The Neuroregenerative Capacity of Olfactory Stem Cells Is Not Limitless: Implications for Aging

Abstract

The olfactory epithelium (OE) of vertebrates is a highly regenerative neuroepithelium, maintained under normal condition by a population of stem and progenitor cells - globose basal cells (GBCs) that also contribute to epithelial reconstitution after injury. However, aging of the OE often leads to neurogenic exhaustion - the disappearance of both GBCs and olfactory sensory neurons (OSNs). Aneuronal tissue may remain as olfactory, with an uninterrupted sheet of apically arrayed microvillar-capped sustentacular cell, or may undergo respiratory metaplasia. We have generated a transgenic mouse model for neurogenic exhaustion using OMP-driven Tet-off regulation of the A subunit of toxin such that the death of mature OSNs is accelerated. As early as 2 months of age the epithelium of transgenic mice, regardless of sex, recapitulates what is seen in the aged OE of humans and rodents. Areas of the epithelium completely lack neurons and GBCs, while the horizontal basal cells, a reserve stem cell population, show no evidence of activation. Surprisingly, other areas that were olfactory undergo respiratory metaplasia. The impact of accelerated neuronal death and reduced innervation on the olfactory bulb (OB) is also examined. Constant neuronal turnover leaves glomeruli shrunken and impacts the dopaminergic interneurons in the periglomerular layer. Moreover, the acceleration of OSN death can be reversed in those areas where some GBCs persist. However, the projection onto the OB recovers incompletely and the reinnervated glomeruli are markedly altered. Thus, the capacity for OE regeneration is tempered when GBCs disappear.A large percentage of humans lose or suffer a significant decline in olfactory function as they age. Consequently, quality of life suffers, and safety and nutritional status are put at risk. With age, the OE apparently becomes incapable of fully maintaining the neuronal population of the epithelium despite its well-known capacity for recovering from most forms of injury when younger which may contribute to age-related olfactory loss. Efforts to identify the mechanism by which olfactory neurogenesis becomes exhausted with age require a powerful model for accelerating age-related tissue pathology. The current ; transgenic mouse model, in which olfactory neurons die when they reach maturity and accelerated death can be aborted to assess the capacity for structural recovery, satisfies that need.

Alzheimer’s Disease: What Can We Learn From the Peripheral Olfactory System?

“…This study is the only reported exploitation of OE stem cells in AD research. Note that in both mice and humans the OE tends to lose its neuroregenerative ability with age (Child et al, 2018): GBCs somehow run out, HBCs alone are no longer sufficient, and the OE becomes nonneurogenic (Schwob et al, 2017).…”

Olfactory dysfunction in the pathophysiological continuum of dementia

“…Interestingly, the inflammatory reaction to xenobiotics contributes to the neurogenesis of basal progenitors stem cells through the macrophages-mediated release of TNF-α and nuclear factor kappa-light-chain-enhancer of activated B cells (NFk-B) (Borders et al, 2007;Chen et al, 2017). As for other organs the regenerative capacity of the olfactory neuroepithelium decays with aging both in humans and rodents (Child et al, 2018;Holbrook et al, 2011;Kondo et al, 2010), limiting the neurogenesis-promoting action of the innate immunity, while maintaining the inflammatory effect. This scenario is common in patients with chronic rhinosinusitis with hyposmia or transient anosmia, showing structurally and functionally altered neuroepithelium (Doty and Mishra, 2001).…”

Transplantation of Mesenchymal Stem Cells Overexpressing Fibroblast Growth Factor 21 Facilitates Cognitive Recovery and Enhances Neurogenesis in a Mouse Model of Traumatic Brain Injury

“…The depletion of neural stem cells attributed to accelerated proliferation has been reported in an induced neural degeneration mouse model, suggesting that the neuroregenerative capacity of neural stem cells is limited. 45 Our results indicating long-term effects of TBI on hippocampal neurogenesis and ability of generating immature neurons at the chronic stage after TBI are demonstrated by the significant reduction in the DCX-positive immature neurons in the DG 28 days post-injury.…”