Inner ear organoids: new tools to understand neurosensory cell development, degeneration and regeneration

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ABSTRACT

The development of therapeutic interventions for hearing loss requires fundamental knowledge about the signaling pathways controlling tissue development as well as the establishment of human cell-based assays to validate therapeutic strategies ex vivo. Recent advances in the field of stem cell biology and organoid culture systems allow the expansion and differentiation of tissue-specific progenitors and pluripotent stem cells in vitro into functional hair cells and otic-like neurons. We discuss how inner ear organoids have been developed and how they offer for the first time the opportunity to validate drug-based therapies, gene-targeting approaches and cell replacement strategies.

Abstract

Summary: Inner ear organoids from pluripotent stem cells and tissue-specific progenitors provide new tools to validate drug-based therapies, gene-targeting approaches and cell replacement strategies for hearing loss.

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Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny.

XiaoLei Yin, Henner F. Farin, Johan H van Es … (2014)

Although Lgr5(+) intestinal stem cells have been expanded in vitro as organoids, homogeneous culture of these cells has not been possible thus far. Here we show that two small molecules, CHIR99021 and valproic acid, synergistically maintain self-renewal of mouse Lgr5(+) intestinal stem cells, resulting in nearly homogeneous cultures. The colony-forming efficiency of cells from these cultures is ~100-fold greater than that of cells cultured in the absence of CHIR99021 and valproic acid, and multilineage differentiation ability is preserved. We made use of these homogeneous cultures to identify conditions employing simultaneous modulation of Wnt and Notch signaling to direct lineage differentiation into mature enterocytes, goblet cells and Paneth cells. Expansion in these culture conditions may be feasible for Lgr5(+) cells from the mouse stomach and colon and from the human small intestine. These methods provide new tools for the study and application of multiple intestinal epithelial cell types.

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Noise-induced cochlear neuropathy is selective for fibers with low spontaneous rates.

Adam C Furman, Sharon G Kujawa, M Charles Liberman (2013)

Acoustic overexposure can cause a permanent loss of auditory nerve fibers without destroying cochlear sensory cells, despite complete recovery of cochlear thresholds (Kujawa and Liberman 2009), as measured by gross neural potentials such as the auditory brainstem response (ABR). To address this nominal paradox, we recorded responses from single auditory nerve fibers in guinea pigs exposed to this type of neuropathic noise (4- to 8-kHz octave band at 106 dB SPL for 2 h). Two weeks postexposure, ABR thresholds had recovered to normal, while suprathreshold ABR amplitudes were reduced. Both thresholds and amplitudes of distortion-product otoacoustic emissions fully recovered, suggesting recovery of hair cell function. Loss of up to 30% of auditory-nerve synapses on inner hair cells was confirmed by confocal analysis of the cochlear sensory epithelium immunostained for pre- and postsynaptic markers. In single fiber recordings, at 2 wk postexposure, frequency tuning, dynamic range, postonset adaptation, first-spike latency and its variance, and other basic properties of auditory nerve response were all completely normal in the remaining fibers. The only physiological abnormality was a change in population statistics suggesting a selective loss of fibers with low- and medium-spontaneous rates. Selective loss of these high-threshold fibers would explain how ABR thresholds can recover despite such significant noise-induced neuropathy. A selective loss of high-threshold fibers may contribute to the problems of hearing in noisy environments that characterize the aging auditory system.

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Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery

Holly A. Rees, Alexis Komor, Wei-Hsi Yeh … (2017)

We recently developed base editing, a genome-editing approach that enables the programmable conversion of one base pair into another without double-stranded DNA cleavage, excess stochastic insertions and deletions, or dependence on homology-directed repair. The application of base editing is limited by off-target activity and reliance on intracellular DNA delivery. Here we describe two advances that address these limitations. First, we greatly reduce off-target base editing by installing mutations into our third-generation base editor (BE3) to generate a high-fidelity base editor (HF-BE3). Next, we purify and deliver BE3 and HF-BE3 as ribonucleoprotein (RNP) complexes into mammalian cells, establishing DNA-free base editing. RNP delivery of BE3 confers higher specificity even than plasmid transfection of HF-BE3, while maintaining comparable on-target editing levels. Finally, we apply these advances to deliver BE3 RNPs into both zebrafish embryos and the inner ear of live mice to achieve specific, DNA-free base editing in vivo.

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Author and article information

Journal

Journal ID (nlm-ta): Development

Journal ID (iso-abbrev): Development

Journal ID (publisher-id): DEV

Journal ID (hwp): develop

Title: Development (Cambridge, England)

Publisher: The Company of Biologists Ltd

ISSN (Print): 0950-1991

ISSN (Electronic): 1477-9129

Publication date (Print): 1 September 2019

Publication date (Electronic): 2 September 2019

Publication date PMC-release: 1 September 2020

Volume: 146

Issue: 17

Electronic Location Identifier: dev177188

Affiliations

[1 ] Inner Ear Research Laboratory , Department of Biomedical Research (DBMR), University of Bern , Bern 3008, Switzerland

[2 ] Department of Otorhinolaryngology, Head & Neck Surgery, Inselspital, Bern University Hospital, University of Bern , Bern 3010, Switzerland

[3 ] Department of Otolaryngology, Harvard Medical School , Boston, MA 02115, USA

[4 ] Eaton-Peabody Laboratory, Massachusetts Eye and Ear , Boston, MA 02114, USA

[5 ] Harvard Stem Cell Institute , Cambridge, MA 02138, USA

Author notes

[* ]Author for correspondence ( marta.roccio@ 123456dbmr.unibe.ch )

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Marta Roccio http://orcid.org/0000-0001-7568-9429

Article

Accession ID: PMC6765123 Pmcid ID: PMC6765123 Pmc-uid ID: 6765123 Publisher ID: DEV177188

DOI: 10.1242/dev.177188

PMC ID: 6765123

PubMed ID: 31477580

SO-VID: aebe62a5-13f7-45e1-ae8f-4e918ced552f

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Funding

Funded by: National Institutes of Health, http://dx.doi.org/10.13039/100000002;

Award ID: DC14089

Funded by: European Union Seventh Framework Programme, http://dx.doi.org/10.13039/100011102;

Award ID: 603029

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Inner ear organoids: new tools to understand neurosensory cell development, degeneration and regeneration

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Hearing Loss and Restoration

Most cited references 135

Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny.

Noise-induced cochlear neuropathy is selective for fibers with low spontaneous rates.

Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery

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