The isochromosome 20q abnormality of pluripotent cells interrupts germ layer differentiation

Chromosome 20 abnormalities are some of the most frequent genomic changes acquired by human pluripotent stem cell (hPSC) cultures worldwide. Yet their effects on differentiation remain largely unexplored. We investigated a recurrent abnormality also found on amniocentesis, the isochromosome 20q (iso20q), during a clinical retinal pigment epithelium differentiation. Here we show that the iso20q abnormality interrupts spontaneous embryonic lineage specification. Isogenic lines revealed that under conditions that promote the spontaneous differentiation of wild-type hPSCs, the iso20q variants fail to differentiate into primitive germ layers and to downregulate pluripotency networks, resulting in apoptosis. Instead, iso20q cells are highly biased for extra-embryonic/amnion differentiation following inhibition of DNMT3B methylation or BMP2 treatment. Finally, directed differentiation protocols can overcome the iso20q block. Our findings reveal in iso20q a chromosomal abnormality that impairs the developmental competency of hPSCs toward germ layers but not amnion, which models embryonic developmental bottlenecks in the presence of aberrations. [Display omitted] •Pluripotent cells frequently acquire the isochromosome 20q abnormality•Cells with iso20q interrupt spontaneous differentiation by undergoing apoptosis•The iso20q cells are biased for an extra-embryonic fate•Iso20q is an in vitro example of aneuploidy depletion from the epiblast For an associated discussion of this work, listen to the latest episode of The Stem Cell Report podcast at https://www.isscr.org/podcast/s2-e8, brought to you by the ISSCR. In this article, Vitillo and colleagues identify a common karyotype abnormality of pluripotent stem cells, iso20q, also found on amniocentesis, which self-depletes via apoptosis during spontaneous germ layer differentiation. Before depletion, iso20q cells fail to downregulate pluripotency networks. Moreover, iso20q cells exhibit a bias toward extra-embryonic phenotypes. Iso20q cells offer a karyotypically defined in vitro model of aneuploidy depletion.