Aneuploid embryonic stem cells exhibit impaired differentiation and increased neoplastic potential

Zhang M1, Cheng L1, Jia Y1, Liu G1, Li C2, Song S2, Bradley A3, Huang Y1 *

EMBO J. 2016 Aug 24. pii: e201593103. [Epub ahead of print]
PMID:27558554, DOI:10.15252/embj.201593103

Abstract
Aneuploidy leads to severe developmental defects in mammals and is also a hallmark of cancer. However, whether aneuploidy is a driving cause or a consequence of tumor formation remains controversial. Paradoxically, existing studies based on aneuploid yeast and mouse fibroblasts have shown that aneuploidy is usually detrimental to cellular fitness. Here, we examined the effects of aneuploidy on mouse embryonic stem (ES) cells by generating a series of cell lines that each carries an extra copy of single chromosomes, including trisomy 6, 8, 11, 12, or 15. Most of these aneuploid cell lines had rapid proliferation rates and enhanced colony formation efficiencies. They were less dependent on growth factors for self-renewal and showed a reduced capacity to differentiate in vitro Moreover, trisomic stem cells formed teratomas more efficiently, from which undifferentiated cells can be recovered. Further investigations demonstrated that co-culture of wild-type and aneuploid ES cells or supplementation with extracellular BMP4 rescues the differentiation defects of aneuploid ES cells.  

    本所重點(diǎn)實(shí)驗室黃粵課題組的研究論文“Aneuploid embryonic stem cells exhibit impaired differentiation and increased neoplastic potential”于2016年8月24日在線(xiàn)發(fā)表于the EMBO Journal。異倍體（aneuploidy），即染色體數目的非整倍性變異，是發(fā)育缺陷的重要原因，也是大多數腫瘤細胞的共同特征。然而異倍體是腫瘤發(fā)生的原因還是腫瘤產(chǎn)生的副產(chǎn)物一直是學(xué)術(shù)界爭論的熱點(diǎn)。已有的幾種細胞模型體外研究發(fā)現異倍體會(huì )導致細胞增殖能力下降，這顯然與腫瘤細胞普遍的惡性增殖能力相矛盾，被學(xué)術(shù)界稱(chēng)為“異倍體悖論”（Aneuploidy Paradox）。為揭示異倍體在腫瘤形成中的作用，本研究利用精心設計的遺傳篩選策略，成功獲得了6、8、11、12、15號染色體分別三體（Trisomy）的小鼠胚胎干細胞（ESC）株系，發(fā)現這些細胞株都表現生長(cháng)增殖較快，克隆形成率提高，而細胞分化能力顯著(zhù)下降。當這些細胞被接種到免疫缺陷鼠皮下時(shí)，與野生型ESC相比，它們形成畸胎瘤的能力顯著(zhù)增強，而且其中含有大量未分化細胞，具有畸胎癌的特征。進(jìn)而利用三體回復實(shí)驗，我們嚴格論證了異倍體和上述表型的因果關(guān)系。機制研究指出，將野生型細胞與異倍體細胞共培養或者添加細胞因子BMP4可以挽救部分異倍體ESC的分化缺陷，初步表明異倍體會(huì )影響ESC正常分泌的細胞外因子，從而導致其分化能力被削弱。該研究為理解異倍體在腫瘤發(fā)生發(fā)展中的作用提供了新思路，合理地解釋了“異倍體悖論”，并為腫瘤的誘導分化治療策略提供了支持。
    黃粵課題組的張美麗助理研究員為該研究論文的第一作者，其他作者包括黃粵課題組的博士研究生程麗，賈玉艷助理研究員和劉光助理研究員；中國科學(xué)院北京基因組研究所的宋述慧副研究員和研究生李翠萍；英國Sanger Institute的Allan Bradley教授。黃粵研究員為本文通訊作者。該研究由科技部973計劃項目，國家自然科學(xué)基金，教育部博士點(diǎn)基金資助。