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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC012058-02
Application #
8507714
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2012-07-10
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$350,313
Indirect Cost
$112,813
Name
Medical University of South Carolina
Department
Pathology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Panganiban, Clarisse H; Barth, Jeremy L; Darbelli, Lama et al. (2018) Noise-induced dysregulation of Quaking RNA binding proteins contributes to auditory nerve demyelination and hearing loss. J Neurosci :
Noble, Kenyaria V; Reyzer, Michelle L; Barth, Jeremy L et al. (2018) Use of Proteomic Imaging Coupled With Transcriptomic Analysis to Identify Biomolecules Responsive to Cochlear Injury. Front Mol Neurosci 11:243
Brown, LaShardai N; Xing, Yazhi; Noble, Kenyaria V et al. (2017) Macrophage-Mediated Glial Cell Elimination in the Postnatal Mouse Cochlea. Front Mol Neurosci 10:407
Lang, Hainan; Nishimoto, Eishi; Xing, Yazhi et al. (2016) Contributions of Mouse and Human Hematopoietic Cells to Remodeling of the Adult Auditory Nerve After Neuron Loss. Mol Ther 24:2000-2011
Stevens, Shawn M; Brown, LaShardai N; Ezell, Paula C et al. (2015) The Mouse Round-window Approach for Ototoxic Agent Delivery: A Rapid and Reliable Technique for Inducing Cochlear Cell Degeneration. J Vis Exp :
Lang, Hainan; Xing, Yazhi; Brown, LaShardai N et al. (2015) Neural stem/progenitor cell properties of glial cells in the adult mouse auditory nerve. Sci Rep 5:13383
Yuan, Yasheng; Shi, Fuxin; Yin, Yanbo et al. (2014) Ouabain-induced cochlear nerve degeneration: synaptic loss and plasticity in a mouse model of auditory neuropathy. J Assoc Res Otolaryngol 15:31-43
Hao, Xinping; Xing, Yazhi; Moore, Michael W et al. (2014) Sox10 expressing cells in the lateral wall of the aged mouse and human cochlea. PLoS One 9:e97389
Stevens, Shawn M; Xing, Yazhi; Hensley, Christopher T et al. (2014) Heptanol application to the mouse round window: a model for studying cochlear lateral wall regeneration. Otolaryngol Head Neck Surg 150:659-65
Luo, Hongmei; Yount, Caroline; Lang, Hainan et al. (2013) Activation of p53 with Nutlin-3a radiosensitizes lung cancer cells via enhancing radiation-induced premature senescence. Lung Cancer 81:167-73

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