Age-Dependent Activation and Neuronal Differentiation of Lgr5+ Basal Cells in Injured Olfactory Epithelium via Notch Signaling Pathway

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.

Functional bioengineered models of the central nervous system

“…Olfactory neurospheroids can serve as models of schizophrenia 192 , autism spectrum disorder (ASD) 193 and Parkinson disease 194 . In addition, bioprinted scaffold-based models 195 and organoid models of the olfactory epithelium are being explored 196 , 197 .…”

Research Progress of Olfactory Nerve Regeneration Mechanism and Olfactory Training

“…Wnt signaling can promote the proliferation of Lgr5+ GBCs and regeneration of olfactory neurons. 10 , 11 Li et al used a strain a strain that destroyed the function of endogenous Lgr5 gene to characterize Sox2 expression in GBCs under normal conditions and in a lesion-regeneration model. They showed that a lack of Sox2 expression reduced the proportion of natural ORNs significantly.…”

Lgr5+ cells are required and dynamically participate in olfactory epithelium regeneration: a revisiting shows Lgr5 expression in multiple cell lineages

“…Lgr5 also labels stem and progenitor cells in sensory organs such as eye [33], ear [33][34][35], and tongue [36]. In nose, Lgr5 marks the GBCs located in the OE and functions in the recovery of injured OE [37][38][39]. However, how Lgr5 + cells behave in the homeostasis and regeneration of OE is still not very clear.…”