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Generation of innervated cochlear organoid recapitulates early development of auditory unit.

ABSTRACT: Functional cochlear hair cells (HCs) innervated by spiral ganglion neurons (SGNs) are essential for hearing, whereas robust models that recapitulate the peripheral auditory circuity are still lacking. Here, we developed cochlear organoids with functional peripheral auditory circuity in a staging three-dimensional (3D) co-culture system by initially reprogramming cochlear progenitor cells (CPCs) with increased proliferative potency that could be long-term expanded, then stepwise inducing the differentiation of cochlear HCs, as well as the outgrowth of neurites from SGNs. The function of HCs and synapses within organoids was confirmed by a series of morphological and electrophysiological evaluations. Single-cell mRNA sequencing revealed the differentiation trajectories of CPCs toward the major cochlear cell types and the dynamic gene expression during organoid HC development, which resembled the pattern of native HCs. We established the cochlear organoids with functional synapses for the first time, which provides a platform for deciphering the mechanisms of sensorineural hearing loss.

SUBMITTER: Xia M

PROVIDER: S-EPMC9860115 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Generation of innervated cochlear organoid recapitulates early development of auditory unit.

Xia Mingyu M Ma Jiaoyao J Wu Mingxuan M Guo Luo L Chen Yan Y Li Geng-Lin GL Sun Shan S Chai Renjie R Li Huawei H Li Wenyan W

Stem cell reports 20221229 1

Functional cochlear hair cells (HCs) innervated by spiral ganglion neurons (SGNs) are essential for hearing, whereas robust models that recapitulate the peripheral auditory circuity are still lacking. Here, we developed cochlear organoids with functional peripheral auditory circuity in a staging three-dimensional (3D) co-culture system by initially reprogramming cochlear progenitor cells (CPCs) with increased proliferative potency that could be long-term expanded, then stepwise inducing the diff ...[more]

PMID: 36584686

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Project description:PurposeThis current study aimed to explore early prelingual auditory development (EPLAD) and early language development in Mandarin-speaking children who received simultaneous bilateral cochlear implants (BICI) during the first year of cochlear implantation and compare the performance of the children who received BICI with those received unilateral cochlear implant (UCI).Methods39 Mandarin-speaking children who received BICIs simultaneously and 36 children with UCIs were enrolled in this study. To access the EPLAD, the Infant-Toddler Meaningful Auditory Integration Scale (IT/MAIS) was conducted, and a subtest of the simplified short-form version of the Mandarin Communicative Development Inventory (SSF-MCDI) was used to evaluate the development of expressive and receptive vocabulary for the children at indicated time points after surgery.ResultsIn both the simultaneous BICI and UCI groups, we observed significantly increased scores of the SSF-MCDI and IT/MAIS 1 year after the surgery. There are indications of early advantages in children with BICI in IT/MAIS scores (at 1, 3, and 6 months after activation). For early development of language, a great difference between the expressive vocabulary scores and the receptive vocabulary scores was observed in both groups. We found there were not significant differences between the two groups on expressive or receptive vocabulary scores, the use of more differentiated measures might be required in future research. We further found that the development of the receptive or expressive vocabulary is dramatically correlated with the age at implantation and the total scores of IT/MAIS for children with simultaneous BICIs.ConclusionThese results may supplement the skills development of early language and auditory in Mandarin-native children with simultaneous CIs. It is obvious that children with normal hearing have mastery of receptive vocabulary before that of expressive vocabulary, which is the same as children with unilateral and bilateral CIs in this research. IT/MAIS total scores and age at CI were important factors for early language performance in children with simultaneous BICIs.

Project description:BackgroundHearing loss, a major public health issue, affects 1.33 per 1,000 live births worldwide. Genetic factors contribute to over half of congenital cases, with X-linked inheritance accounting for 1-5%. POU3F4 mutations are associated with approximately 50% of X-linked non-syndrome hearing loss cases. POU3F4 plays a critical role in cochlear development by regulating otic mesenchyme cell differentiation. The study investigates the impact of a novel POU3F4 p.E294G mutation on cochlear structure and function using cellular and animal model.MethodsThe study utilized immortalized lymphoblastoid cell lines, POU3F4 overexpressed HEK293 cells and generated Pou3f4 knock-in (Pou3f4KI) mice via CRISPR/Cas9 to introduce the p.E294G mutation. Alterations in expression and subcellular localization of POU3F4 were detected at the cellular level. Auditory function was assessed using auditory brainstem response testing. Cochlear structure was analyzed through histology, immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. RNA sequencing, qPCR and Western blot were conducted to evaluate gene expression and mitochondrial function.ResultsThe transcription of POU3F4 was abnormal and the expression was normal in lymphoblastoid cell lines. Abnormal nuclear localization of POU3F4 p.E294G was found in overexpressed HEK293 cells. Pou3f4KI mice exhibited cochlear malformations, including modiolus hypoplasia and reduced stria vascularis cell populations. Auditory testing revealed progressive hearing loss. Pou3f4 affect mitochondrial protein expression by affecting the expression of TFAM. Mitochondrial dysfunction was evident, with reduced oxidative phosphorylation (OXPHOS) complex assembly and activity, decreased ATP levels. The level of reactive oxygen species, mitochondrial fission and apoptosis in cochlea were elevated.ConclusionsThe POU3F4 p.E294G resulted in abnormal nuclear localization. Pou3f4 mutant disrupts cochlear development and function, impairs mitochondrial integrity, induces oxidative stress, and promotes apoptosis, leading to progressive hearing loss. The findings enhance the understanding of POU3F4-related hearing loss mechanisms and highlight the importance of early genetic screening and audiological monitoring.

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Generation of innervated cochlear organoid recapitulates early development of auditory unit.

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Generation of innervated cochlear organoid recapitulates early development of auditory unit.

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