Stem Cell-Based Therapeutic Approaches to Restore Sensorineural Hearing Loss in Mammals

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Abstract

The hair cells that reside in the cochlear sensory epithelium are the fundamental sensory structures responsible for understanding the mechanical sound waves evoked in the environment. The intense damage to these sensory structures may result in permanent hearing loss. The present strategies to rehabilitate the hearing function include either hearing aids or cochlear implants that may recover the hearing capability of deaf patients to a limited extent. Therefore, much attention has been paid on developing regenerative therapies to regenerate/replace the lost hair cells to treat the damaged cochlear sensory epithelium. The stem cell therapy is a promising approach to develop the functional hair cells and neuronal cells from endogenous and exogenous stem cell pool to recover hearing loss. In this review, we specifically discuss the potential of different kinds of stem cells that hold the potential to restore sensorineural hearing loss in mammals and comprehensively explain the current therapeutic applications of stem cells in both the human and mouse inner ear to regenerate/replace the lost hair cells and spiral ganglion neurons.

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Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo.

Evert Kroon, Laura Martinson, Kuniko Kadoya … (2008)

Development of a cell therapy for diabetes would be greatly aided by a renewable supply of human beta-cells. Here we show that pancreatic endoderm derived from human embryonic stem (hES) cells efficiently generates glucose-responsive endocrine cells after implantation into mice. Upon glucose stimulation of the implanted mice, human insulin and C-peptide are detected in sera at levels similar to those of mice transplanted with approximately 3,000 human islets. Moreover, the insulin-expressing cells generated after engraftment exhibit many properties of functional beta-cells, including expression of critical beta-cell transcription factors, appropriate processing of proinsulin and the presence of mature endocrine secretory granules. Finally, in a test of therapeutic potential, we demonstrate that implantation of hES cell-derived pancreatic endoderm protects against streptozotocin-induced hyperglycemia. Together, these data provide definitive evidence that hES cells are competent to generate glucose-responsive, insulin-secreting cells.

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Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture

Karl Koehler, Andrew Mikosz, Andrei I. Molosh … (2013)

The inner ear contains sensory epithelia that detect head movements, gravity and sound. It is unclear how to derive these sensory epithelia from pluripotent stem cells, a process which will be critical for modeling inner ear disorders or developing cell-based therapies for profound hearing loss and balance disorders 1,2 . To date, attempts to derive inner ear mechanosensitive hair cells and sensory neurons have resulted in inefficient or incomplete phenotypic conversion of stem cells into inner ear-like cells 3–7 . A key insight lacking from these previous studies is the importance of the non-neural and pre-placodal ectoderm, two critical precursors during inner ear development 8–11 . Here we report the step-wise differentiation of inner ear sensory epithelia from mouse embryonic stem cells (ESCs) in three-dimensional culture 12,13 . We show that by recapitulating in vivo development with precise temporal control of BMP, TGFβ and FGF signaling, ESC aggregates transform sequentially into non-neural, pre-placodal and otic placode-like epithelia. Remarkably, in a self-organized process that mimics normal development, vesicles containing prosensory cells emerge from the presumptive otic placodes and give rise to hair cells bearing stereocilia bundles and a kinocilium. Moreover, these stem cell-derived hair cells exhibit functional properties of native mechanosensitive hair cells and form specialized synapses with sensory neurons that have also arisen from ESCs in the culture. Finally, we demonstrate how these vesicles are structurally and biochemically comparable to developing vestibular end organs. Our data thus establish a novel in vitro model of inner ear differentiation that can be used to gain deeper insight into inner ear development and disorder.

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Sox2 is required for sensory organ development in the mammalian inner ear.

Amy E. Kiernan, Anna L Pelling, Keith Leung … (2005)

Sensory hair cells and their associated non-sensory supporting cells in the inner ear are fundamental for hearing and balance. They arise from a common progenitor, but little is known about the molecular events specifying this cell lineage. We recently identified two allelic mouse mutants, light coat and circling (Lcc) and yellow submarine (Ysb), that show hearing and balance impairment. Lcc/Lcc mice are completely deaf, whereas Ysb/Ysb mice are severely hearing impaired. We report here that inner ears of Lcc/Lcc mice fail to establish a prosensory domain and neither hair cells nor supporting cells differentiate, resulting in a severe inner ear malformation, whereas the sensory epithelium of Ysb/Ysb mice shows abnormal development with disorganized and fewer hair cells. These phenotypes are due to the absence (in Lcc mutants) or reduced expression (in Ysb mutants) of the transcription factor SOX2, specifically within the developing inner ear. SOX2 continues to be expressed in the inner ears of mice lacking Math1 (also known as Atoh1 and HATH1), a gene essential for hair cell differentiation, whereas Math1 expression is absent in Lcc mutants, suggesting that Sox2 acts upstream of Math1.

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Author and article information

Contributors

Yunfeng Wang:

ORCID: https://orcid.org/0000-0001-7627-0929

He Li:

ORCID: https://orcid.org/0000-0002-6636-1904

Zhongshou Zhu:

ORCID: https://orcid.org/0000-0003-0163-7743

Shuangba He:

ORCID: https://orcid.org/0000-0002-5171-8819

Journal

Journal ID (nlm-ta): Neural Plast

Journal ID (iso-abbrev): Neural Plast

Journal ID (publisher-id): NP

Title: Neural Plasticity

Publisher: Hindawi

ISSN (Print): 2090-5904

ISSN (Electronic): 1687-5443

Publication date Collection: 2020

Publication date (Electronic): 1 August 2020

Volume: 2020

Electronic Location Identifier: 8829660

Affiliations

¹Department of Biotechnology, Federal Urdu University of Arts, Science and Technology, Gulshan-e-Iqbal Campus, Karachi, Pakistan

²Department of Otolaryngology Head and Neck, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing 211102, China

³ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Fudan University, Shanghai 200031, China

⁴NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai 200031, China

⁵Department of Otolaryngology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, 325000 Zhejiang Province, China

⁶Department of Otolaryngology, Ningde Municipal Hospital Affiliated of Fujian Medical University (Ningde Institute of Otolaryngology), Ningde, Fujian 352100, China

Author notes

Academic Editor: Geng lin Li

Author information

Muhammad Waqas https://orcid.org/0000-0003-2932-0633

Yunfeng Wang https://orcid.org/0000-0001-7627-0929

He Li https://orcid.org/0000-0002-6636-1904

Zhongshou Zhu https://orcid.org/0000-0003-0163-7743

Shuangba He https://orcid.org/0000-0002-5171-8819

Article

DOI: 10.1155/2020/8829660

PMC ID: 7416290

PubMed ID: 32802037

SO-VID: 04acf8a2-5681-4c09-b289-64939bb06692

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 10 April 2020

Date revision received : 1 June 2020

Date accepted : 3 July 2020

Funding

Funded by: Higher Education Commission, Pakistan

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Stem Cell-Based Therapeutic Approaches to Restore Sensorineural Hearing Loss in Mammals

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Abstract

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Hearing Loss and Restoration

Most cited references 102

Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo.

Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture

Sox2 is required for sensory organ development in the mammalian inner ear.

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