導(dǎo)讀：近期（2010年6月2日）國(guó)際學(xué)術(shù)期刊Stem Cells發(fā)表了以裴鋼研究組為主完成的最新研究成果：小分子化合物通過E-cadherin 蛋白加速重編程過程。
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2010干細(xì)胞技術(shù)與應(yīng)用講座圓滿結(jié)束
細(xì)胞重編程是指已經(jīng)分化的細(xì)胞重新獲得分化多能性的過程,。誘導(dǎo)多能干細(xì)胞即iPS細(xì)胞是通過向體細(xì)胞中以病毒方式導(dǎo)入外源的四個(gè)轉(zhuǎn)錄因子Oct3/4,，Sox2，c-Myc及Klf4而獲得,，具有與胚胎干細(xì)胞（ESC）相似的形態(tài)和表觀遺傳特征,，更重要的是，二者具有相似的分化能力,，即分化的全能性,。iPS細(xì)胞的出現(xiàn)使得無(wú)倫理爭(zhēng)議的病人特異性的干細(xì)胞獲得成為可能,，而由病人特異性的iPS細(xì)胞分化得到的特異性前體細(xì)胞和成熟細(xì)胞即可應(yīng)用在組織器官移植治療、基因治療,、藥物篩選模型的建立,、以及特異疾病分子機(jī)制的研究等多方面。了解重編程過程復(fù)雜的分子機(jī)制有利于開發(fā)更加安全和有效的iPS誘導(dǎo)方法,。
在已有的iPS細(xì)胞誘導(dǎo)體系的基礎(chǔ)上,，裴鋼等研究組此項(xiàng)研究工作發(fā)現(xiàn)細(xì)胞粘附相關(guān)分子E-cadherin蛋白在iPS形成過程中起著重要作用。E-cadherin蛋白的表達(dá)水平在細(xì)胞重編程過程的早期即開始上調(diào),；在完全重編程的iPS細(xì)胞中存在著與ES細(xì)胞中相同的由E-cadherin蛋白介導(dǎo)的細(xì)胞-細(xì)胞連接,，下調(diào)E-cadherin的表達(dá)會(huì)降低iPS形成效率，反之,，過表達(dá)E-cadherin能夠促進(jìn)iPS形成效率,。在重編程過程中過表達(dá)E-cadherin而得到的iPS細(xì)胞具有和ES細(xì)胞一樣的分化全能性。進(jìn)一步,，研究人員篩選得到了兩種能夠通過促進(jìn)E-cadherin蛋白表達(dá)而提高iPS細(xì)胞誘導(dǎo)效率的小分子化合物,，從而提供了優(yōu)化iPS細(xì)胞誘導(dǎo)效率的新策略。
該項(xiàng)工作得到了國(guó)家科技部,、國(guó)家自然科學(xué)基金委及中國(guó)科學(xué)院經(jīng)費(fèi)支持,。(生物谷Bioon.com)
生物谷推薦原文出處：
STEM CELLS DOI:10.1002/stem.456
Embryonic Stem Cells/Induced Pluripotent Stem Cells
Taotao Chen 1, Detian Yuan 1, Bin Wei 1, Jing Jiang 1, Jiuhong Kang 1 2, Kun Ling 3, Yijun Gu 1, Jinsong Li 1, Lei Xiao 1, Gang Pei 1 2 *
1Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
2Shanghai key laboratory of signaling and disease research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
3Department of Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Rochester, MN 55902, USA
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 ES cells. Our experiments also demonstrate that overexpression of E-cadherin significantly enhances reprogramming efficiency, whereas knockdown of endogenous E-cadherin by shRNA 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.
