Non-autonomous Cellular Responses to Ototoxic Drug-Induced Stress and Death

Abstract

The first major recognition of drug-induced hearing loss can be traced back more than seven decades to the development of streptomycin as an antimicrobial agent. Since then at least 130 therapeutic drugs have been recognized as having ototoxic side-effects. Two important classes of ototoxic drugs are the aminoglycoside antibiotics and the platinum-based antineoplastic agents. These drugs save the lives of millions of people worldwide, but they also cause irreparable hearing loss. In the inner ear, sensory hair cells (HCs) and spiral ganglion neurons (SGNs) are important cellular targets of these drugs, and most mechanistic studies have focused on the cell-autonomous responses of these cell types in response to ototoxic stress. Despite several decades of studies on ototoxicity, important unanswered questions remain, including the cellular and molecular mechanisms that determine whether HCs and SGNs will live or die when confronted with ototoxic challenge. Emerging evidence indicates that other cell types in the inner ear can act as mediators of survival or death of sensory cells and SGNs. For example, glia-like supporting cells (SCs) can promote survival of both HCs and SGNs. Alternatively, SCs can act to promote HC death and inhibit neural fiber expansion. Similarly, tissue resident macrophages activate either pro-survival or pro-death signaling that can influence HC survival after exposure to ototoxic agents. Together these data indicate that autonomous responses that occur within a stressed HC or SGN are not the only (and possibly not the primary) determinants of whether the stressed cell ultimately lives or dies. Instead non-cell-autonomous responses are emerging as significant determinants of HC and SGN survival vs. death in the face of ototoxic stress. The goal of this review is to summarize the current evidence on non-cell-autonomous responses to ototoxic stress and to discuss ways in which this knowledge may advance the development of therapies to reduce hearing loss caused by these drugs.

Necroptosis and apoptosis contribute to cisplatin and aminoglycoside ototoxicity

“…A hair cell with necroptotic response thus would only make sense if the inner ear was not “immune privileged” as historically assumed but was capable of mounting a significant immunological response. In fact, more recent studies suggest that the resolution of ototoxic insults is aided by immune cells infiltrating into the inner ear (Kaur, 2015; Kaur et al, 2015, 2018; Francis and Cunningham, 2017; Mizushima et al, 2017; Wood and Zuo, 2017; Barald et al, 2018; Liu et al, 2018). Such immune activity, beneficial under normal circumstances, might become counterproductive when ototoxins overwhelm the system, creating a massive, detrimental immune response.…”

Transcriptional reprogramming in fused cells is triggered by plasma-membrane diminution

“…Another representative feature shared by different syncytia is the loss of their competence to enter the cell cycle (Chuprin et al, 2013;Duelli and Lazebnik, 2003;Goldman-Wohl and Yagel, 2014). To test whether VSV-G mediated cell fusion leads to cell cycle arrest, we measured the levels of the cell cycle arrest marker P21 (Sherr and Roberts, 1995).…”

“…Upon fusion, plasma membranes and cytoplasmic content from fusing cells are combined to form the new syncytium. The resulting multi-nucleated syncytia can be comprised of hundreds to millions of cells, creating a unique cellular environment in which individual nuclei stop dividing and differentiation programs are deployed to promote overall homeostasis within the fused cells (Mayhew and Simpson, 1994) (Goldman-Wohl and Yagel, 2014;Zhou and Platt, 2011). This physical transformation suggests an underlying process controlling syncytial differentiation.…”

Supporting cell survival after cochlear implant surgery

“…As reviewed by Monzack and Cunningham, cochlear SCs are responsible for critical functions in the inner ear, including the maintenance of both spiral ganglion neurons and hair cells . In response to ototoxic stress causing damage or death of hair cells and spiral ganglion neurons, SCs serve to limit the extent of injury and facilitate recovery . In the presence of damage to hair cells, avian auditory and vestibular SCs, as well as some mammalian vestibular SCs, have the capacity to transdifferentiate and replace hair cells .…”

“…2 In response to ototoxic stress causing damage or death of hair cells and spiral ganglion neurons, SCs serve to limit the extent of injury and facilitate recovery. 3 In the presence of damage to hair cells, avian auditory and vestibular SCs, as well as some mammalian vestibular SCs, have the capacity to transdifferentiate and replace hair cells. 4 However, in the adult mammalian cochlea, mature auditory hair cells cannot regenerate after injury, which results in permanent hearing loss.…”