Degeneration of spiral ganglion neurons (SGNs) results in permanent sensorineural hearing loss (SNHL) and is irreversible. Transplantation of exogenous neural stem cells (NSCs) offers a promising therapeutic strategy for the treatment of a variety of neural degenerative disorders including SNHL. However, studies of various animal models of neurodegenerative diseases indicate that the time window for the successful transplantation of NSCs after injury is narrow, and that long-term survival and functional integration of NSCs is limited, particularly, in the chronically degenerated host environment. Despite the assumption that a favorable microenvironment is required for the survival and appropriate differentiation of NSCs after transplantation, little attention has been paid to exactl how the host microenvironment affects the behavior of transplanted NSCs. To address this gap, we have documented that survival of transplanted NSCs is significantly greater in the injured auditory nerve at early post-injury intervals compared to later post-injury intervals using a well-characterized animal model of ouabain-induced acute SGN injury. More recently, we have shown that acute SGN injury induces up-regulation of Sox2, a transcription factor that is highly expressed in undifferentiated neural cells during development and adult neurogenesis and gliogenesis. This up-regulation, along with the proliferation of Sox2+ glial cells in the injured adult auditory nerve, suggests that mature glial cells can revert to a less differentiated phenotype and re-enter the cell cycle in response to acute SGN injury. Based on these new findings, we hypothesize that SGN injury stimulates the quiescent glial cells to undergo a phenotypic transformation resulting in a microenvironment more conducive to the survival and differentiation of transplanted NSCs. The objective of this project is to determine the role of the host microenvironment, with a focus on endogenous glial cells, in regulating the survival and differentiation of transplanted NSCs. We will characterize phenotypic changes of glial cells in response to acute SGN injury (Aim 1);determine the mechanisms whereby acute injury-induced glial phenotypic changes mediate NSC survival and differentiation in vitro (Aim 2);and determine the ability of de-differentiated glial cells to influence the survival, neuronal differentiation and morphological integration of transplanted NSCs in vivo (Aim 3). The proposed experiments will reveal 1) the key molecular factors associated with glial cell phenotypic changes in response to SGN injury and 2) the molecular mechanisms promoting the survival of transplanted NSCs by de-differentiated glial cells. Such data will provide answers to basic questions about glial cell biology and establish in vitro and in vivo models for studies of glial cells in the auditory system. In addition, information obtained will be of great public health interest for the design of therapeutic strategies for SNHL and other neurodegenerative disorders using glial cells as targets.
The proposed studies will provide new knowledge of how changes in the microenvironment of the inner ear influence the outcome of stem cell transplantation. In particular, we will establish the critical roles glial cells play in regulatingthe survival and development of the transplanted stem cells. Such knowledge will impact the design of efficient therapies for sensorineural hearing loss and other neurodegenerative disorders using glial cells as targets.
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