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Chromosome silencing in vitro reveals trisomy 21 causes cell-autonomous deficits in angiogenesis and early dysregulation in Notch signaling

ABSTRACT: Despite the prevalence and clinical importance of Down syndrome, little is known as to the specific cell pathologies that underlie this multi-system disorder. To understand which cell types and pathways are more directly impacted by trisomy 21, we used an inducible-XIST system to silence the extra chromosome 21 in a panel of patient-derived iPSCs. Transcriptomic analysis showed significant dysregulation of potentially impacting programming of multiple cell-types as well as Notch. Analysis revealed prominent dysregulation in two major cell type processes: neurogenesis and angiogenesis. Angiogenesis is important for many systems impacted in Down syndrome but has been understudied. An in vitro assay for microvasculature formation used in a tightly controlled system reveals a novel cellular pathology that showed impairment in angiogenic response during tube formation. Results demonstrate that this is a cell-autonomous effect of trisomy 21 and transcriptomic analysis of differentiated endothelial cells shows deficits in known angiogenesis regulators. This study reveals a major unknown cell pathology caused by trisomy 21 and highlights the importance of endothelial cell function for Down syndrome pathologies, with wide reaching implications for development and disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166849 | GEO | 2022/07/05

REPOSITORIES: GEO

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