Characterization of Lgr5+ Progenitor Cell Transcriptomes after Neomycin Injury in the Neonatal Mouse Cochlea.
Characterization of Lgr5+ Progenitor Cell Transcriptomes after Neomycin Injury in the Neonatal Mouse Cochlea.
复制标题
新生小鼠耳蜗新霉素损伤后 Lgr5 祖细胞转录组的表征。
DOI：
10.3389/fnmol.2017.00213
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发表时间：
2017
影响因子：
4.8
通讯作者：
Chai R
中科院分区：
文献类型：
--
作者：
Zhang S;Zhang Y;Yu P;Hu Y;Zhou H;Guo L;Xu X;Zhu X;Waqas M;Qi J;Zhang X;Liu Y;Chen F;Tang M;Qian X;Shi H;Gao X;Chai R
Lgr 5+支持细胞（SC）是耳蜗中富集的毛细胞（HC）祖细胞。体外和体内研究均表明，HC损伤可自发激活新生小鼠耳蜗中的Lgr 5+祖细胞以再生HC。促进HC再生需要理解HC再生的机制，这需要了解参与HC损伤诱导的自我修复反应的关键基因，这些基因促进Lgr 5+祖细胞的增殖和分化。在这里，正如预期的那样，我们发现，与未处理的Lgr5+祖细胞（ULP）相比，新霉素处理的Lgr5+祖细胞（NLP）响应于新霉素暴露具有显著更大的HC再生能力，以及更大但不显著的增殖能力。接下来，我们使用RNA-seq分析来确定来自新生小鼠耳蜗的NLP和ULP的转录组之间的基因表达谱的差异。我们首先分析了在NLP和ULP中富集和差异表达的基因，然后分析了可能调控Lgr5+祖细胞增殖和分化的细胞周期基因、转录因子和信号通路基因。我们发现9个细胞周期基因，88个转录因子，8个microRNA和16个细胞信号通路基因在NLP中新霉素损伤后显著上调或下调。最后，我们构建了一个蛋白质-蛋白质相互作用网络，以显示在NLP和ULP中差异表达的基因的相互作用和连接。这项研究已经确定了新霉素损伤后可能调控Lgr5+祖细胞增殖和HC再生的基因，未来应该对这些基因在耳蜗中的作用和机制进行调查，以确定HC再生的潜在治疗靶点。
Lgr5+ supporting cells (SCs) are enriched hair cell (HC) progenitors in the cochlea. Both in vitro and in vivo studies have shown that HC injury can spontaneously activate Lgr5+ progenitors to regenerate HCs in the neonatal mouse cochlea. Promoting HC regeneration requires the understanding of the mechanism of HC regeneration, and this requires knowledge of the key genes involved in HC injury-induced self-repair responses that promote the proliferation and differentiation of Lgr5+ progenitors. Here, as expected, we found that neomycin-treated Lgr5+ progenitors (NLPs) had significantly greater HC regeneration ability, and greater but not significant proliferation ability compared to untreated Lgr5+ progenitors (ULPs) in response to neomycin exposure. Next, we used RNA-seq analysis to determine the differences in the gene-expression profiles between the transcriptomes of NLPs and ULPs from the neonatal mouse cochlea. We first analyzed the genes that were enriched and differentially expressed in NLPs and ULPs and then analyzed the cell cycle genes, the transcription factors, and the signaling pathway genes that might regulate the proliferation and differentiation of Lgr5+ progenitors. We found 9 cell cycle genes, 88 transcription factors, 8 microRNAs, and 16 cell-signaling pathway genes that were significantly upregulated or downregulated after neomycin injury in NLPs. Lastly, we constructed a protein-protein interaction network to show the interaction and connections of genes that are differentially expressed in NLPs and ULPs. This study has identified the genes that might regulate the proliferation and HC regeneration of Lgr5+ progenitors after neomycin injury, and investigations into the roles and mechanisms of these genes in the cochlea should be performed in the future to identify potential therapeutic targets for HC regeneration.