Chi Congwu, Knight Walter E, Riching Andrew S, Zhang Zhen, Tatavosian Roubina, Zhuang Yonghua, Moldovan Radu, Rachubinski Angela L, Gao Dexiang, Xu Hongyan, Espinosa Joaquin M, Song Kunhua
Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA.
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA.
iScience. 2023 Jun 5;26(7):107012. doi: 10.1016/j.isci.2023.107012. eCollection 2023 Jul 21.
Congenital heart defects (CHDs) are frequent in children with Down syndrome (DS), caused by trisomy of chromosome 21. However, the underlying mechanisms are poorly understood. Here, using a human-induced pluripotent stem cell (iPSC)-based model and the Dp(16)1Yey/+ (Dp16) mouse model of DS, we identified downregulation of canonical Wnt signaling downstream of increased dosage of interferon (IFN) receptors (IFNRs) genes on chromosome 21 as a causative factor of cardiogenic dysregulation in DS. We differentiated human iPSCs derived from individuals with DS and CHDs, and healthy euploid controls into cardiac cells. We observed that T21 upregulates IFN signaling, downregulates the canonical WNT pathway, and impairs cardiac differentiation. Furthermore, genetic and pharmacological normalization of IFN signaling restored canonical WNT signaling and rescued defects in cardiogenesis in DS and . Our findings provide insights into mechanisms underlying abnormal cardiogenesis in DS, ultimately aiding the development of therapeutic strategies.
先天性心脏病（CHD）在唐氏综合征（DS）患儿中很常见，由21号染色体三体引起。然而，其潜在机制尚不清楚。在这里，我们使用基于人类诱导多能干细胞（iPSC）的模型和DS的Dp(16)1Yey/+（Dp16）小鼠模型，确定了21号染色体上干扰素（IFN）受体（IFNR）基因剂量增加下游的经典Wnt信号通路下调是DS中心脏发生失调的一个致病因素。我们将来自患有DS和CHD的个体以及健康整倍体对照的人类iPSC分化为心脏细胞。我们观察到T21上调IFN信号，下调经典WNT通路，并损害心脏分化。此外，IFN信号的基因和药理学正常化恢复了经典WNT信号，并挽救了DS中的心脏发生缺陷。我们的研究结果为DS中异常心脏发生的潜在机制提供了见解，最终有助于治疗策略的开发。
