Understanding prosensory specification for improved regenerative therapies in the inner ear

Lead Research Organisation: University College London
Department Name: Ear Institute

Abstract

Our senses of hearing and balance depend on specialized 'hair' cells located in the sensory organs of the inner ear. The hair cells are only produced during the embryonic development of the inner ear, and their disappearance in adult life is the leading cause of hearing loss, in particular in the ageing population. The treatments for hearing loss are limited to hearing aids or cochlear implants, and there is considerable need and pressure for new and more efficient therapies. One possible cure could be to induce hair cell regeneration in the damaged inner ear - a process that is naturally occurring in non-mammalian vertebrates. The current approaches to achieve this rely on the artificial re-activation of 'pro-hair cell' signals, responsible for the induction of hair cell formation during embryonic development. However, growing evidence indicate that the cells of the adult cochlea cannot easily convert into hair cells when exposed to those signals.
An alternative strategy might be to turn cells of the adult inner ear into 'prosensory' cells, which during normal development are the parent cells giving rise to both hair cells and their associated 'supporting' cells. A first step towards this goal is to understand how these prosensory cells are formed during normal development. Using DNA-Sequencing and bioinformatics methods, we have already identified a number of genes and signals that could be potentially be important for the formation of prosensory cells. The aims of this project are to test their functions, by artificially modifying their expression or activity during the development of the embryonic chicken inner ear. The results of this project will help us to pinpoint the specific genes and cell-to-cell communication systems that could be manipulated to trigger hair cell regeneration in the damaged inner ear. In the future, this research could open up new venues for more efficient therapies for hearing loss in humans.

Technical Summary

The prevalence of hearing loss is steadily increasing: one in six people in the UK has a hearing disability, rising to one in two for over 70 year-old. The main cause of sensorineural hearing loss is the irreversible loss of the hair cells residing in the organ of Corti, the sensory epithelium of the cochlea. A potential therapy for hearing loss could be to induce in the damaged auditory organ the regeneration of new hair cells - a process that is occurring spontaneously in non-mammalian vertebrates. However the current strategies relying on the manipulation of the molecular signals controlling hair cell differentiation alone are relatively inefficient. An alternative approach might be to re-activate the developmental signals that drive the formation of the 'prosensory' cells, which are the progenitors for both hair cells and their associated supporting cells. The essential step to achieve this is to understand how prosensory specification is regulated during ear development. We have already identified two important signals with opposing effects on prosensory specification: Notch signalling and the transcription factor Lmx1a. Using RNA-Seq screenings in the chicken and mouse inner ear, we have started to uncover some of their transcriptional targets, and several of these are components of the Wnt signalling pathway. The objectives of this project are i) to elucidate the role of Wnt/beta-catenin signalling and its interactions with Notch signalling during prosensory specification, ii) to investigate the function of specific candidate targets of Notch/Lmx1a and iii) to establish a new mouse model (Sox2-tdTomato knock-in) to investigate the transcriptional profile of otic cells at different stages of commitment towards the sensory fate. The outcomes of this research could be exploited in the future to induce hair cell regeneration by means of gene therapies or to improve existing methods for the generation of hair cells from embryonic stem cells in vitro.

Planned Impact

The main beneficiaries from this research are the biomedical and hearing research community. An estimated 250 million people suffer from hearing loss, and the prevalence of this disease is particularly high in the ageing population. The main cause for hearing loss is the disappearance of the sensory 'hair cells' of the inner ear. In this project, we will investigate the mechanisms of formation of these cells during the embryonic development of the inner ear. Our results could uncover some of the key molecular signals that regulate sensory cell differentiation. This knowledge could be used to promote hair cell regeneration in the damaged inner ear through genetic or pharmacological approaches. It could alternatively be used to guide the in vitro differentiation of stem cells into specific inner ear cell types. Both strategies are currently envisioned as future therapies for hearing loss. Hence, additional beneficiaries of our research include charities that support the development of the 'next-generation cures' for deafness, the biotechnology and pharmaceutical industry, and hearing loss sufferers.
The results of our research will be published in scientific journals with open-access policies, presented at international conferences, and some will be made available online before publication to ensure the fastest and widest possible dissemination of the outcomes of this project. The proximity of the UCL Ear Institute with the Royal National Throat, Nose and Ear Hospital will also facilitate knowledge exchange with medical student and ENT medical staff, which could in turn communicate some of the results of our research to their patients. Finally, the Ear Institute hosts regular events with hearing research charities and their supporters, during which we can directly engage with the public and wider beneficiaries of our research.

Publications

10 25 50
publication icon
Daudet N (2020) Notch Signalling: The Multitask Manager of Inner Ear Development and Regeneration. in Advances in experimental medicine and biology

 
Description Zhiyong Liu 
Organisation Chinese Academy of Sciences
Country China 
Sector Public 
PI Contribution Host laboratory for team of Dr Zhiyong Liu as part of Newton Fellowship funded project to develop new Crispr/Cas9 tools for genome editing in the chicken embryo
Collaborator Contribution Training to Crispr/Cas9 techniques
Impact - Newton Fellowship awarded to Dr Liu (Royal Society and Chinese Academy of Sciences)
Start Year 2020
 
Description In2Science students visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Visit sparked further interest of the student for a scientific career. This was the first time the lab participated to the program and I intend to carry on this activity in the future,

Plans have been discussed for future visits, feedback from the organisers was also very positive.
Year(s) Of Engagement Activity 2014,2015,2016,2017,2018,2019,2020
URL http://in2scienceuk.org/
 
Description Pint of Science UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Pint of Science is a worldwide science festival during which thousands of scientists simultaneously bringing their research out of the lab to share with the public in a relaxing atmosphere of a pub in almost 400 cities across 24 countries. The Research Associate and Technician on the grant were responsible for promoting the UCL PoS events by organising a launch event and disseminating information about the talks of UCL researchers during the PoS festival.
Year(s) Of Engagement Activity 2019,2020
URL https://pintofscience.co.uk/city/london
 
Description World Hearing Day at the British Library 2019 (MZ) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Explaining our research and raise awareness of hearing loss to the general public, with opportunities for questions and discussion throughout the day.
Year(s) Of Engagement Activity 2019,2020