A novel therapeutic pathway to the human cochlear nerve.

Traditional approaches to the human cochlear nerve have been impeded by its bony encasement deep inside the skull base. We present an innovative, minimally invasive, therapeutic pathway for direct access to the nerve to deliver novel regenerative therapies. Neuroanatomical studies on 10 cadaveric human temporal bones were undertaken to identify a potentially safe therapeutic pathway to the cochlear nerve.

Unlocking the human inner ear for therapeutic intervention.

The human inner ear contains minute three-dimensional neurosensory structures that are deeply embedded within the skull base, rendering them relatively inaccessible to regenerative therapies for hearing loss. Here we provide a detailed characterisation of the functional architecture of the space that hosts the cell bodies of the auditory nerve to make them safely accessible for the first time for therapeutic intervention. We used synchrotron phase-contrast imaging which offers the required microscopic soft-tissue contrast definition while simultaneously displaying precise bony anatomic detail.

Neural Crest-Derived Stem Cells (NCSCs) Obtained from Dental-Related Stem Cells (DRSCs): A Literature Review on Current Knowledge and Directions toward Translational Applications.

Evidence from dental-related stem cells (DRSCs) suggests an enhanced potential for ectodermal lineage differentiation due to their neural crest origin. Growing evidence that DRSC cultures can produce cells with a neural crest-derived stem cell (NCSC)-like phenotype supports their potential for future therapeutic approaches for neurodegenerative diseases and nerve injuries. However, most of the evidence is limited to the characterization of DRSCs as NCSCs by detecting the expression of neural crest markers.

Establishment and neural differentiation of neural crest-derived stem cells from human dental pulp in serum-free conditions.

The potential of obtaining cell cultures with neural crest resemblance (neural crest-derived stem cells [NCSCs]) from dental-related tissues, including human dental pulp cells (hDPCs), has been discussed in the literature. However, most reports include the use of serum-rich conditions and do not describe the potential for neural differentiation, slowing translation to the clinic. Therefore, we aimed to culture and characterize NCSCs from the human dental pulp in vitro and evaluate their ability to differentiate into neurons; we also investigated the effectiveness of the addition of BMP4 to enhance this potential.

Generation of Otic Lineages from Integration-Free Human-Induced Pluripotent Stem Cells Reprogrammed by mRNAs.

Damage to the sensory hair cells and the spiral ganglion neurons of the cochlea leads to deafness. Induced pluripotent stem cells (iPSCs) are a promising tool to regenerate the cells in the inner ear that have been affected by pathology or have been lost. To facilitate the clinical application of iPSCs, the reprogramming process should minimize the risk of introducing undesired genetic alterations while conferring the cells the capacity to differentiate into the desired cell type.

The use of animal models to study cell transplantation in neuropathic hearing loss.

Auditory neuropathy (AN) is a form of sensorineural deafness specifically affecting the conduction of the nerve impulse from the cochlear hair cells to the auditory centres of the brain. As such, the condition is a potential clinical target for 'cell replacement therapy', in which a functioning auditory nerve is regenerated by transplanting an appropriated neural progenitor. In this review, we survey the current literature and examine possible experimental models for this condition, with particular reference to their compatibility as suitable hosts for transplantation.

Building an Artificial Stem Cell Niche: Prerequisites for Future 3D-Formation of Inner Ear Structures-Toward 3D Inner Ear Biotechnology.

In recent years, there has been an increased interest in stem cells for the purpose of regenerative medicine to deliver a wide range of therapies to treat many diseases. However, two-dimensional cultures of stem cells are of limited use when studying the mechanism of pathogenesis of diseases and the feasibility of a treatment. Therefore, research is focusing on the strengths of stem cells in the three-dimensional (3D) structures mimicking organs, that is, organoids, or organ-on-chip, for modeling human biology and disease.

Science-based assessment of source materials for cell-based medicines: report of a stakeholders workshop.

