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

Vitillo, Loriana; Anjum, Fabiha; Hewitt, Zoe; Stavish, Dylan; Laing, Owen; Baker, Duncan; Barbaric, Ivana; (2023) The isochromosome 20q abnormality of pluripotent cells interrupts germ layer differentiation. Stem Cell Reports , 18 (3) pp. 782-797. 10.1016/j.stemcr.2023.01.007. Green open access

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Abstract

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.

Type: Article
Title: The isochromosome 20q abnormality of pluripotent cells interrupts germ layer differentiation
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.stemcr.2023.01.007
Publisher version: https://doi.org/10.1016/j.stemcr.2023.01.007
Language: English
Additional information: © 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: embryonic stem cells, pluripotency, differentiation, retinal pigment epithelium, trophoblast, chromosome 20, isochromosome 20q, aneuploidy, chromosomal abnormalities, germ layers
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10167179
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