Differential sensitivity of the inner ear sensory cell populations to forced cell cycle re‐entry and p53 induction

Sulg, Marilin; Kirjavainen, Anna; Pajusola, Katri; Ylikoski, Jukka; Laiho, Marikki; Pirvola, Ulla

doi:10.1111/j.1471-4159.2009.06563.x

Cited by 16 publications

(25 citation statements)

References 48 publications

(53 reference statements)

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“…Specifically, the numerous doublets of EdU-labeled Deiters' cells and the signs of impaired separation of the nuclei of the doublets suggested that the cell cycles were incomplete. Interestingly, this has also been found in developing hair cells after cell cycle reactivation [11, 41]. We found that p53, a mediator of cycle arrest and apoptosis, was upregulated in Deiters' cells of AdcD1-infected cochkeas, in most cases in the cell doublets.…”

Section: Discussionsupporting

confidence: 68%

“…Upon forced proliferation, γH2AX induction has been shown in neurons of the central nervous system and in the inner ear hair cells, and was found to lead to apoptosis of these highly differentiated cells [10, 11]. Upon DNA damage triggered by genotoxic agents, activation of other components of the DDR pathway, besides H2AX, has been shown in postmitotic neurons and epithelial cells [12-14], but, surprisingly, not in astrocytes, even though these cells were found to be DNA repair-proficient [9].…”

Section: Introductionmentioning

confidence: 99%

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DNA damage signaling regulates age-dependent proliferative capacity of quiescent inner ear supporting cells

Laos

Anttonen

Kirjavainen

et al. 2014

Aging

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Supporting cells (SCs) of the cochlear (auditory) and vestibular (balance) organs hold promise as a platform for therapeutic regeneration of the sensory hair cells. Prior data have shown proliferative restrictions of adult SCs forced to re-enter the cell cycle. By comparing juvenile and adult SCs in explant cultures, we have here studied how proliferative restrictions are linked with DNA damage signaling. Cyclin D1 overexpression, used to stimulate cell cycle re-entry, triggered higher proliferative activity of juvenile SCs. Phosphorylated form of histone H2AX (γH2AX) and p53 binding protein 1 (53BP1) were induced in a foci-like pattern in SCs of both ages as an indication of DNA double-strand break formation and activated DNA damage response. Compared to juvenile SCs, γH2AX and the repair protein Rad51 were resolved with slower kinetics in adult SCs, accompanied by increased apoptosis. Consistent with the in vitro data, in a Rb mutant mouse model in vivo, cell cycle re-entry of SCs was associated with γH2AX foci induction. In contrast to cell cycle reactivation, pharmacological stimulation of SC-to-hair-cell transdifferentiation in vitro did not trigger γH2AX. Thus, DNA damage and its prolonged resolution are critical barriers in the efforts to stimulate proliferation of the adult inner ear SCs.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

DNA damage signaling regulates age-dependent proliferative capacity of quiescent inner ear supporting cells

Laos

Anttonen

Kirjavainen

et al. 2014

Aging

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“…Alternatively, we did observe a small number of hair cells that were transduced with Ad.GFP, and we have not yet ruled out that the BrdU-positive/myosin VIIA-positive cells were pre-existing hair cells that reentered the cell cycle after being transduced with Ad.MT58A. Conditional deletion of the retinoblastoma protein or ectopic expression of the HPV-16 E7 oncogene within hair cells can drive their reentry into the cell cycle, so it is reasonable to suspect that ectopic expression of c-Myc may produce similar effects [55]–[57], [59], [62], [83]. If the BrdU-positive/myosin VIIA-positive cells we observed did originate from the supporting cell population infected with Ad.MT58A, then ectopic c-Myc expression may be capable of dedifferentiating supporting cells into cells with characteristics of otic progenitors.…”

Section: Discussionmentioning

confidence: 97%

“…Directly reprogramming postmitotic supporting cells into hair cells could decrease the size of the supporting cell population without some form of nonautonomous cell replacement [92], which makes restoration of self-renewal capacity vital to the reprogramming strategy. Cyclins, cyclin dependent kinase inhibitors (CDKIs), and pocket proteins have been shown to regulate proliferation and cell cycle exit during development of the sensory epithelium, and a growing list of these genes have been targeted to force reentry of supporting cells into the cell cycle [41], [54]–[62], [83], [94]–[98]. MYC controls the expression and activity of various cyclins, CDKIs, and pocket proteins [65], [76], which may make it more suitable for orchestrating the complex fluctuations of cell cycle proteins that are necessary to drive efficient progression through the various restriction points.…”

