Abstract
Aging is an important factor affecting function of smell, leading to the degeneration of mature olfactory sensory neurons and inducing the occurrence of smell loss. The mammalian olfactory epithelium (OE) can regenerate when subjected to chemical assaults. However, this capacity is not limitless. Inactivation of globose basal cells and failure to generate sensory neurons are the main obstacles to prevent the OE regeneration. Here, we found the significant attenuation in mature sensory neuronal generation and apparent transcriptional alternation in the OE from aged mice compared with young ones. The recruitment of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-positive cells in injured OE was weakened in aged mice, and more Lgr5+ cells remained quiescence in aged OE postinjury. Lineage-traced progenies from Lgr5+ cells were significantly fewer in the OE with aging. Moreover, Notch activation enhanced the neuronal regeneration in aged OE, making the regenerative capacity of aged OE comparable with that of young animals after injury. The growth and morphology of three-dimensional (3D)-cultured organoids from the OE of young and aged mice varied and was modulated by small molecules regulating the Notch signaling pathway. Thus, we concluded that activation of Lgr5+ cells in injured OE was age dependent and Notch activation could enhance the capacity of neuronal generation from Lgr5+ cells in aged OE after injury.
Highlights
The mammalian olfactory epithelium (OE) is a neuroepithelial structure that has self-renewal capacity throughout life
Notch activation could recover the neuronal differentiation in aged OE, making it comparable with the OE of young animals
leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)+ cells are active globose basal cells and are recruited in injured OE (Chen et al, 2014; Dai et al, 2018). It is still not clear whether dormant Lgr5+ cells are present in the OE, and this may lead to the discrepancy in the recruitment of Lgr5+ cells when OE is exposed to toxic reagent
Summary
The mammalian olfactory epithelium (OE) is a neuroepithelial structure that has self-renewal capacity throughout life. The neuro-regenerative capacity of basal cells in the OE is not limitless and aging is a principal element causing the sensory neuronal death and inactivation of GBCs (Child et al, 2018). Studies on both human and laboratory animals such as mice have shown age-related morphology and functional changes in the olfactory nerve epithelium (Mobley et al, 2014). Age-associated decline in the neuro-regenerative capacity of the injured OE is related with the weakness in proliferative activity (Suzukawa et al, 2011). Strategies against age-related neuronal degradation have been reported, including insulin-like growth factor 1 (IGF1) administration (Ueha et al, 2018a), intranasal treatment with fibroblast growth factor-2 (FGF-2; Fukuda et al, 2018), activation of inositol trisphosphate receptor type 3 (IP3R3), and the neuroproliferative factor neuropeptide Y (NPY) signaling (Jia and Hegg, 2015)
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