Otic organoids: A model to study spiral ganglion neuron characteristics in Tmprss3-deficiency

TL;DR

Researchers developed a model using otic organoids to study how a gene deficiency affects spiral ganglion neurons, which are important for cochlear implant performance.

Contribution

A refined protocol for generating SGN-like cells in otic organoids to study TMPRSS3-deficiency in human iPSCs.

Findings

TMPRSS3-deficient iPSC clones developed smaller and less differentiated organoids.

TMPRSS3-deficient SGN-like cells showed reduced currents and action potential firing.

The model recapitulates disease phenotypes linked to impaired cochlear implant performance.

Abstract

Organoids are valuable models to study human diseases. Cochlear implants (CIs) electrically stimulate spiral ganglion neurons (SGNs) to enable severely hearing-impaired people vocal communication. However, some studies found in patients with mutations in the TMPRSS3 gene that speech comprehension with CI was lower than for other etiologies. The reduced CI performance might be associated with reduced SGN excitability, the causes for which are largely unclear. We refined a protocol for generating SGN-like cells in otic organoids from human induced pluripotent stem cells (iPSC) and confirmed their identity through marker expression and electrophysiological characterization. TMPRSS3-deficient iPSC clones developed smaller and less differentiated organoids. Moreover, TMPRSS3-deficient SGN-like cells displayed smaller currents and were less likely to exhibit action potentials, which recapitulate the expected disease phenotype. Ultimately, we seek to use this organoid model to study SGN function in human patients for enhancing our understanding and prediction of CI performance.

•Human otic organoids generate glutamatergic SGN-like neurons and glial cells•SGN-like cells from otic organoids recapitulate spiral ganglion neuron subtypes•TMPRSS3-deficient organoids show loss of SOX2/POU4F1 neuronal progenitors•TMPRSS3 KO reduces Na+ currents and action potential firing in SGN-like cells

Human otic organoids generate glutamatergic SGN-like neurons and glial cells

SGN-like cells from otic organoids recapitulate spiral ganglion neuron subtypes

TMPRSS3-deficient organoids show loss of SOX2/POU4F1 neuronal progenitors

TMPRSS3 KO reduces Na+ currents and action potential firing in SGN-like cells

Neuroscience; Cell biology

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