Human pluripotent stem cells (hPSCs) have the potential to transform medicine. However, hurdles remain to ensure safety for such cellular products. Science-based understanding of the requirements for source materials is required as are appropriate materials.

Neuronal differentiation of hair-follicle-bulge-derived stem cells co-cultured with mouse cochlear modiolus explants.

Stem-cell-based repair of auditory neurons may represent an attractive therapeutic option to restore sensorineural hearing loss. Hair-follicle-bulge-derived stem cells (HFBSCs) are promising candidates for this type of therapy, because they (1) have migratory properties, enabling migration after transplantation, (2) can differentiate into sensory neurons and glial cells, and (3) can easily be harvested in relatively high numbers. However, HFBSCs have never been used for this purpose.

Isolation, expansion and neural differentiation of stem cells from human plucked hair: a further step towards autologous nerve recovery.

Stem cells from the adult hair follicle bulge can differentiate into neurons and glia, which is advantageous for the development of an autologous cell-based therapy for neurological diseases. Consequently, bulge stem cells from plucked hair may increase opportunities for personalized neuroregenerative therapy. Hairs were plucked from the scalps of healthy donors, and the bulges were cultured without prior tissue treatment.

Aminoglycoside ototoxicity and hair cell ablation in the adult gerbil: A simple model to study hair cell loss and regeneration.

The Mongolian gerbil, Meriones unguiculatus, has been widely employed as a model for studies of the inner ear. In spite of its established use for auditory research, no robust protocols to induce ototoxic hair cell damage have been developed for this species. In this paper, we demonstrate the development of an aminoglycoside-induced model of hair cell loss, using kanamycin potentiated by the loop diuretic furosemide.

New strategies for the restoration of hearing loss: challenges and opportunities.

Introduction: For most types of hearing impairments, a definitive therapy would rest on the ability to restore hair cells and the spiral ganglion neurons. The only established technique to treat deafness is based on the functional replacement of hair cells with a cochlear implant, but this still has important limitations.

Sources Of Data: A systematic revision of the relevant literature is presented.

Generation of inner ear sensory cells from bone marrow-derived human mesenchymal stem cells.

Aim: Hearing loss is the most common sensory disorder in humans, its main cause being the loss of cochlear hair cells. We studied the potential of human mesenchymal stem cells (hMSCs) to differentiate towards hair cells and auditory neurons.

Materials & Methods: hMSCs were first differentiated to neural progenitors and subsequently to hair cell- or auditory neuron-like cells using in vitro culture methods.

Inner ear progenitor cells can be generated in vitro from human bone marrow mesenchymal stem cells.

Aim: Mouse mesenchymal stem cells (MSCs) can generate sensory neurons and produce inner ear hair cell-like cells. An equivalent source from humans is highly desirable, given their potential application in patient-specific regenerative therapies for deafness. In this study, we explored the ability of human MSCs (hMSCs) to differentiate into otic lineages.

Restoration of auditory evoked responses by human ES-cell-derived otic progenitors.

Deafness is a condition with a high prevalence worldwide, produced primarily by the loss of the sensory hair cells and their associated spiral ganglion neurons (SGNs). Of all the forms of deafness, auditory neuropathy is of particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells, is responsible for a substantial proportion of patients with hearing impairment.

Neural crest stem cells and their potential application in a therapy for deafness.

Neurosensory hearing loss is a common condition that has major social and economic implications. Recent advances in stem cell research and in cochlear implantation are offering renewed hopes to people suffering from damage to the auditory hair cells and their associated neurons. Several putative donor cell types are currently being explored, including embryonic stem cells, different types of adult stem cell and the recently described induced-pluripotent stem cells.

Stem cell based therapy in the inner ear: appropriate donor cell types and routes for transplantation.

