Regenerating hair cells in human vestibular sensory epithelia

  1. Ruth Rebecca Taylor  Is a corresponding author
  2. Anastasia Filia
  3. Ursula Paredes
  4. Yukako Asai
  5. Jeffrey R Holt
  6. Michael Lovett
  7. Andrew Forge  Is a corresponding author
  1. University College London, United Kingdom
  2. Imperial College London, United Kingdom
  3. Harvard Medical School, United States

Abstract

Human vestibular sensory epithelia in explant culture were incubated in gentamicin to ablate hair cells. Subsequent transduction of supporting cells with ATOH1 using an Ad-2 viral vector resulted in generation of highly significant numbers of cells expressing the hair cell marker protein myosin VIIa. Cells expressing myosin VIIa were also generated after blocking the Notch signalling pathway with TAPI-1 but less efficiently. Transcriptomic analysis following ATOH1 transduction confirmed up-regulation of 335 putative hair cell marker genes, including several downstream targets of ATOH1. Morphological analysis revealed numerous cells bearing dense clusters of microvilli at the apical surfaces which showed some hair cell-like characteristics confirming a degree of conversion of supporting cells. However, no cells bore organised hair bundles and several expected hair cell markers genes were not expressed suggesting incomplete differentiation. Nevertheless, the results show a potential to induce conversion of supporting cells in the vestibular sensory tissues of humans.

Data availability

All sequencing data from all of these samples have been deposited in NCBI GEO (accession number: GSE109320)

The following data sets were generated

Article and author information

Author details

  1. Ruth Rebecca Taylor

    UCL Ear Institute, University College London, London, United Kingdom
    For correspondence
    Ruth.r.taylor@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Anastasia Filia

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Ursula Paredes

    UCL Ear Institute, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Yukako Asai

    FM Kirby Neurobiology Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeffrey R Holt

    FM Kirby Neurobiology Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Michael Lovett

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Andrew Forge

    UCL Ear Institute, University College London, London, United Kingdom
    For correspondence
    a.forge@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0995-0219

Funding

Medical Research Council (Project grant,G1000068)

  • Ruth Rebecca Taylor
  • Andrew Forge

Dunhill Medical Trust (Project grant R395/1114)

  • Andrew Forge

Rosetrees Trust (Project grant M58-F1)

  • Andrew Forge

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Ethical approval from NHS Health Research Authority, NRES Committee London -Surrey Borders. REC reference 11/LO/0475; IRAS project ID 73422. Tissue was collected anonymously with informed consent of the patient for tissue harvesting and publication of the results of the study.

Reviewing Editor

  1. Tanya T. Whitfield, University of Sheffield, United Kingdom

Publication history

  1. Received: January 4, 2018
  2. Accepted: July 16, 2018
  3. Accepted Manuscript published: July 18, 2018 (version 1)
  4. Version of Record published: August 6, 2018 (version 2)

Copyright

© 2018, Taylor et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ruth Rebecca Taylor
  2. Anastasia Filia
  3. Ursula Paredes
  4. Yukako Asai
  5. Jeffrey R Holt
  6. Michael Lovett
  7. Andrew Forge
(2018)
Regenerating hair cells in human vestibular sensory epithelia
eLife 7:e34817.
https://doi.org/10.7554/eLife.34817

Further reading

    1. Developmental Biology
    2. Neuroscience
    Emily L Heckman, Chris Q Doe
    Research Advance

    The organization of neural circuits determines nervous system function. Variability can arise during neural circuit development (e.g. neurite morphology, axon/dendrite position). To ensure robust nervous system function, mechanisms must exist to accommodate variation in neurite positioning during circuit formation. Previously we developed a model system in the Drosophila ventral nerve cord to conditionally induce positional variability of a proprioceptive sensory axon terminal, and used this model to show that when we altered the presynaptic position of the sensory neuron, its major postsynaptic interneuron partner modified its dendritic arbor to match the presynaptic contact, resulting in functional synaptic input (Sales et al., 2019). Here we investigate the cellular mechanisms by which the interneuron dendrites detect and match variation in presynaptic partner location and input strength. We manipulate the presynaptic sensory neuron by (a) ablation; (b) silencing or activation; or (c) altering its location in the neuropil. From these experiments we conclude that there are two opposing mechanisms used to establish functional connectivity in the face of presynaptic variability: presynaptic contact stimulates dendrite outgrowth locally, whereas presynaptic activity inhibits postsynaptic dendrite outgrowth globally. These mechanisms are only active during an early larval critical period for structural plasticity. Collectively, our data provide new insights into dendrite development, identifying mechanisms that allow dendrites to flexibly respond to developmental variability in presynaptic location and input strength.

    1. Epidemiology and Global Health
    2. Neuroscience
    Lorenza Dall'Aglio, Hannah H Kim ... Henning Tiemeier
    Research Article Updated

    Background:

    Associations between attention-deficit/hyperactivity disorder (ADHD) and brain morphology have been reported, although with several inconsistencies. These may partly stem from confounding bias, which could distort associations and limit generalizability. We examined how associations between brain morphology and ADHD symptoms change with adjustments for potential confounders typically overlooked in the literature (aim 1), and for the intelligence quotient (IQ) and head motion, which are generally corrected for but play ambiguous roles (aim 2).

    Methods:

    Participants were 10-year-old children from the Adolescent Brain Cognitive Development (N = 7722) and Generation R (N = 2531) Studies. Cortical area, volume, and thickness were measured with MRI and ADHD symptoms with the Child Behavior Checklist. Surface-based cross-sectional analyses were run.

    Results:

    ADHD symptoms related to widespread cortical regions when solely adjusting for demographic factors. Additional adjustments for socioeconomic and maternal behavioral confounders (aim 1) generally attenuated associations, as cluster sizes halved and effect sizes substantially reduced. Cluster sizes further changed when including IQ and head motion (aim 2), however, we argue that adjustments might have introduced bias.

    Conclusions:

    Careful confounder selection and control can help identify more robust and specific regions of associations for ADHD symptoms, across two cohorts. We provided guidance to minimizing confounding bias in psychiatric neuroimaging.

    Funding:

    Authors are supported by an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200 to HT) for HT, LDA, SL, and the Sophia Foundation S18-20, and Erasmus University and Erasmus MC Fellowship for RLM.