Professor Marcelo N. Rivolta

Marcelo Rivolta

Professor of Sensory Stem Cell Biology
Centre for Stem Cell Biology
Department of Biomedical Science
The University of Sheffield
Western Bank, Sheffield S10 2TN
United Kingdom

Room: C226 Alfred Denny building
Phone: +44 (0) 114 222 2385
Email: m.n.rivolta@sheffield.ac.uk

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General

Brief career history

  • 2013-present: Professor of Sensory Stem Cell Biology, Department of Biomedical Science, University of Sheffield. UK.
  • 2012-2013: Reader in Sensory Stem Cell Biology, Department of Biomedical Science, University of Sheffield. UK.
  • 2003-2011: Senior Research Fellow, Department of Biomedical Science, University of Sheffield. UK.
  • 2001-2003: Research Fellow, Department of Biomedical Science, University of Sheffield. UK.
  • 1998-2001: Research Fellow, Department of Physiology, University of Bristol. UK.
  • 1995-1998: Postdoctoral Research Associate, Department of Physiology, University of Bristol. UK.
  • 1992-1995: Ph.D., NIH. Bethesda, Maryland, USA and University of Córdoba, Argentina.
  • 1992-1995: Visiting Associate at the Laboratory of Molecular Genetics, NIDCD, NIH. Bethesda. Maryland. USA.
  • 1992-1991: Visiting Fellow at the Laboratory of Molecular Biology, NIDCD, NIH. Bethesda. Maryland. USA.
  • 1989-1991: Visiting Fellow at the Laboratory of Cellular Biology, NIDCD, NIH. Bethesda. Maryland. USA.
  • 1989: M.D. School of Medicine, University of Córdoba. Argentina.
  • 1984-1989: Research Assistant. Institute of Cell Biology and Department of Histology, Embryology and Genetics. School of Medicine, University of Córdoba. Argentina.

Research interests

Deafness is a major public health issue worldwide, with more than 3 million people in the UK alone enduring a moderate to profound hearing loss. The Rivolta laboratory is dedicated to study the biology and behaviour of auditory stem cells (primarily human) and to explore their potential to regenerate the damaged inner ear.

Professional activities

  • Reviewer for leading scientific journals.
  • Reviewer for research proposals submitted to Action on Hearing Loss, Deafness Research UK, The Wellcome Trust, MRC, BBSRC and other funding bodies.
  • Invited speaker at several national and international meetings.
  • Trustee of the charity ‘The Ear Foundation’.

Invited Seminars

Invited to give numerous seminars, opening and plenary lectures.

In the media

Full publications

Research

Regenerative therapies for hearing loss: The development and use of human stem cells

Hearing loss has substantial personal, social and economic implications. It is most commonly caused by damage to the sensory hair cells and/or the auditory neurons in the cochlea. One possible therapeutic path would be to use otic progenitors generated in vitro to functionally replace the damaged cells.

Our group has made key advances developing stem cell technologies into a potentially viable therapy. We isolated a population of stem cells from the human fetal cochlea, and we have developed robust protocols to drive otic differentiation from human pluripotent stem cells. We also have established the proof of concept that hESC-derived otic progenitors can repair the damaged cochlea. We demonstrated that transplanted cells can graft into an animal model of auditory neuropathy, and elicit functional recovery as measured by auditory brainstem thresholds.

In an integrative regenerative medicine strategy, we are now exploring the combination of stem cells with cochlear implants, aiming to develop a true bionic implant. This device should conceptually combine stem cells with stimulatory electrodes. For this we are developing animal models of cell transplantation and implantation. On a parallel strategy, we are also using stem cells to develop in vitro platforms that would facilitate drug discovery and analysis.

We have several collaborations with industry and academia, within the UK as well as worldwide. We are part of Otostem, an international consortium with partners in Stanford, Harvard, Geneva, Uppsala, Tübigen and Marseille.

