Engineering of functional auditory neurons from human induced pluripotent stem cells

Minjin Jeong; Lucas G. Vattino; Maja Djurisic; Kevin P. Rose; Hiroshi Hyakusoku; Svetolik Spasic; Xiao-Jie Ma; Hiroaki Mohri; Ronna Hertzano; Anne E. Takesian; Konstantina M. Stankovic

doi:10.1016/j.mmr.2026.100008

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Engineering of functional auditory neurons from human induced pluripotent stem cells

RESEARCH | Updated：2026-05-11

- Engineering of functional auditory neurons from human induced pluripotent stem cells
- Engineering of functional auditory neurons from human induced pluripotent stem cells
- 军事医学研究（英文） 2026年
- Affiliations：
  
  Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94304, USA
  Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA 02114, USA
  Section on Omics and Translational Science of Hearing, Neurotology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA
  Department of Otorhinolaryngology, Yokosuka Kyosai Hospital, Kanagawa 238-8558, Japan
  Department of Otolaryngology, Qilu Hospital of Shandong University, Jinan 250062, China
  Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94304, USA
  Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94304, USA
- Author bio：
  
  *Konstantina M. Stankovic, kstankovic@stanford.edu
- Funds：
  
  the National Institutes of Health (NIH) grants(U24 DC020857;U01 DC019370;R01 DC018353);the NIH-NIDCD Division of Intramural Research fund(DC000094-01);the Hearing Health Foundation (to RH);the Pew Latin American Fellows Program in the Biomedical Sciences (to LGV);the Remondi Foundation (to KMS);the Bertarelli Foundation Endowed Professorship (to KMS);Jennifer and Louis Hernandez (to KMS)
- DOI：10.1016/j.mmr.2026.100008
  中图分类号：
- 收稿：2025-07-07，
  
  录用：2026-03-06，
  
  纸质出版：2026-04
- Accepted：
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Minjin Jeong, Lucas G. Vattino, Maja Djurisic, 等. Engineering of functional auditory neurons from human induced pluripotent stem cells[J/OL]. 军事医学研究（英文）, 2026.

Jeong M, Vattino LG, Djurisic M, Rose KP, Hyakusoku H, Spasic S, et al. Engineering of functional auditory neurons from human induced pluripotent stem cells. Mil Med Res. 2026;13(1):100008.
Minjin Jeong, Lucas G. Vattino, Maja Djurisic, 等. Engineering of functional auditory neurons from human induced pluripotent stem cells[J/OL]. 军事医学研究（英文）, 2026. DOI： 10.1016/j.mmr.2026.100008.

Jeong M, Vattino LG, Djurisic M, Rose KP, Hyakusoku H, Spasic S, et al. Engineering of functional auditory neurons from human induced pluripotent stem cells. Mil Med Res. 2026;13(1):100008. DOI： 10.1016/j.mmr.2026.100008.

摘要

Abstract

Background:

Spiral ganglion neurons (SGNs) relay auditory sensory information from the cochlea to the brain. Their loss results in permanent hearing impairment in humans due to their limited regenerative capacity. Progress in hearing restoration has been constrained by the inaccessibility of human inner ear tissue and challenges in generating functionally mature human SGN-like neurons from stem cells

in vitro

Methods:

To generate human SGN-like neurons from human induced pluripotent stem cells (hiPSCs)

we recapitulated key signaling pathways involved in human inner ear development. On day (D) 11 of differentiation

nerve growth factor receptor-positive cells (precursors of pre-placodal ectoderm and neural crest) were isolated using magnetic sorting. From D18 to D25

cultures were treated with sonic hedgehogs to induce otic neural progenitors. Neuronal maturation was subsequently promoted by a cocktail of brain-derived neurotrophic factor

neurotrophin-3

and insulin-like growth factor-1

which supports SGN development. Cellular identity and functionality were assessed using single-cell RNA sequencing

immunocytochemistry

whole-cell patch-clamp electrophysiology

co-culture assays

and calcium ion (Ca

) imaging.

Results:

hiPSC-derived SGN-like neurons exhibited morphological

molecular

electrophysiological

and functional characteristics of SGNs

in vivo

. Neurons acquired bipolar morphology and were wrapped by glial cells. Transcriptomic analysis revealed that SGN-like neurons were distinct from other neuronal lineages and showed similarity to type I and type Ⅱ SGNs based on expression of synaptic and intrinsic excitability-related genes. Electrophysiological recordings revealed progressive hyperpolarization of resting membrane potential and emer

gence of overshooting action potentials

consistent with neuronal maturation. In co-culture systems

human SGN-like neurons formed functional synaptic connections with mouse cochlear hair cells and cochlear nucleus neurons

evidenced by Ca

transients and induction of the immediate early gene

c-Fos

Conclusions:

This study reports a robust and reproducible protocol for generating human SGN-like neurons from hiPSCs

providing a versatile platform for studying human auditory development

disease modeling

drug screening

and cell-based therapies for hearing restoration.

关键词

Keywords

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