Investigating a cell replacement therapy in the inner ear
Author: Hu, Zhengqing
Date: 2005-01-13
Location: Hörselklinikens föreläsningssal, Karolinska Universitetssjukhuset, 2tr, huvudbyggnaden
Time: 9.00
Department: Institutionen för klinisk neurovetenskap / Department of Clinical Neuroscience
View/ Open:
Thesis (665.8Kb)
Abstract
The mammalian auditory system is sensitive to genetic disorders, aging and injuries caused by overstimulation, ototoxic drugs and viral infections. Since the sensory epithelium (the organ of Corti) and the spiral ganglion neurons (SGNs) in adult mammalian do not regenerate spontaneously when they are damaged, a cell substitution strategy was proposed to compensate the function of the degenerated SGNs. The current study investigated different aspects of cell transplantations in order to test the feasibility of a cell therapy approach in the adult auditory system.
Transplanted cells, including embryonic neuronal tissue (mouse embryonic dorsal root ganglion neurons, DRGs) and stem cells (adult neural stem cells, NSCs; embryonic stem cells, ES cells) were found to survive for up to ten weeks in the adult auditory system following transplantation. Supplementing exogenous neurotrophic factors significantly enhanced the survival of DRG neurons. Similarly, ES cell survival was remarkably enhanced by cografting embryonic neuronal tissue.
Further research was focused on identifying possible interactions between implanted cells and the host SGNs. The results showed that neurite projections were formed by implanted cells and seemed to contact the host SGNs. The supplement of exogenous nerve growth factor (NGF), chronic electrical stimulation or embryonic neuronal cograft promoted neurite formation. The implanted cells were observed to migrate through the bony modiolus to reach the SGN region in Rosenthal's canal. When tissue was transplanted along the auditory nerve (N. VIII), DRG neurons were found to migrate centrally to the internal meatus while ES cells migrated even further centrally and reached the cochlear nucleus in the brain stem. The results suggest that implanted cells have the potential to structurally integrate with the host auditory system, or even have the capability to replace degenerated SGNs and form connections between the peripheral auditory structures and the central nervous system.
Neuronal differentiation of the transplanted stem cells was also investigated. Adult NSCs did not seem to differentiate into a neuronal fate in a normal inner ear. Interestingly, NSCs differentiated into neuron-like cells when they were transduced with neurogenin2 prior to transplantation. ES cells showed differentiation when cografted with embryonic neuronal tissue.
The possible function of implanted cells was evaluated in the DRG model by recording electrically-evoked auditory brain stem responses (EABRs). The results showed that exogenous NGF and/or chronic electrical stimulation enhanced neurite outgrowth from the DRG neurons. However, this did not translate to a functional change as measured by EABR.
In conclusion, the survival, neurite formation, migration and differentiation of cells implanted into the adult inner ear suggest that a cell replacement approach may provide an alternative for the development of an effective new treatment for hearing loss.
Transplanted cells, including embryonic neuronal tissue (mouse embryonic dorsal root ganglion neurons, DRGs) and stem cells (adult neural stem cells, NSCs; embryonic stem cells, ES cells) were found to survive for up to ten weeks in the adult auditory system following transplantation. Supplementing exogenous neurotrophic factors significantly enhanced the survival of DRG neurons. Similarly, ES cell survival was remarkably enhanced by cografting embryonic neuronal tissue.
Further research was focused on identifying possible interactions between implanted cells and the host SGNs. The results showed that neurite projections were formed by implanted cells and seemed to contact the host SGNs. The supplement of exogenous nerve growth factor (NGF), chronic electrical stimulation or embryonic neuronal cograft promoted neurite formation. The implanted cells were observed to migrate through the bony modiolus to reach the SGN region in Rosenthal's canal. When tissue was transplanted along the auditory nerve (N. VIII), DRG neurons were found to migrate centrally to the internal meatus while ES cells migrated even further centrally and reached the cochlear nucleus in the brain stem. The results suggest that implanted cells have the potential to structurally integrate with the host auditory system, or even have the capability to replace degenerated SGNs and form connections between the peripheral auditory structures and the central nervous system.
