytes identified Semaphorin\u20104A (SEMA4A) as possible mediator of melanocyte\u2010nerve fibers interactions. SEMA4A protein levels in Gp100<jats:sup>+<\/jats:sup>\u2010epidermal melanocytes were significantly higher in re\u2010innervated skin, and reduced by UV\u2010B treatment. Analysis of melanocytes in\u00a0vitro showed reduced SEMA4A protein expression 24\u2009h after UV\u2010B\u2010irradiation while SEMA4A secretion into the medium was increased. Beta\u2010tubulin expression and axon growth in sensory neurons were stimulated by conditioned media (CM) from UV\u2010B irradiated melanocytes. When this neuronal\u2010conditioned medium was transferred to fresh melanocytes, melanin content increased, but only if neurons had been treated with CM from UV\u2010B irradiated melanocytes. These findings highlight the importance of melanocyte\u2010neuron interactions for UV\u2010B\u2010induced melanogenesis and suggest that secreted proteins (e.g., SEMA4A) can function as a novel target to treat hypo\u2010 and hyperpigmentation disorders.<\/jats:p>","DOI":"10.1111\/pcmr.13217","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T08:25:56Z","timestamp":1737447956000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Melanocyte and Nerve Fiber Cross\u2010Talk, Facilitated Also by Semaphorin\u2010<scp>4A<\/scp>, Enhances <scp>UV<\/scp>\u2010B\u2010Induced Melanogenesis"],"prefix":"10.1111","volume":"38","author":[{"given":"Onur","family":"Egriboz","sequence":"first","affiliation":[{"name":"QIMA Life Sciences QIMA Monasterium GmbH  M\u00fcnster Germany"},{"name":"DWI Labs Deriworks A.S.  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