Aneuploid embryonic stem cells exhibit impaired differentiation and increased neoplastic potential. (24th August 2016)

• Record Type: Journal Article
• Authors: Zhang, Meili; Cheng, Li; Jia, Yuyan; Liu, Guang; Li, Cuiping; Song, Shuhui; Bradley, Allan; Huang, Yue
• Is Part Of: EMBO journal. Volume 35:Number 21(2016)
• Page Start: 2285
• Page End: 2300
• Publication Date: 2016-08-24
• Subjects: aneuploidy -- differentiation -- ES cells -- extracellular factors -- tumorigenesis; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201593103
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: Acquisition of single chromosomes in trisomies is thought to lead to growth disadvantage. Here, aneuploidy is generated in mouse ES cell lines and shown to shift the balance toward increased self‐renewal but impaired differentiation. Stimulated aneuploid ES cells fail to enter development and their retained "stemness" can be overcome by the secreted factor BMP4. A genetic selection strategy using wild‐type AB1 or JM8 ES cells allowed for the generation of "newborn" aneuploid mouse ES cell lines trisomic for chromosomes 6, 8, 11, 12, or 15. Aneuploidy impedes differentiation of ES cells in vitro . Aneuploid ES cells form teratomas more efficiently. Co‐culture of wild type and aneuploid ES cells or supplementation with extracellular BMP4 rescues the differentiation defects of aneuploid ES cells. Abstract : Aneuploid mouse ES cell lines display impaired differentiation, but increased self‐renewal and tumorigenic potential, which can be rescued by extracellular BMP4.