Orexin-A increases the differentiation of human olfactory sensory neurons through orexin receptor type 1.

Introduction: Sensorineural olfactory dysfunction significantly impairs the life quality of patients but without effective treatments to date. Orexin is a neurotrophic factor activates neuronal network activity. However, it is still unknown whether orexin can promote differentiation in human olfactory sensory neurons (OSNs). This study seeks to explore the impact of orexin on the differentiation of human olfactory neuroepithelial cells (HONCs).

Methods: The primary olfactory epithelium cells were cultured with or without orexin-A. The neural maturation-related and functional proteins were analyzed through immunofluorescence staining and Western blot. The function of HONCs were evaluated through the synaptic vesicle recycling assay.

Results: The results showed that HONCs in the orexin-A group expressed higher levels of stage-specific markers, including achaete-scute homolog 1, βIII-tubulin, and olfactory marker protein. Additionally, more components of signaling transduction pathways compared to the control group. The orexin-A-mediated differentiation of OSN effect can be nullified with dual orexin receptor antagonist suvorexant and the selective orexin receptor type 1 antagonist SB674042, instead of selective orexin receptor type 2 antagonist TCS-OX2-29.

Conclusions: Orexin-A elevates the expression of protein markers in human olfactory neuronal progenitor cells to stimulate the differentiation of OSN and enhances the formation of components of the olfactory-specific signaling transduction pathway via orexin receptor type 1.