Transgenic BDNF induces nerve fiber regrowth into the auditory epithelium in deaf cochleae.
Sensory organs typically use receptor cells and afferent neurons to transduce environmental signals and transmit them to the CNS. When sensory cells are lost, nerves often regress from the sensory area. Therapeutic and regenerative approaches would benefit from the presence of nerve fibers in the tissue. In the hearing system, retraction of afferent innervation may accompany the degeneration of auditory hair cells that is associated with permanent hearing loss. The only therapy currently available for cases with severe or complete loss of hair cells is the cochlear implant auditory prosthesis. To enhance the therapeutic benefits of a cochlear implant, it is necessary to attract nerve fibers back into the cochlear epithelium. Here we show that forced expression of the neurotrophin gene BDNF in epithelial or mesothelial cells that remain in the deaf ear induces robust regrowth of nerve fibers towards the cells that secrete the neurotrophin, and results in re-innervation of the sensory area. The process of neurotrophin-induced neuronal regeneration is accompanied by significant preservation of the spiral ganglion cells. The ability to regrow nerve fibers into the basilar membrane area and protect the auditory nerve will enhance performance of cochlear implants and augment future cell replacement therapies such as stem cell implantation or induced transdifferentiation. This model also provides a general experimental stage for drawing nerve fibers into a tissue devoid of neurons, and studying the interaction between the nerve fibers and the tissue.
Shibata
Seiji B
SB
Kresge Hearing Research Institute, Department of Otolaryngology, The University of Michigan, 1150 W. Med. Cntr. Dr., Ann Arbor, MI 48109-5648, USA.
Cortez
Sarah R
SR
Beyer
Lisa A
LA
Wiler
James A
JA
Di Polo
Adriana
A
Pfingst
Bryan E
BE
Raphael
Yehoash
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001489:Basilar Membrane / Q000166:cytology* / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003638:Deafness / Q000503:physiopathology / Q000628:therapy*; D004847:Epithelial Cells / Q000502:physiology; D004848:Epithelium / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000502:physiology / Q000648:ultrastructure; D008297:Male; D009412:Nerve Fibers / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology*; D013136:Spiral Ganglion / Q000166:cytology* / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D049452:Green Fluorescent Proteins