Manipulating cell cycle regulation in the mature cochlea

Minoda, Ryosei; Izumikawa, Masahiko; Kawamoto, Kohei; Zhang, Hui; Raphael, Yehoash

doi:10.1016/j.heares.2007.06.005

Cited by 45 publications

(39 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The current findings show that the flat epithelium fails to undergo transdifferentiation following forced expression of Atoh1 and suggest that the flat epithelium has regressed to a very early state of differentiation and no longer present the commitment to the hair cell or supporting cell phenotype. Based on the lack of response to Atoh1, it can be assumed that the flat epithelium is less differentiated than cells in the vicinity of the organ of Corti, such as interdental cells, where forced Atoh1 expression induces ectopic hair cell formation (Kawamoto et al, 2003;Minoda et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Response of the flat cochlear epithelium to forced expression of Atoh1

et al. 2008

Self Cite

View full text Add to dashboard Cite

Following hair cell elimination in severely traumatized cochleae, differentiated supporting cells are often replaced by a simple epithelium with cuboidal or flat appearance. Atoh1 (previously Math1) is a basic helix-loop-helix transcription factor critical to hair cell differentiation during mammalian embryogenesis. Forced expression of Atoh1 in the differentiated supporting cell population can induce transdifferentiation leading to hair cell regeneration. Here we examined the outcome of adenovirus mediated over-expression of Atoh1 in the non-sensory cells of the flat epithelium. We determined that seven days after unilateral elimination of hair cells with neomycin, differentiated supporting cells are absent, replaced by a flat epithelium. Nerve processes were also missing from the auditory epithelium, with the exception of infrequent looping nerve processes above the habenula perforata. We then inoculated an adenovirus vector with Atoh1 insert into the scala media of the deafened cochlea. The inoculation resulted in upregulation of Atoh1 in the flat epithelium. However, two months after the inoculation, Atoh1-treated ears did not exhibit clear signs of hair cell regeneration. Combined with previous data on induction of supporting cell to hair cell transdifferentiation by forced expression of Atoh1, these results suggest that the presence of differentiated supporting cells in the organ of Corti is necessary for transdifferentiation to occur.

show abstract

Section: Discussionmentioning

confidence: 99%

Response of the flat cochlear epithelium to forced expression of Atoh1

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…By manipulating cell-cycle regulatory genes, it is possible to induce proliferation in the cochlear epithelium [75]. However, it appears that by itself, the addition of new cells is insufficient for generating new hair cells.…”

Section: Therapy For Hair Cell Regenerationmentioning

confidence: 99%

Gene Therapy in the Inner Ear Using Adenovirus Vectors

Husseman

Raphael

2009

Gene Therapy of Cochlear Deafness

Self Cite

View full text Add to dashboard Cite

Therapies for the protection and regeneration of auditory hair cells are of great interest given the significant monetary and lifestyle impact of hearing loss. The past decade has seen tremendous advances in the use of adenoviral vectors to achieve these aims. Preliminary data demonstrated the functional capacity of this technique as adenoviral-induced expression of neurotrophic and growth factors protected hair cells and spiral ganglion neurons from ototoxic insults. Subsequent efforts confirmed the feasibility of adenoviral transfection of cells in the auditory neuroepithelium via cochleostomy into the scala media. Most recently, efforts have focused on regeneration of depleted hair cells. Mammalian hearing loss is generally considered a permanent insult as the auditory epithelium lacks a basal layer capable of producing new hair cells. Recently, the transcription factor Atoh1 has been found to play a critical role in hair cell differentiation. Adenoviral-mediated overexpression of Atoh1 in culture and in vivo have shown the ability to regenerate auditory and vestibular hair cells by causing transdifferentiation of neighboring epithelial-supporting cells. Functional recovery of both the auditory and vestibular systems has been documented following adenoviral induced Atoh1 overexpression.

show abstract

“…p27 kip1 protein is typically expressed only in SCs of the embryonic and postnatal inner ear sensory epithelia (Chen and Segil, 1999; Löwenheim et al, 1999; Minoda et al, 2007). However, some utricular HCs have been shown to weakly express p27 kip1 protein at P7 (Laine et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

Regeneration of mammalian cochlear and vestibular hair cells through Hes1/Hes5 modulation with siRNA

Gao

et al. 2013

Hearing Research

View full text Add to dashboard Cite

The Notch pathway is a cell signaling pathway determining initial specification and subsequent cell fate in the inner ear. Previous studies have suggested that new hair cells (HCs) can be regenerated in the inner ear by manipulating the Notch pathway. In the present study, delivery of siRNA to Hes1 and Hes5 using a transfection reagent or siRNA to Hes1 encapsulated within poly(lactide-co-glycolide acid) (PLGA) nanoparticles increased HC numbers in non-toxin treated organotypic cultures of cochleae and maculae of postnatal day 3 mouse pups. An increase in HCs was also observed in cultured cochleae and maculae of mouse pups pre-conditioned with a HC toxin (4-hydroxy-2-nonenal or neomycin) and then treated with the various siRNA formulations. Treating cochleae with siRNA to Hes1 associated with a transfection reagent or siRNA to Hes1 delivered by PLGA nanoparticles decreased Hes1 mRNA and up-regulated Atoh1 mRNA expression allowing supporting cells (SCs) to acquire a HC fate. Experiments using cochleae and maculae of p27kip1/-GFP transgenic mouse pups demonstrated that newly generated HCs trans-differentiated from SCs. Furthermore, PLGA nanoparticles are non-toxic to inner ear tissue, readily taken up by cells within the tissue of interest, and present a synthetic delivery system that is a safe alternative to viral vectors. These results indicate that when delivered using a suitable vehicle, Hes siRNAs are potential therapeutic molecules that may have the capacity to regenerate new HCs in the inner ear and possibly restore human hearing and balance function.

show abstract

Manipulating cell cycle regulation in the mature cochlea

Cited by 45 publications

References 36 publications

Response of the flat cochlear epithelium to forced expression of Atoh1

Response of the flat cochlear epithelium to forced expression of Atoh1

Gene Therapy in the Inner Ear Using Adenovirus Vectors

Regeneration of mammalian cochlear and vestibular hair cells through Hes1/Hes5 modulation with siRNA

Contact Info

Product

Resources

About