Rescue, Repair and Regeneration, Institute of Ophthalmology, University College London, EC1V 9EL London, UK.
Rescue, Repair and Regeneration, Institute of Ophthalmology, University College London, EC1V 9EL London, UK.
Stem Cell Reports. 2023 Mar 14;18(3):782-797. doi: 10.1016/j.stemcr.2023.01.007. Epub 2023 Feb 16.
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.
20 号染色体异常是全球人类多能干细胞（hPSC）培养中最常见的基因组改变之一。然而，其对分化的影响在很大程度上仍未得到探索。我们在一项临床视网膜色素上皮分化研究中发现了一种复发性异常，即 20q 等臂染色体（iso20q）。在这里，我们表明 iso20q 异常中断了自发胚胎谱系特化。同基因系揭示，在促进野生型 hPSC 自发分化的条件下，iso20q 变体无法分化为原始生殖层，并下调多能性网络，导致细胞凋亡。相反，iso20q 细胞在抑制 DNMT3B 甲基化或 BMP2 处理后，高度偏向于胚胎外/羊膜分化。最后，定向分化方案可以克服 iso20q 阻断。我们的发现揭示了 iso20q 是一种染色体异常，它损害了 hPSC 向生殖层的发育能力，但不会向羊膜分化，这模拟了存在异常时胚胎发育的瓶颈。
