Presentation Details
| Activation of Horizontal Basal Cells in the OE Restores Neurogenesis after Neurogenic Exhaustion Sets In Vanessa Carignan1, Woochan Jang1, Eric H Holbrook2, James E Schwob1, Brian Lin1. 1Tufts University School of Medicine, Boston, MA, USA.2Massachusetts Eye and Ear Infirmary, Boston, MA, USA |
Abstract
Age-related anosmia and postinfectious olfactory dysfunction afflict millions of individuals, but effective molecular therapies are lacking. Progress toward their development requires animal models that mimic the pathology of the human olfactory epithelium (OE). Here, we introduce a highly efficient, genetically encoded neuron-specific ablation platform based on OMP–driven expression of Nitroreductase 2.0 (OMP-NTR) in mature olfactory sensory neurons (mOSNs). The administration of metronidazole, which the enzyme converts to an intracellular toxin, causes the rapid, reversible, and temporally precise elimination of mOSNs. In the short-term, despite the complete ablation of mOSNs, the epithelium’s neuroregenerative capacity remains intact. However, chronic accelerated neuronal turnover drives progressive regenerative failure that closely phenocopies human olfactory aging at the histological level, including neural stem cell exhaustion, aneuronal OE, respiratory epithelial metaplasia, and persistent anosmia. Horizontal basal cells (HBCs) remain extant in the degenerated OE and are a therapeutically attractive stem cell reservoir. Although HBCs are dormant in the unlesioned OE or in the setting of abbreviated neuronal lifespan (as seen after olfactory bulbectomy or with the OMP-NTR model described here), HBCs can be activated after olfactotoxin injury to make globose basal cells (the active neuronal stem cells and progenitors) and non-neuronal cells. Our findings demonstrate that targeted downregulation of the master transcription factor, deltaNp63, in the OMP-NTR pathological setting activates HBCs, restores neurogenesis, and promotes reinnervation of the olfactory bulb. This work provides the proof-of-concept for a molecularly defined therapeutic strategy to reverse olfactory dysfunction.
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