Lgr5 positive stem cells sustain homeostasis and drive regeneration of the nasal septum olfactory epithelium

Abstract

Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-expressing cells function as stem cells in various epithelial tissues. However, their specific roles in the olfactory epithelium (OE) are still not well understood. In this study, we aimed to clarify their roles using a genetically modified mouse model that expresses a diphtheria toxin receptor specific to Lgr5 cells. We conducted RNAscope analysis, which confirmed the presence of Lgr5 transcripts throughout the septal OE and revealed their reduction following DT treatment and subsequent reappearance over time. After administering diphtheria toxin, we observe initial epithelial disorganization by day 3, followed by marked thinning by week 1. Regenerative changes are evident by week 4 and continue through week 6. We noted dynamic changes in the markers of basal and progenitor cells. Keratin 14-positive horizontal basal cells became distributed across multiple layers by day 3. SRY-box transcription factor (Sox)2, which is typically expressed in sustentacular and globose basal cells, was confined to the globose basal cells by day 3. However, by week 1, it appeared in multiple layers of the thinned epithelium showing a trend toward its typical localization by week 6. Markers for sensory neurons, cilia, and Bowman's glands exhibited coordinated degeneration followed by ongoing regenerative processes through 6 weeks. Overall, these findings suggest that Lgr5-positive cells are closely associated with epithelial homeostasis and regenerative processes in the olfactory epithelium.