Research Group Reproduction and Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Laarbeeklaan 103, Jette, 1090, Brussels, Belgium.
Centrum Voor Medische Genetica, UZ Brussel, Laarbeeklaan 101, Jette, 1090, Brussels, Belgium.
Sci Rep. 2021 Apr 15;11(1):8242. doi: 10.1038/s41598-021-87547-7.
We identified a human embryonic stem cell subline that fails to respond to the differentiation cues needed to obtain endoderm derivatives, differentiating instead into extra-embryonic mesoderm. RNA-sequencing analysis showed that the subline has hyperactivation of the WNT and BMP4 signalling. Modulation of these pathways with small molecules confirmed them as the cause of the differentiation impairment. While activation of WNT and BMP4 in control cells resulted in a loss of endoderm differentiation and induction of extra-embryonic mesoderm markers, inhibition of these pathways in the subline restored its ability to differentiate. Karyotyping and exome sequencing analysis did not identify any changes in the genome that could account for the pathway deregulation. These findings add to the increasing evidence that different responses of stem cell lines to differentiation protocols are based on genetic and epigenetic factors, inherent to the line or acquired during cell culture.
我们鉴定出一个人类胚胎干细胞亚系，它不能响应获得内胚层衍生物所需的分化信号，而是分化为胚胎外中胚层。RNA 测序分析表明，该亚系中 WNT 和 BMP4 信号通路过度激活。用小分子对这些通路进行调节证实了它们是导致分化障碍的原因。虽然在对照细胞中激活 WNT 和 BMP4 会导致内胚层分化丧失和诱导胚胎外中胚层标记物的产生，但在亚系中抑制这些通路则恢复了其分化能力。染色体组型分析和外显子组测序分析未发现任何可能导致通路失调的基因组变化。这些发现增加了越来越多的证据，即不同的干细胞系对分化方案的不同反应是基于遗传和表观遗传因素，这些因素是细胞系固有的或在细胞培养过程中获得的。
