Hearing loss and vestibular schwannoma: new insights into Schwann cells implication

Abstract

Hearing loss (HL) is the most common and heterogeneous disorder of the sensory system, with a large morbidity in the worldwide population. Among cells of the acoustic nerve (VIII cranial nerve), in the cochlea are present the hair cells, the spiral ganglion neurons, the glia-like supporting cells, and the Schwann cells (SCs), which alterations have been considered cause of HL. Notably, a benign SC-derived tumor of the acoustic nerve, named vestibular schwannoma (VS), has been indicated as cause of HL. Importantly, SCs are the main glial cells ensheathing axons and forming myelin in the peripheral nerves. Following an injury, the SCs reprogram, expressing some stemness features. Despite the mechanisms and factors controlling their biological processes (i.e., proliferation, migration, differentiation, and myelination) have been largely unveiled, their role in VS and HL was poorly investigated. In this review, we enlighten some of the mechanisms at the base of SCs transformation, VS development, and progression, likely leading to HL, and we pose great attention on the environmental factors that, in principle, could contribute to HL onset or progression. Combining the biomolecular bench-side approach to the clinical bedside practice may be helpful for the diagnosis, prediction, and therapeutic approach in otology.

Fig. 1

Schematic representation of main cells forming the auditory structure in the organ of Corti, including the afferent fibers and the glial cells.

Fig. 2. Causes of hearing loss (HL) and vestibular schwannoma (VS).

A Illustration of HL and demyelination of Schwann cells (SCs). Among many different etiologies of sensorineural HL (SNHL), the extensive loss of the myelinated axonal processes in the auditory nerve may be followed by alteration or degeneration of hair cells (HCs) and spiral ganglion neurons (SGNs). The resulting degenerative process reduces the neuronal capability in initiating and propagating action potentials in response to electrical stimuli, leading to nerve conduction vulnerability. B Anatomical illustration of the internal ear structures affected by VS (also called acoustic neurinoma).

Fig. 3. Vestibular schwannoma (VS) pathogenic mechanisms.

Genetic mutations in the neurofibromin 2 gene (coding for the protein merlin), but also in other genes (e.g., LZTR1, SMARCB1, or COQ6, RAD54B) cause VS. Also the exposure to electromagnetic field (EMF) and macrophages activation, potentially, might be cause of VS. From a biomolecular point of view, these triggers induce upregulation and activation of some signaling pathways in Schwann cells (SCs), such as Rac1, PAK1, EGFR-Ras-ERK, PI3K-Akt, mTORC1, and Wnt, concomitant with a de-regulation of the Hippo-YAP/TAZ signaling. As a result, SCs growth and migrate, giving the oncotransformation into VS.

Fig. 4. Exposure to electromagnetic field (EMF) might potentially induce changes in the Schwann cells (SCs) of the auditory nerve.

Findings obtained from in vitro experiments in rat, even limited by the lack of corresponding data in humans, suggested that SCs exposed to the EMF showed modification in cell proliferation, migration, and differentiation, mediated through an activation of the Hippo transcriptional co-activators YAP/TAZ [114, 115]. Generally, the protein complex YAP/TAZ shuttles between the cytoplasm and the nucleus (see upper part of the figure). When Hippo is on, the oncosuppressor merlin activates the kinase LATS1/2, that in turn phosphorylate YPA/TAZ causing its cytoplasmic retention; thus, the gene expression is inhibited. When Hippo is off, YAP/TAZ moves into the nucleus, links some transcription factors and stimulates the gene expression. When SCs are exposed to EMFs, other proteins downstream merlin, mostly involved in cell polarity, such as Amotl2 and Crb (see the text) are modulated, determining the loss of SCs adhesion and the increase in migration [115]. In parallel, changes in metabolic pathways related to translation and mitochondrial activities, were observed [116]. Notably, the EMF exposure of SCs induces the gene expression alteration of some other genes involved in hearing loss, such as NEFL, TPRN, HMOX1, OTOGL, GJB2, and REST (see the text).