How do Olfactory Reserve Stem Cells Differentiate into Neuronal Cells? – A Combined in vitro/in vivo Approach

• Applicant: Privatdozent Dr. Constantin Hintschich
• Subject Area: Otolaryngology, Phoniatrics and Audiology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504647467

Age-related olfactory dysfunction affects up to 70% of the population over the age of 80 years. The olfactory epithelium has a distinctive potential to regenerate due to two kinds of stem cells: (1) Globose basal cells which are the first level of regeneration and undergo constant neurogenesis to renew the olfactory epithelium, and (2) horizontal basal cells which are dormant reserve stem cells and only activated in severe damage of the olfactory epithelium. In presbyosmia, the loss of olfactory sensory neurons and globose basal cells leads to a neurogenic exhaustion. However, the population of dormant horizontal basal cells fails to activate. Hence, the deliberate activation of horizontal basal cells in situ is an attractive therapeutic goal in age-related olfactory dysfunction. Previous studies have showed that horizontal basal cells can be activated by downregulation of the transcription factor p63. This can be achieved by the exogenous administration of retinoic acid. However, even after successful activation, the activated HBCs can adopt four different fates. Of them, only one leads to neuronal differentiation into globose basal cells and olfactory neuronal cells. Thus, this therapeutic approach to activate horizontal basal cells also necessitates driving the stem cell reserve toward a neuronal lineage. The underlying mechanisms of the subsequent neuronal differentiation into globose basal cells and olfactory neuronal cells are still largely elusive. This should be elucidated in the following combined in vitro/in vivo approach: First, the effect of different factors on the differentiation will be assessed in cultured murine horizontal basal cells using immunohistochemistry. In a second step this neurogenically differentiated olfactory tissue will be transplanted into a murine host olfactory epithelium. The outcome will also be assessed using immunohistochemistry, too. The aim is to establish optimal culture conditions to regenerate olfactory epithelium in vitro which then can be transplanted into a damaged host olfactory epithelium.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Hosts: Professor Dr. Eric Holbrook; Professor James E. Schwob, Ph.D.