High-resolution transcriptional dissection of in vivo Atoh1-mediated hair cell conversion in mature cochleae identifies Isl1 as a co-reprogramming factor.
High-resolution transcriptional dissection of in vivo Atoh1-mediated hair cell conversion in mature cochleae identifies Isl1 as a co-reprogramming factor.
复制标题
DOI：
10.1371/journal.pgen.1007552
复制
发表时间：
2018-07
期刊：
影响因子：
4.5
通讯作者：
Zuo J
中科院分区：
文献类型：
--
作者：
Yamashita T;Zheng F;Finkelstein D;Kellard Z;Carter R;Rosencrance CD;Sugino K;Easton J;Gawad C;Zuo J
In vivo direct conversion of differentiated cells holds promise for regenerative medicine; however, improving the conversion efficiency and producing functional target cells remain challenging. Ectopic Atoh1 expression in non-sensory supporting cells (SCs) in mouse cochleae induces their partial conversion to hair cells (HCs) at low efficiency. Here, we performed single-cell RNA sequencing of whole mouse sensory epithelia harvested at multiple time points after conditional overexpression of Atoh1. Pseudotemporal ordering revealed that converted HCs (cHCs) are present along a conversion continuum that correlates with both endogenous and exogenous Atoh1 expression. Bulk sequencing of isolated cell populations and single-cell qPCR confirmed 51 transcription factors, including Isl1, are differentially expressed among cHCs, SCs and HCs. In transgenic mice, co-overexpression of Atoh1 and Isl1 enhanced the HC conversion efficiency. Together, our study shows how high-resolution transcriptional profiling of direct cell conversion can identify co-reprogramming factors required for efficient conversion. The ongoing ATOH1 gene therapy clinical trial offers promise for hearing restoration in humans. However, in animal models, Atoh1-mediated sensory regeneration is inefficient and incomplete. Here we performed high-resolution gene expression profiling of single cochlear cells at multiple time points in a mouse model whereby we discovered a continuous regeneration process that leads to the formation of immature sensory cells. We identified 51 key reprogramming transcription factors that may increase the efficiency and completion of the regeneration process and confirmed that Isl1 in transgenic mice promotes Atoh1-mediated sensory regeneration as a co-reprogramming factor. Our studies identify molecular mechanisms and novel co-reprogramming factors for sensory restoration in humans with irreversible hearing loss.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
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：
10.1073/pnas.1408064111
发表时间：
2014-11-25
影响因子：
11.1
作者：
Lagarde, Marcia M. Mellado;Wan, Guoqiang;Corfas, Gabriel
通讯作者：
Corfas, Gabriel
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
3.5
作者：
Faherty SL;Campbell CR;Larsen PA;Yoder AD
通讯作者：
Yoder AD