Schwann cells in the inner ear: development, disease, and regeneration

Abstract

Schwann cells are classically known as the constituent supporting cells of the peripheral nervous system. Beyond the scope of merely myelinating axons of the more saliently known neurons, Schwann cells comprise the majority of peripheral nervous system tissue. Through the lens of the inner ear, additional properties of Schwann cells are becoming elucidated. Therein, the process of myelin formation in development is more aptly understood as a homeostatic oscillation of differentiation status. Perpetual interaction between neural and non-neural cells of the inner ear maintains an intricate balance of guidance, growth, and maturation during development. In disease, aberration to Schwann cell myelination contributes to sensorineural hearing loss in conditions such as Guillain-Barre Syndrome and Charcot-Marie-Tooth disease, and tumorigenic over proliferation of Schwann cells defines vestibular schwannomas seen in neurofibromatosis type 2. Schwann cells demonstrate plasticity during oscillations between differentiation and dedifferentiation, a property that is now being leveraged in efforts to regenerate lost neurons. Emerging strategies of reprogramming, small molecule modulation, and gene therapy suggest that Schwann cells could serve as progenitor cells for regenerated neurons. Understanding the duality of Schwann cells in pathology and repair could transform the approach to treating sensorineural hearing loss.

Keywords: NF2; Schwann cells; cochlea; glia; inner ear; myelin; regeneration; schwannoma.

Figure 1

Cochlear structure and glial cell anatomy. This figure illustrates the anatomical structure of the cochlea with a focus on the cellular components involved in hair cell innervation by spiral ganglion neurons and the associated glial interactions. The left upper panel shows a schematic of the inner ear, highlighting the cochlea. The right upper panel shows a magnified cross-sectional view of the cochlear duct. The bottom panel provides a depiction of an inner hair cell within the organ of Corti and adjacent structures. The inner hair cell is innervated by the peripheral processes of spiral ganglion neurons. The peripheral processes are myelinated by Schwann cells. Within the spiral ganglion, neuronal cell bodies are surrounded by satellite glial cells. This figure highlights the spatial relationships between the inner hair cells that compose the sensory epithelium, spiral ganglion neurons, Schwann cells, and satellite glia. Created in BioRender. Montigny, D. (2025) https://BioRender.com/3b16cek.

Figure 2

Myelination and dedifferentiation via ErbB2 and TrkC signaling. This schematic illustrates molecular signaling pathways that influence Schwann cell myelination and dedifferentiation in response to axonal feedback. Neuregulin1 and Neurotrophin-3 are key ligands interacting with ErbB2 on Schwann cells and TrkC on axons, respectively. On the left side, Neurotrophin-3 from Schwann cells binds TrkC on axons, leading to Neuregulin1 signaling from axons which will then bind ErbB2, reinforcing myelination in a homeostatic manner. When this process is disrupted, the Schwann cell will trend toward dedifferentiation, and no longer produce Neurotrophin-3. TrkC is likewise not bound, and the axon does not produce Neuregulin1, subsequently not binding ErbB2, reinforcing the de-differentiated state. Created in BioRender. Montigny, D. (2025) https://BioRender.com/gdz3ihk.

Figure 3

Histologic and immunohistochemical human temporal bone samples with Schwannoma involvement. This figure presents hematoxylin and eosin (H&E) stained and SOX10 immunolabeled images for human temporal bone sections highlighting glial pathology and anatomy. Panel (A) shows a low-magnification H&E-stained section of a human temporal one containing a vestibular schwannoma from a patient with neurofibromatosis type 2-associated schwannomatosis (NF2-SWN) occupying the internal auditory canal, illustrating schwannoma localization to inner ear structures. Panel (B) shows higher magnification view focusing on the spiral ganglion, where spiral ganglion neurons and glia reside. Panels (C, D) show immunofluorescent labeling of SOX10, a nuclear glial cell marker, within the spiral ganglia. Panel (D) includes yellow arrows indicating examples of SOX10+ nuclei, emphasizing the presence and distribution of glial cells within the ganglia. These images demonstrate both histological architecture of glial cell populations and pathological human cochlear tissue.

Figure 4

Summary diagram of Schwann cell development, myelination, and pathology in homeostasis and disease. This figure summarizes the developmental origins, pathways of differentiation, and potential outcomes of Schwann cells, highlighting their dynamic roles in homeostasis and pathology. Starting from neural crest cells and later progressing to Schwann cell precursors before developing further to pro-myelinating and mature myelinating Schwann cells. Healthy myelinating Schwann cells interact with neurons through a Neuregulin1/Neurotrophin-3 mediated axis, while myelinopathy or loss of healthy neural tissue can disrupt this feedback loop. Downstream outcomes in pathological states can lead to myelinopathy and subsequent de-differentiation leading to a less differentiated state. It is in this state that Schwann cells can proliferate transiently, leading to formation of a glial scar, or proliferate continuously leading to a schwannoma, or alternatively, be prompted toward a neural fate through cellular reprogramming or transdifferentiation. Created in BioRender. Montigny, D. (2025) https://BioRender.com/s9fe79f.