MYC gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro.
MYC gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro.
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DOI：
10.1371/journal.pone.0048704
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Jackson JD
中科院分区：
文献类型：
--
作者：
Burns JC;Yoo JJ;Atala A;Jackson JD
成年人和其他哺乳动物的内耳再生感觉毛细胞的能力有限，这可能导致永久性的听觉和前庭缺陷。在发育和再生过程中，内耳感觉上皮内未分化的支持细胞可以自我更新并产生新的毛细胞;然而，这些耳祖细胞在出生后变得耗尽。因此，将分化的支持细胞重编程为耳祖细胞是恢复耳再生潜力的潜在策略。诱导多能性转录因子Oct 3/4、Klf 4、Sox 2和c-Myc的瞬时表达在神经促进培养条件下将成纤维细胞重编程为神经祖细胞，因此作为第一步，我们探索这些因子的异位表达是否可以逆转成年小鼠椭圆囊的整个器官培养中的支持细胞静止。用分别编码Oct 3/4、Klf 4、Sox 2和c-Myc的抗降解T58 A突变体（c-MycT 58 A）的腺病毒载体共感染椭圆囊，触发了显著水平的支持细胞S期进入，如通过连续BrdU标记所评估的。在这四种因子中，单独的c-MycT 58 A对于增殖反应是必要的和足够的。BrdU标记的细胞数量在感染后5-7天之间达到平台，然后在3周时减少约60%，因为许多周期细胞似乎进入凋亡。在c-MycT 58 A异位表达后5天切换到分化促进培养基暂时减弱了BrdU标记细胞的损失，并伴随着感觉上皮的非常适度但显著的扩张。这些培养物中的少量增殖细胞标记为毛细胞标记物肌球蛋白VIIA，表明它们已经开始向毛细胞命运分化。结果表明，c-MycT 58 A的异位表达与促进细胞存活和分化的方法相结合，可以恢复成年哺乳动物内耳内支持细胞的再生潜力。
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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DOI：
10.1523/jneurosci.6274-11.2012
发表时间：
2012-05-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Burns JC;Cox BC;Thiede BR;Zuo J;Corwin JT
通讯作者：
Corwin JT
DOI：
10.1083/jcb.153.5.1049
发表时间：
2001-05-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gottardi CJ;Wong E;Gumbiner BM
通讯作者：
Gumbiner BM
DOI：
10.1523/jneurosci.0785-11.2011
发表时间：
2011-05-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Domínguez-Frutos E;López-Hernández I;Vendrell V;Neves J;Gallozzi M;Gutsche K;Quintana L;Sharpe J;Knoepfler PS;Eisenman RN;Trumpp A;Giráldez F;Schimmang T
通讯作者：
Schimmang T
影响因子：
5.6
作者：
Ho, Ritchie;Chronis, Constantinos;Plath, Kathrin
通讯作者：
Plath, Kathrin
影响因子：
11.2
作者：
Chen, ZY;Wang, XS;Tseng, CC
通讯作者：
Tseng, CC