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.
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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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