Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
Stem Cells. 2015 May;33(5):1434-46. doi: 10.1002/stem.1961.
Congenital heart defects (CHD) occur in approximately 50% of patients with Down syndrome (DS); the mechanisms for this occurrence however remain unknown. In order to understand how these defects evolve in early development in DS, we focused on the earliest stages of cardiogenesis to ascertain perturbations in development leading to CHD. Using a trisomy 21 (T21) sibling human embryonic stem cell (hESC) model of DS, we show that T21-hESC display many significant differences in expression of genes and cell populations associated with mesodermal, and more notably, secondary heart field (SHF) development, in particular a reduced number of ISL1(+) progenitor cells. Furthermore, we provide evidence for two candidate genes located on chromosome 21, ETS2 and ERG, whose overexpression during cardiac commitment likely account for the disruption of SHF development, as revealed by downregulation or overexpression experiments. Additionally, we uncover an abnormal electrophysiological phenotype in functional T21 cardiomyocytes, a result further supported by mRNA expression data acquired using RNA-Seq. These data, in combination, revealed a cardiomyocyte-specific phenotype in T21 cardiomyocytes, likely due to the overexpression of genes such as RYR2, NCX, and L-type Ca(2+) channel. These results contribute to the understanding of the mechanisms involved in the development of CHD. Stem Cells 2015;33:1434-1446.
先天性心脏缺陷（CHD）在大约 50%的唐氏综合征（DS）患者中发生；然而，其发生的机制仍不清楚。为了了解这些缺陷在 DS 早期发育中是如何演变的，我们专注于心血管发生的最早阶段，以确定导致 CHD 的发育过程中的干扰。使用三体 21（T21）唐氏综合征人类胚胎干细胞（hESC）模型，我们表明 T21-hESC 在与中胚层相关的基因和细胞群体的表达中表现出许多显著差异，更值得注意的是，次级心脏场（SHF）的发育，特别是 ISL1（+）祖细胞的数量减少。此外，我们提供了位于 21 号染色体上的两个候选基因 ETS2 和 ERG 的证据，它们在心管形成过程中的过度表达可能导致 SHF 发育中断，如通过下调或过表达实验所揭示的。此外，我们在功能 T21 心肌细胞中发现了一种异常的电生理表型，这一结果进一步得到了使用 RNA-Seq 获得的 mRNA 表达数据的支持。这些数据结合起来，揭示了 T21 心肌细胞中存在一种心肌细胞特异性表型，可能是由于 RYR2、NCX 和 L 型 Ca（2+）通道等基因的过度表达所致。这些结果有助于理解 CHD 发展中涉及的机制。干细胞 2015;33:1434-1446。
