TRPM5-expressing Microvillous Cells Regulate Region-specific Cell Proliferation and Apoptosis During Chemical...

The mammalian main olfactory epithelium (MOE) is exposed to a wide spectrum of external chemicals during respiration and relies on adaptive plasticity to maintain its structural and functional integrity. We previously reported that the chemo-responsive and cholinergic transient receptor potential channel M5 (TRPM5)-expressing-microvillous cells (MCs) in the MOE are required for maintaining odor-evoked electrophysiological responses and olfactory-guided behavior during two-week exposure to an inhaled chemical mixture. Here, we investigated the underlying factors by assessing the potential modulatory effects of TRPM5-MCs on MOE morphology and cell proliferation and apoptosis, which are important for MOE maintenance. In the posterior MOE of TRPM5-GFP mice, we found that two-week chemical exposure induced a significant increase in Ki67-expressing proliferating basal stem cells without a significant reduction in the thickness of the whole epithelium or mature olfactory sensory neuron (OSN) layer. This adaptive increase in stem cell proliferation was missing in chemical-exposed transcription factor Skn-1a knockout (Skn-1a^-/-) mice lacking TRPM5-MCs. In addition, a greater number of isolated OSNs from chemical-exposed Skn-1a^-/- mice displayed unhealthily high levels of resting intracellular Ca²⁺. Intriguingly, in the anterior MOE where we found a higher density of TRPM5-MCs, chemical-exposed TRPM5-GFP mice exhibited a time-dependent increase in apoptosis and a loss of mature OSNs without a significant increase in proliferation or neurogenesis to compensate for OSN loss. Together, our data suggest that TRPM5-MC-dependent region-specific upregulation of cell proliferation in the majority of the MOE during chemical exposure contributes to the adaptive maintenance of OSNs and olfactory function.