# Developing novel stem cell-based approaches to treat hearing loss

> **NIH VA I01** · JOHN D DINGELL VA MEDICAL CENTER · 2024 · —

## Abstract

The long-term aim of this project is to develop a stem cell-based approach to regenerate the function of damaged
auditory cells and synaptic connections. Our previous application focused on hair cell regeneration using stem
cell-based epigenetic approaches. The major objectives of this renewal proposal are to determine the molecular
mechanism critical for mouse hair cell synapse formation during normal development and develop a novel stem
cell-based approach to reinnervate mouse auditory hair cells. Hair cell regeneration has obtained significant
progress. Compared to hair cell regeneration, spiral ganglion neuron (SGN) regeneration has been reported but
with relatively limited results. We have identified a stepwise method to guide mouse embryonic stem cells (ESCs)
to differentiate into ESC-derived SGN-like neurons (ESNs) that showed SGN features. Up to date, only a few
reports show that stem cell-derived neurons can form neural contacts with mouse hair cells. However, whether
these neural contacts are bona fide SGN-hair cell synapses remains unclear. The function of these neural
contacts has not been determined at the synaptic level. The molecular mechanism critical for regenerated
neurons to functionally reinnervate hair cells remains obscure. Therefore, there is a critical need to use ESNs to
reinnervate hair cells and determine the molecular mechanism critical for reinnervation. EphrinB family proteins
bind to the EphB receptors, a family of transmembrane receptor tyrosine kinases. EphrinB signaling is involved
in a variety of developmental programs, including synaptogenesis. Previous studies show that EphrinB1
signaling is critical for excitatory synaptic induction. Our preliminary data suggest the role of EphrinB signaling
in ESN-hair cell reinnervation. Based on previous and our preliminary data, we hypothesize that EphrinB
signaling may play a critical role in regulating neurons to form functional synapses with sensory hair cells. To
test this hypothesis, three complementary specific aims are proposed. Aim 1 will determine the role of neuronal
Efnb1 in SGN-hair cell synapse formation during development. Aim 2 will determine the molecular mechanism
of ESN-hair cell reinnervation. Results of Aims 1 and 2 will guide the design of hair cell synapse regeneration
research. In Aim 3, we will determine the extent to which EphrinB1 regulates ESN-hair cell reinnervation.
Completion of this proposal will determine the molecular mechanisms critical for stem cell-derived neurons to
reinnervate sensory hair cells. Identifying the role of Efnb1 in hair cell reinnervation will guide the synapse
regeneration research, which will be translated into clinical trials to treat hearing loss patients. Therefore, the
outcomes of this work will open new avenues to explore a stem cell-based multidisciplinary approach to
regenerate hair cell synapses and restore the hearing function of Veteran and civilian patients.

## Key facts

- **NIH application ID:** 10815554
- **Project number:** 5I01RX002100-07
- **Recipient organization:** JOHN D DINGELL VA MEDICAL CENTER
- **Principal Investigator:** Zhengqing Hu
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-12-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815554

## Citation

> US National Institutes of Health, RePORTER application 10815554, Developing novel stem cell-based approaches to treat hearing loss (5I01RX002100-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10815554. Licensed CC0.

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