Reprogramming Glia Into Neurons in the Peripheral Auditory System as a Solution for Sensorineural Hearing Loss: Lessons From the Central Nervous System

Abstract

Disabling hearing loss affects over 5% of the world's population and impacts the lives of individuals from all age groups. Within the next three decades, the worldwide incidence of hearing impairment is expected to double. Since a leading cause of hearing loss is the degeneration of primary auditory neurons (PANs), the sensory neurons of the auditory system that receive input from mechanosensory hair cells in the cochlea, it may be possible to restore hearing by regenerating PANs. A direct reprogramming approach can be used to convert the resident spiral ganglion glial cells into induced neurons to restore hearing. This review summarizes recent advances in reprogramming glia in the CNS to suggest future steps for regenerating the peripheral auditory system. In the coming years, direct reprogramming of spiral ganglion glial cells has the potential to become one of the leading biological strategies to treat hearing impairment.

Keywords: brain; ear; hearing loss; in vivo; regeneration; reprogramming; tissue repair.

FIGURE 1

Primary auditory neurons (PANs) innervate sensory hair cells in the cochlea. (A) Cross-section through a neonatal mouse cochlea showing spiral ganglion glial cells labeled with Sox2 (green nuclei) surrounding PANs labeled with TuJ1 (red) in the spiral ganglion (SG). PANs innervate mechanosensory hair cells labeled with the specific hair cell marker Myosin7a (white) in the organ of Corti (OC). (B) Higher magnification image of the spiral ganglion showing the PANs (red) and surrounding glial cells (green).

FIGURE 2

Reprogramming glial cells into neurons in vivo. (A) Schematic identifying source cell populations that have been converted into induced neurons either in vitro or in vivo. Induced neurons have been derived from several distinct cell populations in the brain, spinal cord and inner ear. Many of these cells include glial cell types. Peripheral glia (red) are suggested targets for future reprogramming efforts in the inner ear. (B) Schematic identifying the auditory circuit leading from the organ of Corti within the inner ear, through the spiral ganglion and ultimately to the cochlear nucleus within the brainstem. Type I PANs (red) form multiple synapses with inner hair cells (IHC) and Type II PANs (gray) innervate outer hair cells (OHC). Glia (green) are interspersed with PANs in the spiral ganglion. Afferent fibers from both PAN subtypes project to the cochlear nucleus based on their unique characteristics, establishing a tonotopic map. AVCN, anterior ventral cochlear nucleus; DCN, dorsal cochlear nucleus; PVCN, posterior ventral cochlear nucleus.