# Driving the Progeny of Olfactory HBC Stem Cells toward Neuronal Differentiation

> **NIH NIH R21** · TUFTS UNIVERSITY BOSTON · 2022 · $247,500

## Abstract

PROJECT SUMMARY
The capacity of the adult olfactory epithelium (OE) for renewing and regenerating the population of sensory
neurons depends on the persistence and proper function of stem cells. Presbyosmia is accompanied by
pathological changes due to the disordering and eventual depletion of the normally active olfactory stem and
progenitor cells, namely globose basal cells (GBCs). In this setting, the reserve stem cells, namely the
horizontal basal cells (HBCs), remain dormant despite the neurogenic exhaustion and disappearance of GBCs.
In contrast, if the OE is damaged by an olfactotoxin, the HBCs activate and contribute to the repair of the
epithelium. The results of HBC activation are strongly context-dependent and do not always capacitate the
rejuvenation of neurogenesis. That failure can occur in rodents as a consequence of either experimental
lesion or aging/neurogenic exhaustion. Substantial indirect evidence suggests the same is true of the human
OE. A therapeutic strategy that directs HBCs down the pathway toward neuronal regeneration in the setting of
an exhausted OE offers possibly the best approach for treating age-related olfactory dysfunction. We have
demonstrated that the TF p63 is the master switch that regulates HBC activation – a precipitous decline in p63
levels is necessary and sufficient for activation. We are testing factors that are known to enhance neuronal
differentiation (Aim 1) or suppress non-neuronal differentiation (Aim 2). We will use quantitative proteomics to
define the secretome of olfactory stromal cells, which will nominate candidate mechanisms for the intricate
intercommunication between epithelium and cells of the lamina propria that regulates neurogenesis. We will
test their efficacy in vitro using our newly developed HBC culture system by quantifying the proportion of
neurons that emerge after activation by the various factors. Then we will validate the in vitro effect by
transplanting the activated/factor-treated HBCs into the lesioned OE, which provides a neutral environment in
which all neuronal and non-neuronal fates are available to either endogenous HBCs or ones that have been
cultured. We will test efficacy on both mouse and human HBCs, and we will use a novel xenotransplantation
assay to assess the consequences for human HBCs in vivo. When completed, we will have achieved a much
more thorough understanding of the process by which HBCs are directed toward neuronal differentiation so
that they might rejuvenate neurogenesis. That understanding of mechanism both in mouse, where genetic
manipulations offer profound analytic power, and in humans will advance our efforts aimed at identifying
therapeutic strategies for alleviating olfactory sensory dysfunction, particularly the sensory loss which
accompanies aging.

## Key facts

- **NIH application ID:** 10527167
- **Project number:** 1R21DC018681-01A1
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** JAMES E. SCHWOB
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $247,500
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10527167

## Citation

> US National Institutes of Health, RePORTER application 10527167, Driving the Progeny of Olfactory HBC Stem Cells toward Neuronal Differentiation (1R21DC018681-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10527167. Licensed CC0.

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