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

• Published in: The Journal of neuroscience 2018-08, Vol.38 (31), p.6806-6824
• Main Authors: Child, Kevin M, Herrick, Daniel B, Schwob, James E, Holbrook, Eric H, Jang, Woochan
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Aging; Aging - physiology; Animals; Basal cells; Cells (biology); Death; Diphtheria; Diphtheria toxin; Diphtheria Toxin - genetics; Diphtheria Toxin - toxicity; Dopamine receptors; Epithelium; Exhaustion; Female; Humans; Inflammation; Innervation; Interneurons; Male; Metaplasia; Mice; Mice, Transgenic; Middle Aged; Mortality; Nerve Degeneration - chemically induced; Nerve Regeneration - physiology; Neural stem cells; Neural Stem Cells - cytology; Neurogenesis; Neurons; Olfaction Disorders - etiology; Olfaction Disorders - pathology; Olfactory bulb; Olfactory epithelium; Olfactory marker protein; Olfactory Mucosa - cytology; Olfactory Mucosa - growth & development; Olfactory receptor neurons; Olfactory Receptor Neurons - cytology; Olfactory Receptor Neurons - pathology; Peptide Fragments - genetics; Peptide Fragments - toxicity; Progenitor cells; Proteins; Regeneration; Respiration; Rodents; Sensory neurons; Severity of Illness Index; Stem cell transplantation; Stem cells; Transgenic mice; Vertebrates
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3261-17.2018

The olfactory epithelium (OE) of vertebrates is a highly regenerative neuroepithelium that is maintained under normal conditions by a population of stem and progenitor cells, globose basal cells (GBCs), which 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 olfactory marker protein-driven Tet-off regulation of the A subunit of toxin such that the death of mature OSNs is accelerated. At 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; whereas 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) was also examined. Constant neuronal turnover leaves glomeruli shrunken and affects 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. Therefore, 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. Therefore, 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. 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.