Figure 1

Funding

  • Medical Research Council
  • European Union
Teaching

Undergraduate and postgraduate taught modules

Level 2:

  • BMS235 Integrated Physiology and Pharmacology
  • BMS236 Building Nervous Systems

Level 3:

  • BMS382 Stem Cell Biology (Coordinator)
  • BMS339 Patients as Educators Project
  • BMS349 Extended Library Project
  • BMS369 Laboratory Research Project

Masters (MSc):

  • BMS6056 Stem Cell Biology (Coordinator)
  • BMS6051 Retrieval and Evaluation of Research Information (Coordinator)
Opportunities

PhD Studentship starting October 2017

Title: Exploring re-innervation and synaptogenesis between human stem cell-derived auditory neurons and inner hair cells: A therapeutic model for ‘hidden hearing loss’

Supervisors: Professor Marcelo Rivolta and Dr Stuart Johnson

Finding: Competition funded project European/UK students only.

Project Description

Loud noise exposure and aging lead to the permanent loss of afferent synaptic contacts to the primary sensory inner hair cells (IHCs) in the cochlea, whilst causing only a temporary or undetectable hearing threshold shift. This ‘synaptopathy’ reduces IHC afferent innervation by up to 50% leaving an individual unable to detect sounds in a noisy environment and experiencing difficulties with speech discrimination and intelligibility. Since the hearing thresholds are unaltered, it is difficult to detect the condition using conventional hearing tests, hence it is named ‘hidden hearing loss’. The loss of synaptic contacts is also thought to underlie primary neural degeneration in acquired hearing loss and aging.

The causative mechanisms underlying cochlear synaptopathy are not well understood. While it is believed to be a result of the toxic effects of overstimulating these fibres, it is not known whether there are any changes in the properties of the IHCs that lead to axonal retraction or, conversely, whether there are any IHC changes that result from it.

Experimental Plan
We have developed a way to make organotypic cultures of the excised mature mammalian cochlea and record from the sensory IHCs for 11 days in-culture. Interestingly, we found that after one or two days in culture the IHCs lose the physiological characteristics of mature cells and revert to a more immature phenotype without showing signs of degeneration or death. The PhD student will learn to make these cultures and use them to define the progression of this cell ‘de-differentiation’ using electrophysiological recording, staining and immunolabelling to see whether it is triggered by neuronal retraction or vice versa.

We have previously shown that human embryonic stem cell-derived spiral ganglion neurons (SGNs) can be transplanted into an animal model and establish synaptic connections and recovery of function. To address the specific role of the afferent fibres the student will learn to co-culture the adult gerbil organ of Corti with hESC-derived SGNs to see if the IHC properties have changed in order to attract new fibres and/or whether new synaptic innervation of the hair cells can restore their mature phenotype.

This study will allow us to understand the chain of events that lead to the ‘de-differentiation’ of IHCs in culture and whether it can be reversed by re-innervation from stem cell-derived SGNs. The advantages of using the mature organotypic culture as a model system to study IHC and afferent fibre synaptopathy, and cochlear plasticity in general, are that the conditions can be easily manipulated whilst monitoring the characteristics of the IHCs and afferent fibres throughout.

Impact
An understanding of cochlear plasticity in response to aging or trauma, and how to prevent or control it, will be essential for alleviating the effects of cochlear synaptopathy. This knowledge will also be important for slowing the progression of age-related hearing loss as well as the treatment of other poorly understood perceptual phenomena like tinnitus, the sensation of phantom tones, and hyperacusis, a reduced tolerance to moderate level sounds, all of which affect billions of people worldwide.

Keywords: Biophysics, Cell Biology / Development, Molecular Biology, Neuroscience / Neurology, Biophysics

References

  • Kujawa SG, Liberman MC (2015) Synaptopathy in the noise-exposed and aging cochlea: Primary neural degeneration in acquired sensorineural hearing loss. Hear Res 330: 191-199.
  • Johnson SL (2015) Membrane properties specialize mammalian inner hair cells for frequency or intensity encoding. eLife 4 pii: e08177
  • Chen W, Jongkamonwiwat N, Abbas L, Jacob Eshtan S, Johnson SL, Kuhn S, Milo M, Thurlow JK, Andrews PW, Marcotti W, Moore HD, Rivolta MN (2012) Restoration of auditory evoked responses by human ES-cell-derived otic progenitors. Nature 490: 278-282.

Further information about this project can be found on our PhD Opportunities page:

PhD Opportunities

Selected publications

Journal articles