MYC gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro.
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...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3484123?pdf=render |
| _version_ | 1818548028321038336 |
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| author | Joseph C Burns James J Yoo Anthony Atala John D Jackson |
| author_facet | Joseph C Burns James J Yoo Anthony Atala John D Jackson |
| author_sort | Joseph C Burns |
| collection | DOAJ |
| description | 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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| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T08:14:30Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj.art-8cfbf8df92f74ad0a56ce74c947a5aca2022-12-22T00:31:38ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01710e4870410.1371/journal.pone.0048704MYC gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro.Joseph C BurnsJames J YooAnthony AtalaJohn D JacksonThe 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.http://europepmc.org/articles/PMC3484123?pdf=render |
| spellingShingle | Joseph C Burns James J Yoo Anthony Atala John D Jackson MYC gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro. PLoS ONE |
| title | MYC gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro. |
| title_full | MYC gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro. |
| title_fullStr | MYC gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro. |
| title_full_unstemmed | MYC gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro. |
| title_short | MYC gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro. |
| title_sort | myc gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro |
| url | http://europepmc.org/articles/PMC3484123?pdf=render |
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