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.  

    本所重点实验室黄粤课题组的研究论文“Aneuploid embryonic stem cells exhibit impaired differentiation and increased neoplastic potential”于2016年8月24日在线发表于the EMBO Journal。异倍体（aneuploidy），即染色体数目的非整倍性变异，是发育缺陷的重要原因，也是大多数肿瘤细胞的共同特征。然而异倍体是肿瘤发生的原因还是肿瘤产生的副产物一直是学术界争论的热点。已有的几种细胞模型体外研究发现异倍体会导致细胞增殖能力下降，这显然与肿瘤细胞普遍的恶性增殖能力相矛盾，被学术界称为“异倍体悖论”（Aneuploidy Paradox）。为揭示异倍体在肿瘤形成中的作用，本研究利用精心设计的遗传筛选策略，成功获得了6、8、11、12、15号染色体分别三体（Trisomy）的小鼠胚胎干细胞（ESC）株系，发现这些细胞株都表现生长增殖较快，克隆形成率提高，而细胞分化能力显著下降。当这些细胞被接种到免疫缺陷鼠皮下时，与野生型ESC相比，它们形成畸胎瘤的能力显著增强，而且其中含有大量未分化细胞，具有畸胎癌的特征。进而利用三体回复实验，我们严格论证了异倍体和上述表型的因果关系。机制研究指出，将野生型细胞与异倍体细胞共培养或者添加细胞因子BMP4可以挽救部分异倍体ESC的分化缺陷，初步表明异倍体会影响ESC正常分泌的细胞外因子，从而导致其分化能力被削弱。该研究为理解异倍体在肿瘤发生发展中的作用提供了新思路，合理地解释了“异倍体悖论”，并为肿瘤的诱导分化治疗策略提供了支持。
    黄粤课题组的张美丽助理研究员为该研究论文的第一作者，其他作者包括黄粤课题组的博士研究生程丽，贾玉艳助理研究员和刘光助理研究员；中国科学院北京基因组研究所的宋述慧副研究员和研究生李翠萍；英国Sanger Institute的Allan Bradley教授。黄粤研究员为本文通讯作者。该研究由科技部973计划项目，国家自然科学基金，教育部博士点基金资助。