Transplantation of Mouse Embryonic Stem Cells into the Cochlea of an Auditory-Neuropathy Animal Model: Effects of Timing after Injury

Abstract

Application of ouabain to the round window membrane of the gerbil selectively induces the death of most spiral ganglion neurons and thus provides an excellent model for investigating the survival and differentiation of embryonic stem cells (ESCs) introduced into the inner ear. In this study, mouse ESCs were pretreated with a neural-induction protocol and transplanted into Rosenthal's canal (RC), perilymph, or endolymph of Mongolian gerbils either 1-3 days (early post-injury transplant group) or 7 days or longer (late post-injury transplant group) after ouabain injury. Overall, ESC survival in RC and perilymphatic spaces was significantly greater in the early post-injury microenvironment as compared to the later post-injury condition. Viable clusters of ESCs within RC and perilymphatic spaces appeared to be associated with neovascularization in the early post-injury group. A small number of ESCs transplanted within RC stained for mature neuronal or glial cell markers. ESCs introduced into perilymph survived in several locations, but most differentiated into glia-like cells. ESCs transplanted into endolymph survived poorly if at all. These experiments demonstrate that there is an optimal time window for engraftment and survival of ESCs that occurs in the early post-injury period.

Inhalation of hydrogen gas attenuates ouabain-induced auditory neuropathy in gerbils

“…However, ouabain did not damage the morphology of the cochlear hair cells. These results demonstrate that the local npg administration of ouabain successfully induced the AN model in gerbils in this study, which is consistent with previous studies [17][18][19] .…”

“…Following application of ouabain into the round window (RW) niche of gerbil, the animals showed relatively normal otoacoustic emissions and cochlear microphonics in conjunction with increased thresholds for cochlear whole-nerve action potentials (CAPs) and ABRs [17][18][19] . The ouabain-induced AN model has been shown to selectively and permanently destroy most spiral ganglion neurons (SGNs) with little effect on the morphology and function of the sensory hair cells and the cells in the cochlear lateral wall [17][18][19] . Thus, the ouabain-exposed gerbil is believed to be a reliable model of human AN [17] .…”

Ouabain-Induced Cochlear Nerve Degeneration: Synaptic Loss and Plasticity in a Mouse Model of Auditory Neuropathy

“…Several prior studies (Schmiedt et al, 2002;Lang et al, 2005;Lang et al, 2008) have shown that ouabain application to the round window area can cause dramatic attenuation of cochlear neural responses, such as the ABR or the compound action potential, without significantly affecting responses that do not require cochlear synaptic transmission, such as the DPOAEs.…”

“…One particularly powerful one was first discovered in the gerbil, where repeated application of ouabain to the round window membrane, designed as a means to cause strial atrophy, was instead seen to cause massive degeneration of the type-I spiral ganglion cells innervating the inner hair cells (Schmiedt et al, 2002), without significant loss of hair cells, and with preservation of hair cell function, at least as seen via otoacoustic emissions (Lang et al, 2005;Lang et al, 2008).…”

“…This neuropathic model has generated significant interest, mainly because of its utility in experiments designed to test the ability of transplanted neural progenitors to survive, grow, and re-innervate a denervated organ of Corti (Corrales et al, 2006;Lang et al, 2008;Chen et al, 2012). Such experiments could pave the way for cell-based therapies for auditory neuropathy, i.e., human hearing loss characterized by primary neural degeneration in the cochlea (Starr et al, 1996).…”