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bioRxiv · 10.1101/2022.06.01.494361

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

Moon, J. E.·Lawrence, J. B.
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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 Notch signaling occurring as early as pluripotent stem cells, potentially impacting programming of multiple cell-types. Unbiased analysis from iPSCs 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; therefore, we focused on investigating whether trisomy 21 impacts endothelial cells. An in vitro assay for microvasculature formation used in a tightly controlled system reveals a novel cellular pathology involving delays 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 comorbidities, with wide reaching implications for development and disease progression.

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Moon, J. E., Lawrence, J. B.. 2022-06-01. Chromosome silencing in vitro reveals trisomy 21 causes cell-autonomous deficits in angiogenesis and early dysregulation in Notch signaling. https://doi.org/10.1101/2022.06.01.494361

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