Section: Discussionmentioning

confidence: 99%

MYC Gene Delivery to Adult Mouse Utricles Stimulates Proliferation of Postmitotic Supporting Cells In Vitro

et al. 2012

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The inner ears of adult humans and other mammals possess a limited capacity for regenerating sensory hair cells, which can lead to permanent auditory and vestibular deficits. During development and regeneration, undifferentiated supporting cells within inner ear sensory epithelia can self-renew and give rise to new hair cells; however, these otic progenitors become depleted postnatally. Therefore, reprogramming differentiated supporting cells into otic progenitors is a potential strategy for restoring regenerative potential to the ear. Transient expression of the induced pluripotency transcription factors, Oct3/4, Klf4, Sox2, and c-Myc reprograms fibroblasts into neural progenitors under neural-promoting culture conditions, so as a first step, we explored whether ectopic expression of these factors can reverse supporting cell quiescence in whole organ cultures of adult mouse utricles. Co-infection of utricles with adenoviral vectors separately encoding Oct3/4, Klf4, Sox2, and the degradation-resistant T58A mutant of c-Myc (c-MycT58A) triggered significant levels of supporting cell S-phase entry as assessed by continuous BrdU labeling. Of the four factors, c-MycT58A alone was both necessary and sufficient for the proliferative response. The number of BrdU-labeled cells plateaued between 5–7 days after infection, and then decreased ∼60% by 3 weeks, as many cycling cells appeared to enter apoptosis. Switching to differentiation-promoting culture medium at 5 days after ectopic expression of c-MycT58A temporarily attenuated the loss of BrdU-labeled cells and accompanied a very modest but significant expansion of the sensory epithelium. A small number of the proliferating cells in these cultures labeled for the hair cell marker, myosin VIIA, suggesting they had begun differentiating towards a hair cell fate. The results indicate that ectopic expression of c-MycT58A in combination with methods for promoting cell survival and differentiation may restore regenerative potential to supporting cells within the adult mammalian inner ear.

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“…In vivo approaches force inner ear supporting cells to re-enter the cell cycle followed by directed terminal differentiation into hair cells and supporting cells using viral vectors, including adeno-associated virus serotype 2 or adenovirus serotype 5 [33,144,145,146,147,148]. In vitro approaches use stem cell populations and culture them into hair cell-like cells and seed hair cell-like cells onto the cochlea [47,149].…”

Section: Translational Significance and Future Directionsmentioning

confidence: 99%

The Myc Road to Hearing Restoration

Kopecky

Fritzsch

2012

Cells

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Current treatments for hearing loss, the most common neurosensory disorder, do not restore perfect hearing. Regeneration of lost organ of Corti hair cells through forced cell cycle re-entry of supporting cells or through manipulation of stem cells, both avenues towards a permanent cure, require a more complete understanding of normal inner ear development, specifically the balance of proliferation and differentiation required to form and to maintain hair cells. Direct successful alterations to the cell cycle result in cell death whereas regulation of upstream genes is insufficient to permanently alter cell cycle dynamics. The Myc gene family is uniquely situated to synergize upstream pathways into downstream cell cycle control. There are three Mycs that are embedded within the Myc/Max/Mad network to regulate proliferation. The function of the two ear expressed Mycs, N-Myc and L-Myc were unknown less than two years ago and their therapeutic potentials remain speculative. In this review, we discuss the roles the Mycs play in the body and what led us to choose them to be our candidate gene for inner ear therapies. We will summarize the recently published work describing the early and late effects of N-Myc and L-Myc on hair cell formation and maintenance. Lastly, we detail the translational significance of our findings and what future work must be performed to make the ultimate hearing aid: the regeneration of the organ of Corti.

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Differential sensitivity of the inner ear sensory cell populations to forced cell cycle re‐entry and p53 induction

Cited by 16 publications

References 48 publications

DNA damage signaling regulates age-dependent proliferative capacity of quiescent inner ear supporting cells

DNA damage signaling regulates age-dependent proliferative capacity of quiescent inner ear supporting cells

MYC Gene Delivery to Adult Mouse Utricles Stimulates Proliferation of Postmitotic Supporting Cells In Vitro

The Myc Road to Hearing Restoration

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