E-Cadherin-Mediated Cell-Cell Contact Is Critical for Induced Pluripotent Stem Cell Generation
E-Cadherin-Mediated Cell-Cell Contact Is Critical for Induced Pluripotent Stem Cell Generation
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E-钙粘蛋白介导的细胞间接触对于诱导多能干细胞的生成至关重要
DOI：
10.1002/stem.456
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发表时间：
2010-08-01
期刊：
影响因子：
5.2
通讯作者：
Pei, Gang
中科院分区：
文献类型：
--
作者：
Chen, Taotao;Yuan, Detian;Pei, Gang
病毒载体的低效率重编程和基因组整合模糊了诱导多能干细胞（iPS）的潜在应用;因此，鉴定可能改善iPS细胞产生的化学物质和协同因子将具有重要价值。此外，限制重编程效率的细胞机制需要研究。通过筛选一个化学文库，我们发现两种上调E-钙粘蛋白的化学物质显著提高了重编程效率。对该过程的进一步研究表明，E-钙粘蛋白在重编程过程中上调，并且建立的iPS细胞具有E-钙粘蛋白介导的细胞-细胞接触，在形态上与胚胎干（ES）细胞难以区分。我们的实验还表明，E-cadherin的过表达显着提高重编程效率，而内源性E-cadherin的敲低降低效率。一致地，通过抑制肽或针对E-钙粘蛋白的细胞外结构域的中和抗体消除细胞-细胞接触损害iPS细胞生成。进一步的机制研究表明，E-钙粘蛋白的粘附结合活性是必需的。我们的研究结果强调了E-钙粘蛋白介导的细胞间接触在重编程中的关键作用，并提出了更有效的iPS细胞生成的新途径。干细胞2010; 28：1315-1325
The low efficiency of reprogramming and genomic integration of virus vectors obscure the potential application of induced pluripotent stem (iPS) cells; therefore, identification of chemicals and cooperative factors that may improve the generation of iPS cells will be of great value. Moreover, the cellular mechanisms that limit the reprogramming efficiency need to be investigated. Through screening a chemical library, we found that two chemicals reported to upregulate E-cadherin considerably increase the reprogramming efficiency. Further study of the process indicated that E-cadherin is upregulated during reprogramming and the established iPS cells possess E-cadherin-mediated cell-cell contact, morphologically indistinguishable from embryonic stem (ES) cells. Our experiments also demonstrate that overexpression of E-cadherin significantly enhances reprogramming efficiency, whereas knockdown of endogenous E-cadherin reduces the efficiency. Consistently, abrogation of cell-cell contact by the inhibitory peptide or the neutralizing antibody against the extracellular domain of E-cadherin compromises iPS cell generation. Further mechanistic study reveals that adhesive binding activity of E-cadherin is required. Our results highlight the critical role of E-cadherin-mediated cell-cell contact in reprogramming and suggest new routes for more efficient iPS cell generation. STEM CELLS 2010; 28: 1315-1325