Losing one of our main sensory systems such as hearing can have devastating consequences in the way we interact with the world. The main problem lies in the fact that the critical sensory cells, the auditory neurons and hair cells located in the cochlea are only generated during development and, when damaged, cannot be replaced. The options currently available to treat this condition are very limited, and are mostly represented by prosthetic devices such as hearing aids and cochlear implants.

Stem cells and cell lines from the human auditory organ: applications, hurdles and bottlenecks in the development of regenerative therapies for deafness.

The development of any stem-cell-based therapy (and a potential one for deafness is no exception) relies on the generation of the necessary tools: 'cell drugs' that can be safely manufactured for their clinical application. An increasing body of work has focussed on the identification, in animal models, of potential stem cell sources that could have an application for regenerative therapy in the auditory organ. A still more circumscribed effort--owing to ethical and technical difficulties--aims to obtain the actual potential therapeutic candidates (i.

Synaptotagmin IV determines the linear Ca2+ dependence of vesicle fusion at auditory ribbon synapses.

Mammalian cochlear inner hair cells (IHCs) are specialized for the dynamic coding of continuous and finely graded sound signals. This ability is largely conferred by the linear Ca(2+) dependence of neurotransmitter release at their synapses, which is also a feature of visual and olfactory systems. The prevailing hypothesis is that linearity in IHCs occurs through a developmental change in the Ca(2+) sensitivity of synaptic vesicle fusion from the nonlinear (high order) Ca(2+) dependence of immature spiking cells.

Human fetal auditory stem cells can be expanded in vitro and differentiate into functional auditory neurons and hair cell-like cells.

In the quest to develop the tools necessary for a cell-based therapy for deafness, a critical step is to identify a suitable stem cell population. Moreover, the lack of a self-renovating model system for the study of cell fate determination in the human cochlea has impaired our understanding of the molecular events involved in normal human auditory development. We describe here the identification and isolation of a population of SOX2+OCT4+ human auditory stem cells from 9-week-old to 11-week-old fetal cochleae (hFASCs).

The human fetal cochlea can be a source for auditory progenitors/stem cells isolation.

The development of new stem cell-based technologies is creating new hopes in regenerative medicine. Hearing-impaired individuals should benefit greatly from the development of a cell-based regenerative strategy to treat deafness. An important achievement would be to develop a human-based system that could bring the advances made in animal models closer to clinical application.

Generation of inner ear cell types from embryonic stem cells.

The senses of hearing and balance are mediated by hair cells located in the cochlea and in the vestibular organs of the vertebrate inner ear. Loss of hair cells and other cell types of the inner ear results in hearing and balance disorders that substantially diminish the quality of life. The irreversibility of hearing loss in mammals is caused by the inability of the cochlea to replace lost hair cells.

GATA3 and NeuroD distinguish auditory and vestibular neurons during development of the mammalian inner ear.

The function of the zinc finger transcription factor GATA3 was studied in a newly established, conditionally immortal cell line derived to represent auditory sensory neuroblasts migrating from the mouse otic vesicle at embryonic day E10.5. The cell line, US/VOT-33, expressed GATA3, the bHLH transcription factor NeuroD and the POU-domain transcription factor Brn3a, as do auditory neuroblasts in vivo.

Cell lines in inner ear research.

Cell lines have provided important experimental tools that have enhanced our understanding of neural and sensory function. They are particularly valuable in inner ear research because the auditory and vestibular systems are small, complex, and encased in several layers of bone. Organotypic cultures provide an invaluable experimental resource but require repeated microdissection and culture, and remain complex in terms of cell types and states of differentiation.

E-cadherin and the differentiation of mammalian vestibular hair cells.

E-cadherin is expressed in vestibular, mechanosensory epithelia during early embryonic development. During late embryonic and neonatal stages it is expressed in supporting cells but down-regulated in differentiating sensory hair cells. We used a conditionally immortal cell line (UB/UE-1) from the neonatal mouse utricle to test the hypothesis that constitutive expression of E-cadherin inhibits the progression of hair cell differentiation.