Forgotten Fibrocytes: A Neglected, Supporting Cell Type of the Cochlea With the Potential to be an Alternative Therapeutic Target in Hearing Loss

Furness, David N.

doi:10.3389/fncel.2019.00532

Cited by 29 publications

(30 citation statements)

References 68 publications

(93 reference statements)

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“…Similarly, the vestibular dark cells arise from the otocyst and associated melanocytes from the neural crest [91]. Dysfunction of these epithelia can lead to metabolic hearing loss and vestibular dysfunction [92,93]. The ionic regulatory cell types have not been described yet in hPSC-derived inner ear models.…”

Section: Epitheliamentioning

confidence: 99%

Building inner ears: recent advances and future challenges for in vitro organoid systems

et al. 2020

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While inner ear disorders are common, our ability to intervene and recover their sensory function is limited. In vitro models of the inner ear, like the organoid system, could aid in identifying new regenerative drugs and gene therapies. Here, we provide a perspective on the status of in vitro inner ear models and guidance on how to improve their applicability in translational research. We highlight the generation of inner ear cell types from pluripotent stem cells as a particularly promising focus of research. Several exciting recent studies have shown how the developmental signaling cues of embryonic and fetal development can be mimicked to differentiate stem cells into “inner ear organoids” containing otic progenitor cells, hair cells, and neurons. However, current differentiation protocols and our knowledge of embryonic and fetal inner ear development in general, have a bias toward the sensory epithelia of the inner ear. We propose that a more holistic view is needed to better model the inner ear in vitro. Moving forward, attention should be made to the broader diversity of neuroglial and mesenchymal cell types of the inner ear, and how they interact in space or time during development. With improved control of epithelial, neuroglial, and mesenchymal cell fate specification, inner ear organoids would have the ability to truly recapitulate neurosensory function and dysfunction. We conclude by discussing how single-cell atlases of the developing inner ear and technical innovations will be critical tools to advance inner ear organoid platforms for future pre-clinical applications.

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Section: Epitheliamentioning

confidence: 99%

Building inner ears: recent advances and future challenges for in vitro organoid systems

et al. 2020

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“…One crucial function is the maintenance of an endocochlear potential (EP) of +80 mV in the scale media (14). To enable this, SLFs display a unique ion permeability system.…”

Section: Ion Homeostasis and The Epmentioning

confidence: 99%

“…This may play a key role in maintaining a positive RMP of +5 to +12 mV in SLF (15). As a result, the positive RMP contributes to ionic gradients that enable the development of an EP of +80 mV in the endolymph, which is needed for normal hearing function (14). Multiple ion channels and proteins are expressed on the surface of different types of SLFs, to further increase the RMP ( Table 1).…”

Section: Ion Homeostasis and The Epmentioning

confidence: 99%

“…SLFs play an important role in the inflammatory response toward environmental insults such as bacterial infections, noise trauma, ototoxic drugs, etc. SLFs are able to secrete anti-inflammatory chemokines to protect the cochlea from inflammation leading to hearing impairment (14,27). Several studies have demonstrated that SLFs secrete monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), intercellular adhesion molecule-1 (ICAM-1), and vascular endothelial growth factor (VEGF) after stimulation by interleukin 1 (IL-1) and/or tumor necrosis factor α (TNFα).…”

Section: Immune Responsementioning

confidence: 99%

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On the Role of Fibrocytes and the Extracellular Matrix in the Physiology and Pathophysiology of the Spiral Ligament

et al. 2020

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The spiral ligament in the cochlea has been suggested to play a significant role in the pathophysiology of different etiologies of strial hearing loss. Spiral ligament fibrocytes (SLFs), the main cell type in the lateral wall, are crucial in maintaining the endocochlear potential and regulating blood flow. SLF dysfunction can therefore cause cochlear dysfunction and thus hearing impairment. Recent studies have highlighted the role of SLFs in the immune response of the cochlea. In contrast to sensory cells in the inner ear, SLFs (more specifically type III fibrocytes) have also demonstrated the ability to regenerate after different types of trauma such as drug toxicity and noise. SLFs are responsible for producing proteins, such as collagen and cochlin, that create an adequate extracellular matrix to thrive in. Any dysfunction of SLFs or structural changes to the extracellular matrix can significantly impact hearing function. However, SLFs may prove useful in restoring hearing by their potential to regenerate cells in the spiral ligament.

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“…Notably, CAT (asterisk and arrows in Figure 6B), GPX1 (asterisk and arrows in Figure 8C) and SOD1 (asterisk and arrows in Figure 10B) -stained fibrocytes were identified in the spiral ligament. Based on previous studies [33,40,41], they were mostly characterized as type I and III. At the latest time point assessed (30 days), immunostaining for all three antioxidant enzymes in all the above-mentioned cochlear structures was decreased in the noise-exposed cochlea ( Figures 5C, 5I and 6C for CAT; 7D, 7L and 8D for GPX1; 9C, 9I and 10C for SOD1) but it still remained elevated relative to unexposed controls.…”

Section: Distribution Of Immunostaining For Antioxidant Enzymes and Amentioning

confidence: 99%

Oral Antioxidant Vitamins and Magnesium Limit Noise-induced Hearing Loss by Promoting Sensory Hair Cell Survival: Role of Antioxidant Enzymes and Apoptosis Genes

Alvarado

Fuentes–Santamaría

Melgar–Rojas

et al. 2020

Preprint

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Noise induces oxidative stress in the cochlea followed by sensory cell death and hearing loss. The proof of principle that injections of antioxidant vitamins and Mg2+ prevent noise-induced hearing loss (NIHL) has been established. However, effectiveness of oral administration remains controversial and otoprotection mechanisms unclear. Using auditory evoked potentials, quantitative PCR and immunocytochemistry, we explored effects of oral administration of vitamins A, C, E and Mg2+ (ACEMg) on auditory function and sensory cell survival following NIHL in rats. Oral ACEMg reduced auditory thresholds shifts after NIHL. Improved auditory function correlated with increased survival of sensory outer hair cells. In parallel, oral ACEMg modulated the expression timeline of antioxidant enzymes in the cochlea after NIHL. There was increased expression of Glutathione peroxidase-1 and Catalase at 1 and 10 days, respectively. Also, pro-apoptotic Caspase-3 and Bax levels were diminished in ACEMg-treated rats, at 10 and 30 days, respectively, following noise overstimulation, whereas, at day 10 after noise exposure, the levels of anti-apoptotic Bcl-2, were significantly increased. Therefore, oral ACEMg improves auditory function by limiting sensory hair cell death in the auditory receptor following NIHL. Regulation of the expression of antioxidant enzymes and apoptosis-related proteins in cochlear structures is involved in such otoprotective mechanism.

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Forgotten Fibrocytes: A Neglected, Supporting Cell Type of the Cochlea With the Potential to be an Alternative Therapeutic Target in Hearing Loss

Cited by 29 publications

References 68 publications

Building inner ears: recent advances and future challenges for in vitro organoid systems

Building inner ears: recent advances and future challenges for in vitro organoid systems

On the Role of Fibrocytes and the Extracellular Matrix in the Physiology and Pathophysiology of the Spiral Ligament

Oral Antioxidant Vitamins and Magnesium Limit Noise-induced Hearing Loss by Promoting Sensory Hair Cell Survival: Role of Antioxidant Enzymes and Apoptosis Genes

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