Neuronal differentiation of the transplanted stem cells was also investigated. Adult NSCs did not seem to differentiate into a neuronal fate in a normal inner ear. Interestingly, NSCs differentiated into neuron-like cells when they were transduced with neurogenin2 prior to transplantation. ES cells showed differentiation when cografted with embryonic neuronal tissue.
The possible function of implanted cells was evaluated in the DRG model by recording electrically-evoked auditory brain stem responses (EABRs). The results showed that exogenous NGF and/or chronic electrical stimulation enhanced neurite outgrowth from the DRG neurons. However, this did not translate to a functional change as measured by EABR.
In conclusion, the survival, neurite formation, migration and differentiation of cells implanted into the adult inner ear suggest that a cell replacement approach may provide an alternative for the development of an effective new treatment for hearing loss.
List of papers:
I. Hu Z, Ulfendahl M, Olivius NP (2004). Survival of neuronal tissue following xenograft implantation into the adult rat inner ear. Exp Neurol. 185(1): 7-14.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Hu Z, Ulfendahl M, Olivius NP (2005). NGF stimulates extensive neurite outgrowth from implanted dorsal root ganglion neurons following transplantation into the adult rat inner ear. Neurobiol Dis. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Hu Z, Ulfendahl M, Olivius NP (2004). Central migration of neuronal tissue and embryonic stem cells following transplantation along the adult auditory nerve. Brain Res. 1026(1): 68-73.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Hu Z, Wei D, Johansson CB, Holmstrom N, Duan M, Frisen J, Ulfendahl M (2005). Survival and neural differentiation of adult neural stem cells transplanted into the mature inner ear. Exp Cell Res. 302(1): 40-7.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Hu Z, Andang M, Ni D, Ulfendahl M (2004). Integration of embryonic stem cells into the adult mammalian auditory system. [Submitted]
VI. Hu Z, Ulfendahl M, Prieskorn DM, Olivius NP, Miller J (2004). Functional evaluation of a cell replacement therapy in the inner ear. [Manuscript]
I. Hu Z, Ulfendahl M, Olivius NP (2004). Survival of neuronal tissue following xenograft implantation into the adult rat inner ear. Exp Neurol. 185(1): 7-14.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Hu Z, Ulfendahl M, Olivius NP (2005). NGF stimulates extensive neurite outgrowth from implanted dorsal root ganglion neurons following transplantation into the adult rat inner ear. Neurobiol Dis. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Hu Z, Ulfendahl M, Olivius NP (2004). Central migration of neuronal tissue and embryonic stem cells following transplantation along the adult auditory nerve. Brain Res. 1026(1): 68-73.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Hu Z, Wei D, Johansson CB, Holmstrom N, Duan M, Frisen J, Ulfendahl M (2005). Survival and neural differentiation of adult neural stem cells transplanted into the mature inner ear. Exp Cell Res. 302(1): 40-7.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Hu Z, Andang M, Ni D, Ulfendahl M (2004). Integration of embryonic stem cells into the adult mammalian auditory system. [Submitted]
VI. Hu Z, Ulfendahl M, Prieskorn DM, Olivius NP, Miller J (2004). Functional evaluation of a cell replacement therapy in the inner ear. [Manuscript]
Issue date: 2004-12-23
Rights:
Publication year: 2005
ISBN: 91-7140-170-9
Statistics
Total Visits
Views | |
---|---|
Investigating ...(legacy) | 681 |
Investigating ... | 87 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Investigating ... | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 393 |
thesis.pdf | 118 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 332 |
China | 48 |
Germany | 45 |
Sweden | 45 |
South Korea | 16 |
Finland | 7 |
United Kingdom | 7 |
Russia | 7 |
Denmark | 6 |
Ireland | 6 |
Top cities views
Views | |
---|---|
Sunnyvale | 49 |
Romeo | 27 |
Beijing | 26 |
Kiez | 17 |
Seoul | 15 |
Ashburn | 7 |
Ballerup | 6 |
Des Moines | 6 |
Dublin | 6 |
London | 6 |